1 - DOUGHERTY, T.J. Et Al. Photodynamic Therapy. J. Natl. Cancer Inst., Cary, V. 90, N. 12, P. 889 - 905, 1998.

REVIEW
Photodynamic Therapy
Thomas J. Dougherty, Charles J. Gomer, Barbara W. Henderson,
Giulio Jori, David Kessel, Mladen Korbelik, Johan Moan, Qian Peng*
porphyrin mixture that he termed ‘‘hematoporphyrin deriva-

Photodynamic therapy involves administration of a tumor-
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tive’’ (HPD), which was used by Lipson et al. (4) for tumor
localizing photosensitizing agent, which may require meta- detection. HPD contains several porphyrins, monomers as well
bolic synthesis (i.e., a prodrug), followed by activation of the as dimers and oligomers [reviewed in (5)]. HPD has been par-
agent by light of a specific wavelength. This therapy results tially purified, with the less-active porphyrins’ monomers re-
in a sequence of photochemical and photobiologic processes moved, to form Photofrin® (6), the most widely used photosen-
that cause irreversible photodamage to tumor tissues. Re- sitizer in clinical PDT. Because of the long-lasting skin
sults from preclinical and clinical studies conducted world- phototoxicity of Photofrin, several new photosensitizers have
wide over a 25-year period have established photodynamic recently been introduced in clinical trials (7,8). Photofrin ab-
therapy as a useful treatment approach for some cancers. sorbs light only up to about 640 nm; light at longer wavelengths
Since 1993, regulatory approval for photodynamic therapy penetrates farther into tissue, and most of the new sensitizers
involving use of a partially purified, commercially available have stronger absorbance at 650–850 nm.
hematoporphyrin derivative compound (Photofrint) in pa-
tients with early and advanced stage cancer of the lung, Localization of Photosensitizers
digestive tract, and genitourinary tract has been obtained in Why are the tissue/cellular sites of photosensitizer localiza-
Canada, The Netherlands, France, Germany, Japan, and the tion and photodamage important? To facilitate drug develop-
United States. We have attempted to conduct and present a ment, it is often necessary to identify a target. A systematic study
comprehensive review of this rapidly expanding field. of structure-activity relationships can then aid in improving the
Mechanisms of subcellular and tumor localization of photo- therapeutic procedure. As new sensitizers are prepared, studies
sensitizing agents, as well as of molecular, cellular, and tu- on localization, both at a tissue and a subcellular level, can be
mor responses associated with photodynamic therapy, are carried out. A recent summary of current information relating to
discussed. Technical issues regarding light dosimetry are localization sites has now been provided (9). Since the second-
also considered. [J Natl Cancer Inst 1998;90:889–905] generation sensitizers tend to be pure compounds, not mixtures,
loci of localization can often be identified. Mitochondria, lyso-
Background somes, plasma membrane, and nuclei of tumor cells have been
evaluated as potential PDT targets, along with the tumor vascu-
Photochemotherapy of cancer is often called ‘‘photodynamic lature. Vascular shutdown is clearly an important aspect of PDT
therapy (PDT).’’ The term ‘‘photodynamic action’’ (1) is used to (10), but since both vasculature and tumor are composed of
distinguish photosensitized reactions in biology from the phys- individual cells, the identification of an optimal subcellular tar-
icochemical processes occurring in the emulsions of photo- get remains relevant. At this point, clinical efficacy has been
graphic films. Blum (2) suggested that this definition should be described for only a small group of agents. While studies to date
applied only to photochemical reactions in which oxygen was suggest a hypothesis relating to localization and efficacy, it re-
consumed. Such reactions are also called photosensitized pro-
cesses of type I and type II depending on the nature of the
primary steps, namely, the initial involvement of radical inter- *Affiliations of authors: T. J. Dougherty, B. W. Henderson, Photodynamic
Therapy Center, Roswell Park Cancer Institute, Buffalo, NY; C. J. Gomer,
mediates that are subsequently scavenged by oxygen or the gen-
Clayton Ocular Oncology Center, Childrens Hospital, Los Angeles, CA, and
eration of the highly cytotoxic singlet oxygen (1O2) by energy University of Southern California, Los Angeles; G. Jori, Department of Biology,
transfer from the photoexcited sensitizer. 1O2 has a short lifetime University of Padova, Italy; D. Kessel, Department of Pharmacology, Wayne
in biologic systems (<0.04 microsecond) and, therefore, was also State University, School of Medicine, Detroit, MI; M. Korbelik, Cancer Imaging,
shown to have a short radius of action (<0.02 mm) (3). British Columbia Cancer Agency, Vancouver, BC, Canada; J. Moan (Depart-
ment of Biophysics), Q. Peng (Departments of Pathology and Biophysics), In-
The current era of PDT began with studies by R. L. Lipson
stitute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.
and S. Schwartz at the Mayo Clinic in 1960 who observed that Correspondence to: Qian Peng, Ph.D., Department of Biophysics, Institute for
injection of crude preparations of hematoporphyrin led to fluo- Cancer Research, The Norwegian Radium Hospital, Montebello, 0310 Oslo,
rescence of neoplastic lesions visualized during surgery. To gain Norway. E-mail: [email protected]
an optimal tumor localizing preparation, Schwartz treated he- See ‘‘Notes’’ following ‘‘References.’’
matoporphyrin with acetic acid and sulfuric acid and obtained a © Oxford University Press
Journal of the National Cancer Institute, Vol. 90, No. 12, June 17, 1998 REVIEW 889
mains to be seen whether a single target will prove advantageous as swelling (22), bleb formation (22,23), shedding of vesicles
in all instances. containing plasma membrane marker enzymes, cytosolic and
Since most photosensitizing agents are fluorescent, drug lo- lysosomal enzymes (23), reduction of active transport (24), de-
calization can be determined by fluorescence microscopy (9). A polarization of the plasma membrane (25), increased uptake of a
sensitive system is needed, since photobleaching can affect im- photosensitizer (26), increased permeability to chromate (24)
age acquisition and use of high fluences can cause photodamage and even to cytosolic enzymes like lactate dehydrogenase (27),
and dye relocalization. The fluorescence yield can vary with the inhibition of the activities of plasma membrane enzymes such as
binding site, so that sites of photodamage may not be accurately Na+K+-adenosine triphosphatase (ATPase) and Mg2+-ATPase
indicated by fluorescence. Since the cytotoxic product, 1O2, can (28), a rise in Ca2+ (29), up- and down-regulation of surface
migrate less than 0.02 mm after its formation (3), sites of pho- antigens (30), lipid peroxidation (31) that may lead to protein
todamage will reflect the localization of sensitizer at the time of crosslinking (32), and damage to multidrug transporters (17).
irradiation, and many workers have thus chosen to examine sub-
cellular sites of PDT-induced alterations rather than to search for Apoptosis In Vitro
sites of sensitizer binding.

In spite of the heterogeneity of Photofrin, a series of reports The discovery that PDT can lead to an apoptotic response in
(11,12) indicated that the mitochondria were among the targets malignant cells has provided a rationale for the widespread ef-
of photodamage. Consistent with these observations, a cell sub- ficacy observed. While apoptosis was first described in 1972
line selected for PDT resistance showed marked mitochondrial (33), it was not until 1991 that Agarwal et al. (34) reported an
alterations (13). In one of the first systematic studies, Henderson apoptotic response to PDT. Reports that PDT could rapidly in-
et al. (14) examined structure-activity relationships in a duce apoptosis, both in vitro (34,35) and in vivo (36,37), have
pheophorbide series. While hydrophobicity was an important provided an insight into the nature of photokilling. Apoptosis is
factor, a related study (15) showed that a more important factor a mechanism whereby organisms initiate cellular death via a
was the affinity of these agents for a plasma binding site that also process that is normally part of the genetic apparatus (38,39).
binds benzodiazepines. Since there is a corresponding mitochon- The end result is fragmentation of nuclear DNA and dissociation
drial binding site, this report is consistent with the concept of of the cell into membrane-bound particles that are engulfed by
mitochondrial target being optimal for effective PDT. adjoining cells, minimizing release of inflammatory products,
e.g., lysosomal enzymes. Malignant cell types often exhibit an
Damage to Subcellular Targets impaired ability to undergo apoptosis, an effect associated with
the ability to survive chemotherapy (38,40). Since a broad spec-
Because of the limited migration of 1O2 from the site of its trum of clinical PDT responses is observed (10), PDT is effec-
formation (3), sites of initial cell and tissue damage of PDT are tive against otherwise drug-resistant cell types. Although an
closely related to the localization of the sensitizer (9). The most apoptotic response to PDT is not always observed (35,41), this
highly selective sensitizers currently known are the lysyl chlorin might be related to differences in intracellular site(s) of pho-
p6 for lysosomes (16), the monocationic porphyrin for mem- todamage or use of suboptimal detection systems.
branes (17), and the porphycene monomer for mitochondria The time required for initiation of apoptosis varies widely.
(18). Sensitizers that are not taken up by cells, e.g., uroporphy- Most cells, in response to inducing agents, go through a latency
rin, are extremely inefficient even though some of them give a period, variable in duration, which usually results in the death of
high photochemical yield of 1O2. Moreover, since most PDT greater than 80% of a cell population in 1–3 days. A novel
sensitizers do not accumulate in cell nuclei, PDT has generally feature of apoptosis after PDT is the rapidity of execution, as
a low potential of causing DNA damage, mutations, and carci- judged by the appearance of DNA ladders as early as 30 minutes
nogenesis (5). Sensitizers that localize in mitochondria, like after photodamage. It appears that neither DNA, RNA, nor pro-
Photofrin, or are produced in mitochondria, like 5- tein synthesis is needed over such a short time frame. Although
aminolevulinic acid (ALA)-induced protoporphyrin IX, are there are unique aspects to PDT, other examples of apoptotic
likely to induce apoptosis, while sensitizers localized in the responses to oxidative stress have been reported (39,42).
plasma membrane are likely to cause necrosis during light ex- Signal transduction pathways are generally involved in the
posure (see below). Aggregated as well as hydrophilic sensitiz- initiation of an apoptotic program (43–45). Xue and Oleinick’s
ers are likely to be taken up by pinocytosis and/or endocytosis group (46) reported that among the early effects of PDT was
and therefore become localized in lysosomes or endosomes. enhanced phosphorylation of tyrosine residues. It was suggested
Light exposure will then permeabilize the lysosomes so that that the latter may serve to protect cells from the effects of
sensitizers and hydrolytic enzymes are released into the cytosol. photodamage and may therefore not be involved in the apoptotic
Dyes that are present in the cytosol can sensitize tubulin to process. A recent report (47) confirms this proposal: protein
photodamage (19). This leads to accumulation of cells in mito- tyrosine phosphorylation was inhibited by the drug staurosporin,
sis, in some cases followed by cell death (20). The probability of although this agent promotes PDT-induced apoptosis (48).
cell inactivation per quantum of absorbed light is widely differ- The mechanism of apoptosis after PDT has perhaps been
ent among PDT sensitizers (20). Generally, this probability is explained by recent reports that indicate an association between
lower for hydrophilic than for lipophilic sensitizers, indicating mitochondrial photodamage and apoptotic responses, while con-
that membrane structures are notably vulnerable (21). current membrane photodamage can delay the apoptosis
PDT damage to the plasma membrane can be observed within (18,49,50). It is known that release of cytochrome c and other
minutes after light exposure. This type of damage is manifested mitochondrial factors into the cytoplasm can trigger an apoptotic
890 REVIEW Journal of the National Cancer Institute, Vol. 90, No. 12, June 17, 1998
response (51,52), effects that can also be produced by enhanced ecules should expand our understanding of mechanisms of PDT
mitochondrial permeability (53–56). Mitochondrial permeability cytotoxicity.
is known to be involved in a pore transition that can be triggered Biochemical and morphologic studies (7) have identified a
by protoporphyrin (in the dark) (54), and it is interesting to note variety of PDT cellular targets, and molecular studies (58) have
that some other photosensitizing agents have a similar effect further advanced our knowledge of sublethal responses to PDT
(57). by identifying an expanding number of genes activated by PDT-
Marchetti et al. (53) pointed out that the protoporphyrin is a induced oxidative stress. Multiple genes encoding for stress-
ligand for the mitochondrial peripheral benzodiazepine receptor, induced proteins can be activated following PDT. Porphyrin-
a site known for its ability to trigger the pore transition. Tsuchida mediated PDT enhances the transcription and translation of
et al. (15) found a relationship between PDT efficacy and bind- heme oxygenase (61). Likewise, PDT induces increased expres-
ing to an albumin site that mimics specificity of the benzodiaz- sion of glucose-regulated proteins and the translation of these
epine receptor, suggesting that the more effective sensitizers proteins appears to play a role in modulating the cytotoxic ef-
bind to the mitochondrial benzodiazepine receptor. This may fects of oxidative stress (62,63). Heat shock proteins are also
represent the binding site for mitochondrial photosensitizers. It overexpressed following PDT when examined at either the in

is tempting to speculate that irradiation of sensitizers bound to vitro or in vivo level (64,65). Interestingly, PDT-induced expres-
the benzodiazepine receptor can initiate an opening of the mi- sion of heat shock proteins appears to be dependent on the
tochondrial pore, followed by release of apoptosis-initiating fac- specific subcellular targets associated with each photosensitizer.
tors. Such a mechanism could account for the previously re- The observation of strong transcriptional activation of heat
ported structure-activity correlations (15). shock proteins following PDT has been instrumental in initiating
Information summarized above is consistent with the pro- new studies in which PDT oxidative stress is used for the tem-
posal that PDT can directly initiate an apoptotic response, with- poral and spatial activation of heterologous genes ligated to the
out the need for intermediate signal transduction pathways that
heat shock protein promoter (58).
may be missing in certain drug-resistant neoplastic cells. The
Procedures designed to alter the expression of selected genes
prompt apoptotic cell death after PDT is not expected to depend
are also proving useful in understanding the molecular mecha-
on the state of the cell cycle or the status of genetic factors, e.g.,
nisms of PDT cytotoxicity. Hamster fibroblasts transfected with
p53, that can otherwise affect drug responsiveness. These con-
a human Bcl-2 protooncogene expression vector exhibited a de-
siderations are consistent with experimental findings indicating
creased incidence of PDT-induced apoptosis and decreased cy-
a very broad spectrum of responses to PDT in the clinic.
totoxicity when compared with parental cells (66). Photosensi-
Effects of PDT as Revealed by Techniques of tivity has also been compared with HL-60 human promyelocytic
leukemia cells genetically engineered to constitutively express
Molecular Biology either wild-type p53 or mutated p53 versus parental p53 null
Positive clinical results involving PDT have led to an ex- cells. HL-60 cells expressing wild-type p53 were more sensitive
panded desire to identify cellular and molecular responses asso- to porphyrin- and purpurin-mediated photosensitization when
ciated with this treatment (58). Biochemical studies (7) per- compared directly with HL-60 cells with deleted or mutated p53
formed over the past 15 years have provided a plethora of (67). Moreover, porphyrin PDT photosensitivity results have
information on subcellular targets involving PDT-mediated cy- recently been observed in human colon carcinoma cells exhib-
totoxicity. Molecular biology procedures are playing an integral iting either a wild-type or mutated p53 phenotype (68). A dif-
role in current research designed to examine the relevance of ferent molecular approach was used to examine mechanisms
cell-signaling events induced by PDT-mediated oxidative stress. involved in PDT sensitivity. Cell lines with a stable PDT-
The downstream effector molecules of signal transduction path- resistant phenotype were isolated and evaluated using messenger
ways are often proteins encoded for by early response genes. RNA (mRNA) differential display methodology to identify
These proteins function as transcription factors and act by regu- unique transcripts (69). A transcript encoding for alpha-2 mac-
lating the expression of a variety of genes via specific regulatory roglobulin receptor/low density lipoprotein receptor-related pro-
domains. tein was consistently found expressed in parental cells but absent
PDT-mediated oxidative stress induces a transient increase in in the PDT-resistant clones.
the downstream early response genes c-fos, c-jun, c-myc, and The in vivo tumoricidal reaction after PDT is accompanied by
egr-1 (59). Assays of kinase activity have provided clues regard- a complex immune response. A variety of molecular protocols,
ing the upstream molecules expressed and/or activated in cells including reverse transcription–polymerase chain reaction, have
following PDT (46,60). PDT, using a benzoporphyrin, induces a provided an opportunity for examining the underlying mecha-
strong dose and time-dependent activation of stress-activated nisms responsible for these host effects. It has recently been
protein kinase and a high osmolarity glycerol (HOG-1) protein demonstrated that PDT can modulate the expression of interleu-
kinase in keratinocytes (60). Activation of these messenger pro- kin 6 (IL-6) and IL-10 in tumor and normal tissues in vivo (70).
teins is implicated in the transcription of early response genes as These results agree with an earlier study reporting that the tran-
well as the induction of cellular responses such as apoptosis. scription factor AP-1 is involved in the in vitro expression of
Tyrosine phosphorylation of a non-receptor-type protein (HSl) IL-6 following PDT (71). Gel mobility shift assays have also
has also been observed in PDT-treated mouse lymphoma cells demonstrated that PDT can activate the transcription factor,
and concomitantly shown to correlate with protection of cells nuclear factor kappa B, which is also involved in regulating the
from PDT lethality (46). Future studies involving these mol- expression of numerous immunologically important genes (72).
It will be interesting to see how the molecular modulation of ment of the vascular system promoting tumor ischemia and hyp-
cytokines affects in vivo PDT tumoricidal action. oxia, whereas low-density protein-delivered photosensitizers in-
duce an early important damage of malignant cells through both
Mechanisms of Selective Tumor Uptake and random necrotic and apoptotic processes (36). However, several
Localization of Photosensitizers excellent tumor localizers (e.g., meso-tetraphenylporphin tetra-
sulfonate, aluminum phthalocyanine tetrasulfonate, etc.) do not
The mechanisms involved in the preferential distribution of bind to low-density protein while some poor tumor localizers,
sensitizers in tumors are not fully understood. Properties of tu- like hematoporphyrin, bind to low-density protein (88). Thus,
mor tissue may contribute such selective distribution. These in- the significance of low-density protein-binding for selective tu-
clude elevated numbers of low-density protein receptors, the mor uptake has been debated (89,90).
presence of macrophages, and a decreased pH value. The ab- Both microspheres and monoclonal antibodies directed
normal structure of tumor stroma characterized by a large inter- against antigens located at the surface of neoplastic cells have
stitial space, a leaky vasculature, compromised lymphatic drain- been used as carriers of tumor-photosensitizing agents (91,92).
age, a high amount of newly synthesized collagen (that binds The covalent photosensitizer-antibody complexes give excellent

porphyrins) (73–75), and a high amount of lipid (that has a high results with regard to the extent and selectivity of accumulation
affinity for lipophilic dyes) (76) also favors a preferential dis- by cell cultures, however, the efficiency of tumor targeting in
tribution of sensitizers. vivo appears to undergo serious limitations. At present, this ap-
The use of delivery vehicles for formulation of porphyrin- proach can be most usefully adopted for photodiagnostic pur-
type photosensitizers was prompted by the observation (77,78) poses taking advantage of the fluorescence emission properties
that the affinity of such photosensitizers for neoplastic tissues typical of several porphyrin derivatives.
increases upon increasing their degree of hydrophobicity. The It has been shown that tumor-associated macrophages in ani-
selective biodistribution of these sensitizers is enhanced by their mal tumors take up large amounts of HPD (93) and Photofrin
incorporation into amphiphilic systems, e.g., phospholipid (94,95). Thus, tumor-associated macrophages play a role for the
vesicles or oil emulsions, which are stable in an aqueous milieu tumor-selective uptake of aggregated sensitizers.
yet possess apolar compartments where hydrophobic substrates The interstitial fluid is the fluid surrounding the cells and
are embedded (79). This theory was reinforced by early reports localized between their plasma membranes and the vascular
(80) that liposome-associated photosensitizers exhibited greater walls. The pH value of interstitial fluid is lower and the content
efficiency and selectivity of tumor targeting as compared with of lactic acid is higher in tumors than in most normal tissues
the same photosensitizers administered in a homogeneous aque- (96–102). The intracellular pH, however, is identical or slightly
ous solution (81). Some second-generation photosensitizers, higher in tumors than in normal tissue (102,103). The acidic pH
e.g., Sn-etiopurpurin, benzoporphyrin derivative, and Zn- in tumors offers several therapeutic possibilities (101). The equi-
phthalocyanine, are formulated in lipid-based delivery systems. librium between different ionic species of porphyrins is complex
It is now apparent that the delivery vehicle can influence the (104,105), but generally the lipophilicity as well as the cell
serum distribution of a photosensitizer, hence the mechanism uptake increases with decreasing pH (105–107). Thus, the low
and kinetics of its transport to tissues, as well as subcellular tumor pH is probably one of the reasons for the selective uptake
biodistribution. Drug delivery via lipid-type carriers clearly en- of Photofrin by some tumors that takes place in tumor-bearing
hances the tendency of porphyrins to bind with lipoproteins animals (108,109).
where they are almost completely partitioned in the lipid moiety.
In general, the use of liposomal vesicles that are in a fluid state Mechanisms of Tumor Destruction
at the body temperature of 37 °C appears to orient the photosen-
sitizer toward low-density lipoprotein. This is exemplified by the The targets of PDT include tumor cells, the microvasculature
data obtained with dimiristoyl-phosphatidylcholine vesicles of the tumor bed as well as normal microvasculature, and the
(81). A marked low-density lipoprotein-orientating action is also inflammatory and immune host system. PDT effects on all these
shown by Cremophor EL emulsions (82). In any case, a certain targets may influence each other, producing a plethora of re-
degree of interlipoprotein exchange of the porphyrin occurs in sponses, the relative importance of each for the overall tumor
the serum, although the rate of such process is dependent on its response has yet to be fully defined. It seems clear, however, that
physicochemical properties of the porphyrin (83,84). the combination of all these components is required for long-
The association of the photosensitizer to lipoproteins, in par- term tumor control.
ticular to low-density lipoprotein, could result in selective or Exposure of tumors to PDT in vivo can reduce the number of
preferential release to neoplastic cells (85–87). Many types of clonogenic tumor cells through direct photodamage; this is in-
tumor cells express a high number of membrane receptors for sufficient for tumor cure. Studies (10,110–115) in rodent tumor
low-density protein, which promote the internalization of the systems employing curative procedures with several photosen-
low-density protein-bound photosensitizer by endocytotic path- sitizers showed direct photodynamic tumor cell kill to be less
ways (82). The endocytosed porphyrinoids largely localize in than 2 logs and in most cases less than 1 log, i.e., far short of the
membranous domains, including the plasma and mitochondrial 6–8-log reduction required for tumor cure. The in vitro irradia-
membrane, the Golgi apparatus, and the rough endoplasmic re- tion of tumor cells isolated from photosensitized tumors in vivo
ticulum (82). This distribution pattern has obvious implications predicts that total eradication is feasible with a sufficiently high
for the mechanisms by which PDT induces tumor damage: thus, light dose with some photosensitizers (10,110,116). But limi-
albumin-transported photosensitizers cause an extensive impair- tations appear to exist that do not allow the eradication to be
realized for in vivo PDT treatment. Inhomogenous photosensi- the vascular effects of PDT differ greatly with different photo-
tizer distribution within the tumor might be one of these limita- sensitizers. Photofrin–PDT leads to vessel constriction, macro-
tions. Korbelik and Krosl (117) have also shown that both pho- molecular vessel leakage, leukocyte adhesion and thrombus for-
tosensitizer accumulation and tumor cell kill decrease with the mation, all apparently linked to platelet activation and release of
distance of tumor cells from the vascular supply. thromboxane (133,134). PDT with certain phthalocyanine de-
Another parameter that can limit direct tumor cell kill is the rivatives causes primarily vascular leakage (135), and PDT with
availability of oxygen within the tissue undergoing PDT treat- mono-L-aspartyl chlorin e6 results in blood flow stasis primarily
ment. Two mechanisms can produce such limitations: the pho- because of platelet aggregation (136). All of these effects may
tochemical consumption of oxygen during the photodynamic include components related to damage of the vascular endothe-
process and the effects of PDT on the tissue microvasculature. lium. PDT may also lead to vessel constriction via inhibition of
Since 1O2 arises from ground state oxygen, it follows that this the production or release of nitric oxide by the endothelium
process can consume oxygen in the tissue environment. Rapid (137). In preclinical experiments, the microvascular PDT re-
and substantial reductions in tissue oxygen tensions on illumi- sponses can be partially or completely inhibited by the admin-
nation of photosensitized tissue were reported (115,118,119). istration of agents that affect eicosanoid generation, such as

Mathematical modeling supports these findings and demon- indomethacin (138), various other thromboxane inhibitors (133),
strates that the rate of oxygen consumption during Photofrin– and aspirin (139,140), and this inhibition can markedly diminish
PDT can be enough to move a fraction of the tumor into very the tumor response. On the other hand, administration of agents
low levels of oxygenation, outpacing the rate of oxygen diffu- inhibiting nitric oxide synthase or scavenging nitric oxide ap-
sion from the capillaries, and shrinking the radius of oxygenated pears to enhance tumor cure, apparently by enhancing the PDT-
tissue volume around them (120). The rates of 1O2 generation induced disruption of vascular perfusion (141).
and therefore tissue oxygen consumption/depletion are high Much of the above information was obtained from studies on
when both tissue photosensitizer levels and the fluence rate of normal microvasculature. Damage to the tumor-supplying nor-
light are high (115,119,121). mal vasculature may greatly affect tumor curability by PDT as
The fluence rate can be adjusted downward to slow oxygen demonstrated by the lack of tumor cures when the normal tissue
consumption sufficiently to facilitate the maintenance of (tumor) surrounding the tumor was shielded from PDT light (142). This
tissue pO2 levels during treatment. An important parameter in- is also supported by reports on the effects of fluence rate on
fluencing the rate of tissue oxygen consumption is photobleach- vascular responses. A low fluence rate treatment can lead to
ing of the sensitizer because the reduction of sensitizer levels shutdown of normal microvascular perfusion following PDT,
also reduces the rate of photochemical oxygen consumption while a high rate can protect microvascular patency (143). In
(122). Another approach toward maintenance of tissue oxygen- contrast, there were no differences in effects on either tumor
ation during PDT is the fractionation of light delivery (120,123). perfusion or oxygenation when treatment was delivered at low
This consists of very short (in the order of 20–50 seconds) light or high fluence rates (143). In all cases, these response param-
and dark intervals, allowing reoxygenation during the dark pe- eters were equally and greatly reduced in tumors following PDT
riods (119). Generally, treatment regimens using a low fluence exposure. A high fluence rate treatment inhibited tumor curabil-
rate or intermittent light, show superior effectiveness in delaying ity, implying that the protection of the tumor-surrounding nor-
tumor regrowth (115,120,123–126). mal vasculature by high fluence rate PDT adversely affected
Preliminary clinical studies at the Roswell Park Cancer In- long-term tumor control. It had been suggested earlier that PDT
stitute show oxygen depletion also occurring during PDT in effects on normal and tumor vessels may be qualitatively and
patients. The kinetics for this depletion varied from very rapid quantitatively similar (144). However, the above recent studies
(within seconds of light exposure) to slow (>10 minutes of light seem to reveal important differences between PDT effects on
exposure) and to no effect at all in basal cell carcinoma lesions normal and tumor vasculature.
in patients undergoing Photofrin (1 mg/kg)–PDT at a light dose Mathematical models have predicted and experimental mea-
rate of 150 mW/cm2. No oxygen depletion was observed in surements have demonstrated that dynamic, dose-rate-dependent
cutaneous lymphoma lesions during ALA–PDT (20% topical changes in tissue oxygenation can occur during PDT light de-
ALA), possibly because the effects were too superficial to be livery. Large interlesion and interpatient variations make pre-
detected by the interstitial oxygen probe used. dictions of these effects impossible. The need for further devel-
The oxygen supply in the tissue can also be diminished by the opment of instrumentation allowing real-time monitoring of the
damaging effects of PDT on the microvasculature. With high parameters that influence these changes (and thus PDT dose),
doses of certain photosensitizers, e.g., Photofrin, these effects i.e., photosensitizer tissue concentration, photobleaching rates,
can be sufficient to limit the oxygen supply to the tumor during blood flow, pO2 etc., is as great as ever. Further insight into the
PDT (127). With lower photosensitizer doses and certain sec- mechanisms of vascular damage by PDT might uncover ways by
ond-generation sensitizers, many of which exert diminished ef- which the differences between tumor and normal vasculature might
fects on the vasculature, this mechanism becomes less impor- be exploited to enhance treatment effectiveness and selectivity.
tant.
Vascular damage, occurring after completion of the PDT tu- Immunologic Effects of PDT
mor treatment, contributes to long-term tumor control. Micro- PDT-Induced Tumor Inflammation
vascular collapse can be readily observed following PDT
(112,127–130) and can lead to severe and persistent post-PDT The curative properties of PDT arise from the death of cancer
tumor hypoxia/anoxia (131,132). The mechanisms underlying cells spared from the direct cytotoxic effect by a combination of
oxidative stress-initiated secondary tumoricidal activities Antitumor Activity of Nonlymphoid Inflammatory Cells
(145). Contrary to the contemporary prevailing conception,
these secondary effects are by no means limited to the ischemic The inflammatory signaling after PDT initiates and supports
death caused by the occlusion of tumor vasculature. Other events the recruitment of leukocytes from the blood and amplifies their
that are increasingly coming into focus are as follows: 1) activity. A massive regulated invasion of neutrophils, mast cells,
and monocytes/macrophages during and after photodynamic
antitumor activity of inflammatory cells and 2) tumor-sensi-
light treatment has been documented in studies using rodent
tized immune reaction. They all can be elicited by phototoxic
tumor models (70,155). These newly arrived nonspecific im-
damage that is not necessarily lethal and bears an inflammatory
mune effector cells will outnumber resident cancer cells. Most
impact.
notable is a rapid accumulation of large numbers of neutrophils.
Photodynamically induced changes in the plasma membrane
There is increasing evidence that these cells have a profound
and membranes of cellular organelles, which represent the most
impact on PDT-mediated destruction of cancerous tissue. Neu-
abundant damage with a majority of photosensitizers used for
trophils can remain within tumor blood vessels and be a key
PDT, can trigger events with far-reaching consequences. One
contributor to the infliction of endothelial damage or engage in
process initiated at the membrane level involves signal trans- the destruction of tumor parenchyma on extravasation. Degranu-

duction pathways. These include enhanced expression of stress lation of errant neutrophils liberates toxic oxygen radicals, my-
proteins and early response genes (58), activation of genes regu- eloperoxidase, and lysosomal enzymes acting as a potent system
lating the process of apoptotic cell death (45), and possibly the for the breakdown of proteins and causing considerable damage
up-regulation of some cytokine genes. Due to their role in cell to the affected tumor tissue (156). In turn, neutrophils also sus-
adhesion and antigen presentation, some of the PDT-induced tain lethal damage during these events, releasing chemotactic
stress proteins may participate in the development of inflamma- substances that will attract a new wave of invasion of immune
tory/immune responses manifested by this therapy (146). cells.
Another PDT-induced membrane alteration involves inflam- Depletion of neutrophils in tumor-bearing mice using the
matory cellular damage. Photooxidative lesions of membrane anti-GR1 monoclonal antibody, or blocking functions of the
lipids prompt a rapid activation of membranous phospholipases common chain of b integrins by anti-CD18 antibody, was found
(45) leading to accelerated phospholipid degradation with a mas- to decrease the PDT-mediated tumor cure rate (145,149). The
sive release of lipid fragments and metabolites of arachidonic response of rat tumors to PDT was improved by increasing the
acid (145,147). These products are powerful inflammatory me- number of circulating neutrophils in the hosts by treatment with
diators. Another source of such signals relates to the tumor vas- G-CSF; the opposite effect was achieved in rats treated with
culature. After even minor phototoxic lesions, the endothelial anti-rat neutrophil serum that reduced neutrophil levels in these
cells will contract and expose the basement membrane in the animals (157). PDT aroused a selective increase of neutrophils
vessel wall (148). This rapidly attracts the attachment of circu- in the peripheral blood of treated rats peaking around 8 hours
lating neutrophils and platelets, leading to a progressive impair- after light exposure (150). This was preceded by the elevation in
ment of vascular function accompanied with a massive release IL-1b serum levels and an increase in the number of circulating
of various inflammatory mediators. band neutrophils. Treatment with anti-G-CSF polyclonal anti-
A strong inflammatory reaction is a central event in the body impaired not only the increase in neutrophil numbers but
mechanism of PDT-mediated tumor destruction. Differences in also the response of tumors to PDT. In another study, tumor
the nature and intensity of the inflammatory reaction between localized treatment with GM-CSF was shown to enhance the
normal and cancerous tissues may contribute to the selectivity of PDT-mediated cures of mouse squamous cell carcinomas (158).
PDT-induced tissue damage (149). A major hallmark of the Another class of nonspecific immune effector cells whose
inflammatory process is the release of a wide variety of potent activation substantially contributes to the antitumor effects of
mediators, including vasoactive substances, components of the PDT is monocytes/macrophages. The tumoricidal activity of
complement and clotting cascades, acute phase proteins, pro- these cells was found to be potentiated by PDT in vivo and in
teinases, peroxidases, radicals, leukocyte chemoattractants, cy- vitro (155,159,160). Macrophages were reported to release
tokines, growth factors, and other immunoregulators (147,148). TNF-a following PDT treatment (152) and to preferentially rec-
Among cytokines, IL-6 mRNA and protein were found to be ognize PDT treated cancer cells as their targets (161). Adjuvant
strongly enhanced in PDT treated mouse tumors, as well as in treatment with a selective vitamin D3-binding protein macro-
exposed spleen and skin (70). There is also evidence for PDT phage activating factor (DBPMAF) was shown to potentiate the
induced or up-regulated IL-1b, IL-2, tumor necrosis factor-a cures of PDT-treated tumors (162).
(TNF-a) and granulocyte colony-stimulating factor (G-CSF) The Immune Reaction
(150–153). The observed inconsistencies in the detection of
these mediators in different PDT-treated tumors and difficulties There have been substantial advances in the understanding of
to detect other such substances are caused by the following: 1) the PDT-induced tumor-specific immune reaction. This effect
differences in the up-regulation control for the respective genes may not be relevant to the initial tumor ablation, but may be
in different tumors and 2) very short lifetime of these proteins decisive in attaining long-term tumor control. Tumor sensitized
due to extremely high levels of proteinase and RNase activity in lymphocytes can, under reduced tumor burden, eliminate small
tumor tissue after PDT. Some photosensitizers, shown to stimu- foci of viable cancer cells that have escaped other PDT mediated
late the hematopoiesis in treated mice (153,154), may induce antitumor effects.
cytokines or growth factors independently of light treatment. Cancer immunity elicited by PDT has the attributes of an
inflammation primed immune development process (145) and but not fully curative PDT response was observed with x rays
bears similarities to the immune reaction induced by tumor in- used to eradicate EMT6 tumors in future splenocyte donors.
flammation caused by bacterial vaccines or some cytokines These results demonstrate the generation of immune memory
(149). The initial critical step of tumor-specific immune devel- cells sensitized to PDT treated tumor and suggest that PDT may
opment is likely mediated by tumor-associated macrophages be particularly suitable for a combined application with adoptive
and/or dendritic cells serving as antigen presenting cells (145). immunotherapy.
These cells are prompted to phagocytize large numbers of cancer Inflammation is frequently accompanied by immunosuppres-
cells killed or damaged by the antitumor effects of PDT. Di- sive effects, as is the case with PDT. The PDT-induced immu-
rected by powerful inflammation-associated signaling, the anti- nosuppression was detected primarily as a transient reduction in
gen presenting cells will process tumor-specific peptides and the delayed-type contact hypersensitivity response, which ap-
present them on their membranes in the context of major histo- pears to be mediated by antigen nonspecific suppressor cells
compatibility class II molecules. Presentation of tumor peptides, (166). The immunosuppression in mice bearing tumors exposed
accompanied by intense accessory signals, creates conditions for to PDT was greatly reduced by treatment with DBPMAF (162),
the recognition of tumor antigens by helper T lymphocytes. underlying the role of macrophages in this phenomenon. The

These lymphocytes become activated and in turn sensitize cy- severity of immunosuppression is much greater after the PDT
totoxic T cells to tumor specific epitopes. The generation of CD4 treatment of the exposed musculoperitoneal layer than after
and CD8 T cell clones that recognize tumor cells as their targets treatment of subcutaneous tumors (160,164). Mouse skin graft
is followed by their rapid expansion and activation leading to rejection in allogenic recipients is diminished after low-dose
fully developed tumor immunity. There are indications that B PDT of skin grafts, and the mechanism appears to involve im-
lymphocytes and natural killer cells also become activated and paired function of antigen presenting cells (167). The cytokine
may contribute to PDT-elicited immune responses, but the role IL-10, shown to be induced in PDT exposed skin of mice (but
of these cells remains to be fully elucidated. The activity of not in the tumor), appears to play a role in PDT elicited immu-
tumor sensitized lymphocytes is not limited to the original PDT- nosuppression (70). Blocking the induction of immunosuppres-
treated site but can include disseminated and metastatic lesions sion by agents like DBPMAF may augment the efficacy of PDT
of the same cancer. Thus, although the PDT treatment is local- in cancer treatment (162).
ized to the tumor site, its effect can have systemic attributes due Due to its inflammatory/immune character, PDT can be suc-
to the induction of an immune reaction. PDT generated tumor- cessfully combined with various immunotherapy protocols for
sensitized lymphocytes can be recovered from distant lymphoid achieving substantial gains in long-term tumor controls. A common
tissues (spleen, lymph nodes) at protracted times after light treat- strategy to such combination is to sustain and amplify the PDT-
ment (145). Therefore, these lymphocyte populations consist of induced immunity against the treated cancerous lesion. Its effec-
immune memory cells. In contrast to most other cancer thera- tiveness was demonstrated in a number of different rodent tumor
pies, PDT can induce immunity, even against less immunogenic models (including poorly immunogenic tumors) using a wide va-
tumors (145,163). riety of nonspecific or specific immunotherapy agents (145).
The demonstration that lymphoid populations are essential
for preventing the recurrence of PDT-treated tumors was pro- Current Status of Clinical PDT
vided by using a mouse sarcoma model growing in either im-
munocompetent or immunodeficient syngeneic hosts (164). Pho- Regulatory Status—Photofrin
tofrin-based PDT treatment that was fully curative for EMT6
The first health agency approval for PDT (with Photofrin)
tumors growing in immunocompetent BALB/c mice resulted in
was obtained in 1993 in Canada for the prophylactic treatment of
initial ablation but not permanent cures with EMT6 tumors
bladder cancer. Subsequently, approvals for Photofrin were ob-
growing in severe combined immune deficiency (scid) or nude
tained in The Netherlands and France for treatment of advanced
mice. If the bone marrow of scid mice was reconstituted with
esophageal and lung cancers; Germany for treatment of early
BALB/c bone marrow, the EMT6 tumors in these hosts (which
stage lung cancer; Japan for early stage lung, esophageal, gas-
acquired functionally active lymphocytes) were cured by PDT.
tric, and cervical cancers as well as cervical dysplasia; and in the
Similar results were recently reported for PDT based on a ben-
United States for advanced esophageal cancer. In 1998, QLT
zophenothiazine analogue as a photosensitizer using the same
PhotoTherapeutics (Vancouver, Canada) received U.S. Food and
experimental model as above (165). The induction of immunity
Drug Administration (FDA) approval for use of Photofrin for
against a weekly immunogenic murine fibrosarcoma MS-2 by
early stage lung cancer. Approvals are currently being sought in
aluminum phthalocyanine-based PDT was also described (163).
11 additional countries in Europe.
In this case, the mice that remained tumor free 100 days after
PDT were shown to resist a rechallenge with the same tumor. Approved Indications for Photofrin—PDT
In one series of studies, BALB/c mice, which had EMT6
tumors treated by a curative dose of Photofrin-based PDT 5 Advanced Stage Esophageal Tumors
weeks earlier, served as donors of spleen cells adoptively trans-
ferred to scid mice. This fully restored PDT-mediated curability The results of the phase III clinical trial completed in the
of EMT6 tumors growing in recipient scid mice (145). No cures United States that led to U.S. FDA approval in December 1995
were obtained with the host scid mice that received virgin have been published (168). This was a multicenter, randomized,
BALB/c splenocytes or splenocytes from BALB/c mice previ- comparative trial against thermal ablation using a Nd-YAG laser
ously cured by PDT from a different tumor (145). An improved, for treatment of partially obstructing esophageal cancer. The
results of this trial with 236 patients indicated similar relief of and U.S./Canada trials respectively. Improvement in dyspnea
dysphagia in both arms, a longer lasting tumor response for PDT and cough were superior for PDT over Nd-YAG in the European
(32% at 1 month versus 20% for Nd-YAG), and more complete group but similar in the U.S./Canada group.
responses (negative endoscopic biopsies) for PDT than for Nd- It was concluded that PDT is superior to Nd-YAG for relief
YAG (9 versus 2). of dyspnea, cough, and hemoptysis. Overall, adverse reactions
In certain subgroups, objective responses were higher for were similar for PDT and Nd-YAG (73% PDT, 64% Nd-YAG)
PDT than for Nd-YAG in the upper and lower third of the and 20% of patients in the PDT group experienced a photosen-
esophagus as well as for tumors larger than 10 cm, but the sitivity reaction due to lack of compliance with precautions.
number of patients in these groups was too small for statistical There was a prospective trial of PDT plus radiotherapy versus
significance. Fewer procedures were required for PDT (mean radiotherapy alone (171) with 41 randomized patients. The ob-
1.5) than for Nd-YAG (2.4). Overall, median survival was the structed airway in only 10% of patients was completely opened
same for both groups. There were more adverse reactions in the by radiation therapy alone, whereas 70% of patients achieved
PDT group (92%) than in the Nd-YAG group (82%) but the complete reopening when PDT was added to the radiation
withdrawal from the study because of adverse reaction was simi- therapy.

lar in the two arms. There were significantly more esophageal (b) Early stage lung cancer. PDT appears to be particularly
perforations in the Nd-YAG group (7%) than in the PDT arm applicable to treatment of early stage lung cancer, since it pre-
(1%). Sunburn reactions were confined to the PDT group (19%) serves lung function, can be repeated as additional tumors ap-
and were all mild in nature. Efficacy of the two therapies was pear (such patients are at high risk for developing new tumors),
equivalent; severe adverse reactions occurred at the same rate in and does not preclude ultimate surgical intervention if deemed
both treatments except for the more frequent occurrence of per- necessary. In patients with early stage lung tumors less than 2
foration in the Nd-YAG treatment. PDT was considered more cm, the incidence of lymph node metastasis was low to nonex-
comfortable for the patient, was easier to perform than Nd-YAG istent, indicating the appropriateness of conservative treatments
ablation, and was especially advantageous in situations where (172).
Nd-YAG is difficult to carry out due to morphology or tumor Edell and Cortese (173) have reported a group of 13 patients
location. with 14 early stage lung cancers. These patients received 200–
400 J/cm2 of 630 nm irradiation 2–4 days following injection of
Bladder Cancer 2.5 mg/kg HPD. Eleven tumors showed a complete response
after a single treatment and the remaining three after a second
Prophylactic treatment for papillary tumors. The trial re-
treatment; 77% of the tumors showed no recurrence after 7–49
sulting in approval for Photofrin-PDT in Canada in 1993 in-
months. No substantial complications were observed in the pa-
volved a prophylactic PDT treatment following transurethral re-
tients. Three patients had a mild sunburn reaction. The authors
section of papillary bladder tumors in patients at high risk for
conclude that PDT may be an alternative to surgery for patients
recurrence. While final results of this trial have not been pub-
with early squamous cell carcinoma.
lished, a preliminary report was given in 1991 (169). A 1-year
Furuse et al. (174) reported on 54 patients with 64 early stage
follow-up of 34 patients indicated recurrence in 81% of patients
lung cancers using Photofrin (2.0 mg/kg) and 630-nm illumi-
in the control group (no PDT following resection) and 39% in
nation of 100–200 J/cm2. Of 59 tumors assessable, 50 were
the PDT arm. Median time to recurrence was 91 and 394 days
considered a complete response, six were partial responders, and
for the control and PDT group, respectively. Photosensitivity
three had no response. Five of the complete responders had
occurred in one third of patients and urinary symptoms in 93%
recurrence at 6–18 months after treatment. A predictor of re-
of patients receiving PDT.
sponse was the length of the tumor with those less than or equal
Because of severe and long-lasting side effects, Nseyo et al.
to 1 cm obtaining a 97.8% complete response and only 42.9% of
(170) suggested multiple treatments at lower drug dose to reduce
tumors greater than 1 cm achieving this response. The overall
the incidence and severity of symptoms following PDT for su-
survival of patients was 50% after approximately 3 years.
perficial bladder cancer (see below).
Kato et al. (175) described a study involving use of Photo-
Lung Cancer frin–PDT on 95 lesions in 75 patients with early lung cancer
treated. The complete response rate was related to the tumor
(a) Advanced non-small-cell lung cancer. A prospective, size, with complete response rate of 96.8% for lesions less than
randomized trial of PDT versus Nd-YAG ablation for partially 0.5 cm, but only 37.5% for greater than 2 cm. The overall 5-year
obstructive lung cancer has been reported. This included data survival rate for all 75 patients predicted according to Kaplan–
from 15 centers in Europe (141 patients) and 20 centers in the Meier analysis was 68.4%.
United States and Canada (70 patients). In the European trial,
40% of patients had prior therapy while all patients in the U.S./ Pending Photofrin Trials for Regulatory Approval
Canada trial had prior therapy. Tumor response was similar
for both therapies at 1 week, but at 1 month, 61% and 42% of Early Stage Esophageal Cancer
PDT patients were still responding in the European and U.S./
Canada trial, respectively, whereas for the Nd-YAG, 36% and This disease often occurs in conjunction with Barrett’s
19% were responding in the two trials. There were 12% and 6% esophagus, a condition of replacement of the esophageal squa-
of PDT patients versus 3% and 5% of Nd-YAG patients who mous epithelium by stomach glandular epithelium as a result of
achieved a complete biopsy-proven response in the European acid reflux. Patients with Barrett’s esophagus are at risk for
development of esophageal cancer for which the usual procedure drug-resistant superficial bladder cancer, a group at high risk for
is an esophagectomy, a surgical procedure with high mortality muscle invasion often requiring radical cystectomy with its at-
and morbidity. tendant complications [reviewed in (178)]. Some investigators
The largest PDT study was carried out on 55 patients with have concluded that in most trials of bladder cancer, the PDT
superficial esophageal cancer (176). A 6-month follow-up after treatment is overly aggressive (2.0 mg/kg Photofrin, 15 J/cm2
PDT indicated 24 of 36 patients with initial high-grade dysplasia whole bladder) and results in long lasting and severe urinary
and Barrett’s esophagus had no dysplasia, and seven had no symptoms. Recently Nseyo et al. (170) have suggested that three
residual Barrett’s esophagus. Three of 36 patients with high- less aggressive treatments be given every 6 months based on
grade dysplasia showed no response to treatment and nine were their results (12 of 14 treated patients had complete responses)
converted to low-grade dysplasia. Eleven of 12 patients present- obtained in patients receiving 1.5 mg/kg Photofrin with 15 J/cm2
ing with low grade dysplasia had no dysplasia and six had no where bladder contracture has been avoided and symptoms have
residual Barrett’s esophagus after treatment, six of six patients been minimized and reduced to a period of approximately 2
with a T1 cancer had complete response and three had no re- weeks.
sidual Barrett’s esophagus. One patient with a T2 cancer also had

no remaining disease; one with low-grade dysplasia showed re- Adjuvant Therapy Procedures
curring low-grade dysplasia after 6 months. The technique in-
volves injection of 2.0 mg/kg Photofrin with light delivery 48 (a) Brain tumors. Both groups of Muller (179) and Kaye
hours later. In some patients, a balloon catheter was used 3, 5, or (180) have had long-standing programs to combine PDT with
7 cm in length in which the light delivery fiber with a diffuser of resection of brain tumors (mainly glioblastoma or astrocytoma).
appropriate length was centered. The balloon allows proper dis- These tumors are difficult to control by surgery alone, since
tention of the esophagus and assures uniform light delivery to some tumor cells exist beyond the operative bed; PDT after
the affected areas. Complications included stricture in 29 pa- resection may destroy these cells. In Muller’s study of 56 pa-
tients that required dilation to resolve, although the frequency of tients with recurrent tumors, all of whom had failed radiation
this complication appears to be less using larger balloons than therapy, the mean survival time for patients receiving PDT for
with the bare diffuser or shorter balloons. Photosensitivity was glioblastoma, malignant astrocytoma, and mixed astrocytoma–
of low frequency. For PDT versus surgery, mortality was 0% oligodendroglioma was 30, 44, and greater than 61 weeks, re-
and 6%–14%, respectively. Moreover, PDT is an outpatient pro- spectively. For patients undergoing surgery alone, survival was
cedure versus 1.5–3 weeks in hospital for surgery and a recovery only 20 weeks. The survival of patients with malignant astrocy-
time of 3 weeks for PDT versus 2–4 months for surgery. The toma was related to light dose, with those receiving a total of
estimated costs are approximately $20 000 for PDT versus greater than 1800 J (2.0 mg/kg Photofrin) surviving longer (64
$35 000–95 000 for surgery. weeks median, 50% 1-year survival) than patients who received
<1800 J (27 weeks survival, 33% 1-year survival).
Head and Neck Cancers In Kaye’s study (using HPD), there were 120 patients in total,
38 with primary glioblastoma, 40 with recurrent glioblastoma,
Biel (177) has reported excellent results in treatment of early 24 with anaplastic astrocytoma, and 11 with recurrent anaplastic
stage head and neck cancers. In this study, there were 29 patients astrocytoma. The median survival was 24 and 9 months after
with cancer of the larynx (22 superficial), 32 patients with can- treatment for primary glioblastoma and recurrent glioblastoma,
cer of the nasal cavity and pharynx, one of the nasal cavity, two respectively. Fifty percent of the patients with glioblastoma sur-
patients with Kaposi’s sarcoma of the palate, three patients with vived beyond 2 years. The median survival times have not been
cancer of the nasopharynx, and five with papilloma of the lar- reached for the other groups (follow-up to 8 years for anaplastic
ynx-trachea. Patients received 2.0 mg/kg Photofrin, 48 hours astrocytoma). Survival appears to be longer when PDT is used in
prior to 630 nm light delivery via a microlens fiber at 50–75 conjunction with surgery plus radiation therapy; a confirmatory
J/cm2. For tumors greater than 3 cm, diffuser fibers were im- prospective trial is underway in the United States and Canada.
planted and a dose of 100 J/cm fiber delivered interstitially. All (b) Head and neck cancers. In the study of Biel (177) a
22 patients with superficial cancer of the larynx achieved a group of 10 patients with large head and neck tumors recurrent
complete response, with follow-up to 67 months (mean, 30 after surgery, radiation therapy, and chemotherapy received in-
months), as did all patients with oral, intranasal, or nasopharyn- traoperative PDT to the tumor following resection. With follow-
geal cancer, who were followed up for a maximum of 61 months up to 50 months, three patients demonstrated recurrent disease,
(mean, 33 months). Five patients with recurrent laryngeal/ two of which were outside the PDT field. It was noted that PDT
tracheal papillomatosis exhibited an initial response to PDT at 1 did not appear to interfere with wound healing.
month, but had evidence of disease recurrence by 6 months after (c) Intrathoracic tumors. Tochner et al. (181) and Pass and
PDT. Two patients required oral steroids for 5 days because of Donington (182) at the National Institute of Health pioneered the
sunburn. Pain varied from mild to severe and was adequately use of PDT as adjunct to surgery for pleural cancers, especially
controlled with oral analgesics. malignant mesothelioma. Following resection of as much tumor
as possible, the entire involved thoracic cavity is exposed to 630
Superficial Bladder Cancer nm light delivered 2 days following injection of 2.0 mg/kg Pho-
tofrin using intralipid as a diffusing medium. As a follow-up to
Although not yet approved for general use, there are several these studies, Takita and Dougherty (183) have reported pre-
successful reports on use of PDT for treatment of recurrent or liminary results for applying PDT as adjuvant to resection of
malignant pleural mesothelioma. Forty-one patients underwent subcutaneous melanoma lesions undergoing complete response
pleurectomy or pleural pneumonectomy followed by PDT to the with minimal damage to overlying skin.
thoracic cavity (15–35 J/cm2) 2 days following 2.0 mg/kg Pho-
tofrin. The overall estimated median survival of all patients was Benzoporphyrin Derivative-Monoacid Ring A (BPD-MA)
12 months, although patients with stage I and II diseases had a BPD-MA has been in phase I/II trials for treatment of skin
median survival of 37 months. cancers (187) but perhaps the most interesting application is the
(d) Intraperitoneal tumors. Delaney et al. (184) have re- treatment of age-related macular degeneration, the commonest
ported a phase I trial of PDT following debulking surgery for cause of blindness in people over the age of 50 years. In one
intraperitoneal tumors. The majority of patients had ovarian can- form, it is characterized by leaky neovascularization near the
cer (22 of 54), peritoneal studding from sarcoma (13 of 54), or macula that impairs vision. Current treatment involves the use of
gastrointestinal carcinomatosis (eight of 54). Doses of Photofrin thermal lasers which can result in damage of the overlying retina
were increased from 1.5 to 2.5 mg/kg, and light doses ranged with further loss of sight. With PDT, BPD-MA is infused and
from 2.8–3.0 J/cm2 delivered 48–72 hours after injection. In shortly thereafter, when the drug is confined to the vessels as
some patients, a boost of 15 J/cm2 of red light or 5–7.5 J/cm2 of much as possible, the drug is activated at 690 nm through an

green light was used. The green light appeared to reduce small ophthalmoscope generally using a diode laser. This allows se-
bowel complications. Dose-limiting toxic effects (pleural effu- lective closure of the leaky vessels without damage to overlying
sions and gastric perforation) occurred in two of three patients at retinal tissue. In a preliminary report of 107 patients (188) given
the highest dose of 5.0 J/cm2 green light with boost. At a median a single treatment, 44% of the patients experienced improved
follow up of 22 months, 30 of 39 patients were alive and nine are vision although reappearance of leakage was frequently found
disease free. Similarly, Glatstein and Hahn at the University of after 4–12 weeks. With the use of multiple treatments, it appears
Pennsylvania have recently initiated a phase II trial of intraop- that this recurrence may be reduced (189). Phase II trials for
erative PDT for disseminated intraperitoneal cancers. health agency approvals have been completely in the United
New Photosensitizers in Clinical Trials States and Europe with more than 500 patients. Filing for ap-
proval in the United States is expected in 1999 (a 1-year follow-
Tin Etiopurpurin, SnET2 (Purlytin) up of patients is required).
SnET2, a chlorin photosensitizer developed by Miravant Inc. Tetra(m-hydroxyphenyl)chlorin, mTHPC (Foscan)

(formerly PDT Inc., Santa Barbara, CA) currently is in phase II
This chlorin photosensitizer (190) is undergoing clinical trials
trials aimed at the U.S. FDA approval for cutaneous metastatic
for head and neck cancer in Europe and the United States under
breast cancer and Kaposi’s sarcoma in patients with acquired
the sponsorship of Scotia Pharmaceutical (Great Britain). This
immunodeficiency syndrome. In a preliminary trial (185), which
material appears to be the most active of all photosensitizers
included basal cell carcinoma as well as metastatic breast cancer,
studied to date, requiring only very low drug doses (as little as
treated at 1.2 mg/kg SnET2 followed 24 hours later by 200 J/cm2
0.1 mg/kg) and light doses (as low as 10 J/cm2) for efficacy.
(660 nm, dye laser or 664 nm, diode laser), 95%–100% of basal
Grosjean et al. (191) reported 27 patients, most with one or more
cell carcinoma lesions had responded 12 weeks post-treatment.
early stage squamous cell carcinoma of the upper aerodigestive
All metastatic breast carcinoma lesions responded in which 96%
tract, three patients with T1 or T2 tumors, and one with Barrett’s
of the lesions had complete responses and 4% were partial re-
esophagus with superficial adenocarcinoma. Most patients re-
sponses. In the trial of Kaposi’s sarcoma, 60% of the lesions
ceived a bolus injection of 0.3 mg/kg and 652 nm irradiation at
were complete responses and 40% were partial responses. The
8–12 J/cm2 generally 4 days after injection. All patients with
number of patients in each of these optimized trials was not
bronchial and esophageal tumors were treated under general
reported; 10%–15% of patients experienced photosensitivity re-
anesthesia. Treatment of patients with 36 early tumors resulted
actions at one or more months after treatment and one patient
in no recurrences after a follow-up of 3–35 months. Disease in
experienced a mild hypersensitivity to the vehicle (a lipid emul-
only one of the four patients with advanced tumors was con-
sion).
trolled. Major complications included bronchial stenosis (one
patient), esophagotracheal fistula (one patient), and occult per-
Lutetium Texaphyrin (Lu-tex)
foration of the esophagus (two patients). The authors suggested
A phase II/III trial using Lu-tex is about to begin for treat- that the use of green light will reduce the complications without
ment of certain skin lesions. A preliminary report (186) has sacrificing efficacy. Twelve patients experienced phototoxic re-
described some results from phase I trials involving various skin actions within the first week after drug administration.
lesions (15 breast metastases, seven malignant melanomas, five This sensitizer currently is undergoing early clinical trials for
Kaposi’s sarcomas, and two invasive basal cell and two squa- head and neck cancers in the United States and Europe based on
mous cell carcinomas). Drug doses ranged from 0.6 to 7.2 mg/kg results involving a trial of six primary cases and seven patients
infused 3 hours prior to light treatment at 732 nm and 150 J/cm2 treated with palliative intent. All showed excellent responses
from a dye laser or LED source. Of the 163 evaluated lesions at with follow-up ranging to 28 months (192).
all doses, 48 (29%) were complete responses and 28 (17%) were N-Aspartyl Chlorin e6 (NPe6)
partial responses. Severe pain was reported at the higher dose
range (7.2 mg/kg). Unlike most other photosensitizers, Lu-tex NPe6 is undergoing clinical trials in Japan under the spon-
appears to be highly selective for tumors versus normal skin with sorship of Nippon Petrochemicals for treatment of endobron-
chial lung cancer. Results of this trial are not available at this rates of complete response of actinic keratosis (52 lesions), su-
time. Previous reports using NPe6 in skin cancers have shown it perficial basal cell carcinomas (217 lesions) and nodular basal
to be an effective photosensitizer with little or no long term cell carcinomas (237 lesions) were 89%, 86%, and 84%, respec-
cutaneous photosensitivity (193). tively (Warloe T: unpublished data). The high complete re-
sponse rates may be related to a high production of P-1202-
ALA-Based PDT and Diagnosis induced protoporphyrin IX in the lesions. Furthermore, P-1202
produces much less protoporphyrin IX in normal skin than in
ALA-induced endogenous photosensitization is a novel ap- lesions, so that it leads to a high selectivity using this compound
proach to both PDT and tumor detection that utilizes the heme (Peng Q: unpublished data). Generally, PDT with topical appli-
biosynthetic pathway to produce endogenous porphyrins, par- cation of ALA or its methylester has several potential advan-
ticularly protoporphyrin IX, an effective photosensitizer (194– tages over conventional treatments. It is noninvasive, convenient
196). Heme is synthesized from glycine and succinyl CoA. The and well tolerated by patients; can be applied repeatedly; and
rate-limiting step in the pathway is the conversion of glycine and produces excellent cosmetic results regardless of lesion size.
succinyl CoA to ALA, which is under negative feedback control It is not yet fully understood whether there are side effects

by heme (197). Excess exogenous ALA, however, can bypass associated with systemic ALA administration. It appears that
this control point and produce porphyrins that, when photoacti- oral administration of ALA (<60 mg/kg) or intravenous infusion
vated, generate the photosensitizing effect for PDT and porphy- (<30 mg/kg) does not lead to any neurotoxic symptoms, al-
rin fluorescence for photodiagnosis (194–199). though some patients may have mild, transient nausea and/or
There is a great variation of ALA-induced porphyrins in nor- temporary abnormalities of liver functions (198,200). Treatment
mal tissues. Such tissue selectivity may be due to various ca- of patients with oral cavity squamous cell carcinomas was re-
pacities of heme production or to different feedback control ported; there were few complete remissions, but the treated areas
mechanisms. Rapidly proliferating cells may produce more of all other 12 patients with dysplasia lesions were healed with-
ALA-derived porphyrins, probably owing to a low activity or/ out scarring. No patients had cutaneous photosensitivity after 48
and a limited capacity of ferrochelatase (195–200). This differ- hours (201). Barr et al. (202) obtained promising results in the
ential provides a biologic rationale for clinical use of ALA- treatment of five patients with high-grade esophageal dysplasia
based PDT. In 1990 Kennedy et al. (195) first successfully in Barrett’s esophagus. These results suggest that systemically
treated skin disorders with topically ALA–PDT. Since then, this ALA–PDT may have potential for the treatment of superficial
new approach has arisen a great interest and is now being studied mucosal precancerous and cancerous lesions of the aerodigestive
intensively for its potential use for the treatment and/or detection tract without the risk of prolonged skin phototoxicity (203).
of a large variety of superficial lesions (198,199). A preferential accumulation of ALA-induced porphyrins in
In a total of 826 superficial skin basal cell carcinomas treated neoplastic cells provides the possibility of photodetection of the
with topically ALA–PDT in nine hospitals in Europe and porphyrin fluorescence in tumor cells. Such a procedure can be
Canada the weighted average rates of complete response, partial performed by means of fiberoptic point monitoring systems or of
response, and no response were 87%, 5%, and 8% respectively fluorescence imaging systems after topical, local internal or sys-
(199). In addition, promising clinical results have been obtained temic administrations of ALA or its esters. By using the fluo-
for a variety of skin superficial malignant and nonmalignant rescence cystoscopy Kriegmair et al. (204) have observed a
lesions such as squamous cell carcinoma, Bowen’s disease, my- sharply marked red fluorescence induced by ALA in the urothe-
cosis fungoides, psoriasis, etc. (198,199). For example, DUSA lial carcinoma after intravesical instillation of 3% ALA solution.
Pharmaceuticals Inc. (Toronto, Canada) recently reported the In a group of 104 patients with bladder carcinoma examined, the
results of two parallel phase III clinical trials using Levulan detection sensitivity of the ALA-based porphyrin fluorescence
(ALA) for PDT of patients with actinic keratoses (a superficial cystoscopy was 96.9%, substantially higher than that (72.7%) of
benign lesion that can go on to squamous cell carcinoma) of the conventional white light cystoscopy (205). ALA-induced por-
face and scalp. Two hundred forty patients, in total, received phyrin fluorescence may also be used for photodetection of
topically either 20% ALA or a placebo for overnight followed by early-stage lung carcinoma and malignant glioma (199).
irradiation with blue light at 10 J/cm2. In the two trials, 86% and
81% of the treated lesions cleared after a single treatment, with Light
94% and 91% clearing after a second treatment, respectively.
This compared with 32% and 20% clearance with the placebo, Typically, fluences of 50–500 J/cm2 of red light are needed in
respectively. Each trial was statistically significant (P<.001). clinical PDT with Photofrin (206). New sensitizers, e.g.,
The current protocols of the topical modality are, however, mTHPC, are usually more efficient, mainly due to larger ex-
far from ideal for the treatment of nodular skin lesions. In a total tinction coefficients in the red. Consequently, smaller fluences
of 208 nodular basal cell carcinomas treated in six hospitals the are required, typically 10 J/cm2 (207). If the surface irradiance
average rates of complete response, partial response, and no exceeds 200 mW/cm2, hyperthermia may contribute to the
response were 53%, 35%, and 12%, respectively (199). PDT PDT effect (208–212). For interstitial treatment with diffusing
with topical application of P-1202 (ALA methylester), a product fibers inserted into the tumor, the hyperthermia limit is below
currently developed by PhotoCure AS (Oslo, Norway), has in 400 mW/cm diffusing fiber (212). Hyperthermia and PDT
recent clinical studies shown promising results for the treatment may act synergistically when hyperthermia is given after PDT
of skin lesions, particularly for the thick lesions (with prior (213,214). Applying a nonhyperthermic surface irradiance
simple debulking procedure). Among 506 lesions treated the of 100 mW/cm2 for 30 minutes, which is about a maxi-
mum for practical applications, requires 0.27–2.7 W to provide tizer. Since relatively expensive light sources are required, it is
50–500 J/cm2 to a tumor area of 10 cm2. A metal halide lamp of hoped that the advent of diode lasers, not only for the new
250 W filtered carefully to eliminate heat can provide up to 5 W photosensitizers, but now also for Photofrin, will mitigate the
of a 40-nm red light by use of an elliptic reflector and an all- problem. It should be emphasized that substantial aid in protocol
dielectric bandpass filter (215). Such a lamp can be coupled to a development is being provided by both the pharmaceutical com-
0.5-cm diameter light guide out of the distal end of which one panies involved in drug development as well as the device de-
can get up to 450-mW red light (5). A 300-W short arc plasma signers. Thus, development of new drugs with limited skin pho-
discharge (216), or a xenon arc lamp of similar power, is ex- tosensitization, along with improved light sources, should aid in
pected to give a similar fluence rate of red light to the metal convincing physicians that there is a compelling reason for them
halide lamp. This would hardly be enough for bladder PDT nor to learn and use what to most of them is still an unknown entity.
for treatment of a few cm of the oesophagus. Diode lasers giving This will only come with time as those who are considered to be
a few watts of red light down to 630 nm (217) are now com- objective in their assessments indicate its utility to others.
mercially available and are probably the light sources of choice
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porphyrin mixture that he termed ‘‘hematoporphyrin deriva-

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SnET2, a chlorin photosensitizer developed by Miravant Inc. Tetra(m-hydroxyphenyl)chlorin, mTHPC (Foscan)

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