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(The FASEB Journal. 2001;15:612-617.)
© 2001 FASEB

Reactive oxygen-dependent production of novel photochemotherapeutic agents

SHAZIB PERVAIZ1

Department of Physiology, National University of Singapore, Singapore 117597

1Correspondence: Department of Physiology, National University of Singapore, 2 Medical Dr., Singapore 117597. E-mail: phssp{at}nus.edu.sg


   ABSTRACT
TOP
 ABSTRACT
BACKGROUND
 THE PHOTODYNAMIC REACTION
 THE CONCEPT OF PREACTIVATION...
 THE ISSUE OF TARGET...
 CONCLUDING REMARKS
 REFERENCES
 
The reactive nature of species derived from oxygen, such as singlet oxygen and hydrogen peroxide, has been exploited in the clinical setting for targeting bacteria, viruses, and tumor cells by photodynamic excitation of a variety of chromophores. This modality, termed photodynamic therapy (PDT), is currently being used to treat some forms of cancer. However, the applicability of conventional PDT is limited due to the absolute dependence on simultaneous exposure of the target to the photoactive compound and light. In 1990, we demonstrated that the need for simultaneous exposure of the biological target to light and photosensitizer could be circumvented by prior exposure (activation) of the sensitizer molecule to light and its subsequent use as any other anti-cancer or anti-viral drug. By dint of the nature of the protocol, this process was termed preactivation. Since then, the generation of biologically active molecules in vitro by preactivation has been validated using a variety of chromophores, such as merocyanine 540, Photofrin II, and naphthalimide. Here we briefly review the role of reactive oxygen species in the photodynamic effect, and provide an explanation for the mechanism of preactivation. We propose that photo-oxidation not only provides a novel means for the generation of biologically active molecules, but could also explain, at least in part the mechanism of conventional PDT. It is likely that the light-dependent breakdown of the chromophore to generate novel active compounds, in addition to reactive oxygen species, also contributes to the photodynamic damage observed on simultaneous exposure of the chromophore and target tissue to light during PDT.–Pervaiz, S. Reactive oxygen-dependent production of novel photochemotherapeutic agents.


Key Words: PDT • photodynamic reaction • photosensitizer • mitochondrial permeability


   BACKGROUND
TOP
 ABSTRACT
 BACKGROUND
THE PHOTODYNAMIC REACTION
 THE CONCEPT OF PREACTIVATION...
 THE ISSUE OF TARGET...
 CONCLUDING REMARKS
 REFERENCES
 
ACCORDING TO THE postulates of the standard evolutionary theory, the first living organisms evolved in the absence of molecular oxygen. With the appearance of plants, this reducing environment was transformed over a period of time and molecular oxygen began to accumulate, reaching its present concentration of ~20%. Just as the appearance of oxygen made aerobic respiration possible and provided a shield against solar ultraviolet (UV) radiation by ozone formation, the toxic potential of oxygen was also recognized, as oxygen and some of its derivatives are highly reactive (1) . Some of these derivatives are produced by metabolic reactions (2 , 3) ; of special pertinence to this study, several are produced by sensitized photobiological processes involving visible and UV radiations (4 , 5) .

The reactive nature of species derived from oxygen has been exploited in the clinical setting for targeting bacteria, viruses, and tumor cells by photodynamic excitation of a variety of chromophores. This modality, termed photodynamic therapy (PDT), is currently being used to treat some forms of cancer (6 7 8 9) . However, the applicability of conventional PDT is limited due to the absolute dependence on simultaneous exposure of the target to the photoactive compound and light. To circumvent this problem, a novel approach, termed preactivation (10 , 11) , was developed that involved exposure of the chromophore to light prior to its use in biological systems. The photo-exposed compound could then be used as an anti-cancer or anti-viral agent without further dependence on light. It is the purpose of this commentary to briefly review the role of reactive oxygen species in the photodynamic effect and provide an explanation for the mechanism of preactivation.


   THE PHOTODYNAMIC REACTION
TOP
 ABSTRACT
 BACKGROUND
 THE PHOTODYNAMIC REACTION
THE CONCEPT OF PREACTIVATION...
 THE ISSUE OF TARGET...
 CONCLUDING REMARKS
 REFERENCES
 
Although the use of natural products for their therapeutic photodynamic activity goes back to human’s earliest research efforts, the first experimental evidence of photosensitization was reported around the turn of the century from von Tappeiner’s laboratory in Munich. One of his medical students, Oscar Raab, observed that low concentrations of acridines in the presence of light could be lethal to the protozoan paramecium (12) . Tappeiner and his biomedical colleagues contended that these photobiological reactions were highly dynamic and should be distinguished from photosensitization of photographic plates by certain dyes (13) . Hence, the term photodynamic reaction was coined for all photobiological reactions occurring in the presence of molecular oxygen (14) .

With the advent of the quantum theory and modern photochemistry, it became obvious that limits on the photobiological processes were set by the absorption spectrum of the light-absorbing substances or photosensitizers. For a substance to be an efficient photosensitizer, it must be capable of being excited, upon exposure to light, to a relatively long-lived, energy-rich form termed the triplet state (15 , 16) . Organic photosensitizer molecules in the dark almost always exist in the ground state; in this state, the molecule has no unpaired electron spin. Upon absorption of a photon, an electron in the sensitizer shifts to a higher orbital that could undergo fast spin inversion to generate the triplet state, containing two unpaired electrons (type I reaction) (4 , 17) . The metastable triplet state of the photosensitizer could then collide with certain biomolecules, such as molecular oxygen, with the subsequent transfer of energy (type II reaction) (16 , 17) and the return of the photosensitizer to the ground state to carry on another interaction with a photon. The transfer of energy from the triplet photosensitizer to molecular oxygen results in the generation of the highly toxic activated oxygen molecule singlet oxygen (1O2), which has a very short lifetime in biological systems (<40 nanoseconds) and a short radius of action (<0.02 µm) (18) .

Apparently, the earliest attempts to exploit the phenomenon of photosensitization for potential antitumor therapy were made by Jesionek and Tappeiner in 1903 by light exposure of tumors in the presence of eosin (19) . The modern interest in PDT for cancer therapy began with Lipson and Schwartz around 1960, who used a fluorescent tumor localizing mixture of porphyrins, termed the hematoporphyrin derivative (20 , 21) . Since their pioneering work, compounds including Photofrin, purpurins, xanthenes, phthalocyanines, oxazines, cyanines, chlorins, and others have been tested in vitro and in vivo with some success (6 , 22 23 24 25 26) . Membranous intracellular organelles such as mitochondria, lysosomes, and nuclei, apart from the tumor vasculature, are potential targets for attack by 1O2 generated on photoactivation of the sensitizer (27 , 28) . However, due to the limited migration of 1O2 from the site of formation (18) , the initial damage is closely related to the localization of the sensitizer. The potentially lethal damage can take the form of 1O2-mediated lipid peroxidation (29) , and oxidative modification of membrane proteins (30) . Depending on the target organelle, both necrotic and apoptotic forms of cell death have been reported in cells and tissues after PDT (31 , 32) . Photosensitizers that predominantly bind to the plasma membrane may render a necrotic phenotype, whereas mitochondrial specific sensitizers could lead to the induction of mitochondrial permeability transition (MPT) and leakage of proapoptotic factors into the cytosol (33) , thereby triggering the apoptotic caspase cascade (34) . Thus, the efficacy of PDT is dependent on the in situ generation of 1O2 upon photo-exposure of the sensitizer and on the ready accessibility of susceptible lipids and proteins within the bilayer.


   THE CONCEPT OF PREACTIVATION-OXIDATIVE DEGRADATION OF THE PHOTOSENSITIZER
TOP
 ABSTRACT
 BACKGROUND
 THE PHOTODYNAMIC REACTION
 THE CONCEPT OF PREACTIVATION...
THE ISSUE OF TARGET...
 CONCLUDING REMARKS
 REFERENCES
 
Given the absolute requirement for the simultaneous exposure of the target to the photosensitizer and light, the applicability of PDT is limited to solid and accessible tumors, and for extra corporeal purging of autologous bone marrow prior to transplantation (8 , 35) . Early in 1988 our group became interested in looking for ways to separate the process of photoactivation from the actual biological activity. We hypothesized that the need for simultaneous exposure of the biological target to light and photosensitizer could be circumvented by prior exposure (activation) of the sensitizer molecule to light and its subsequent use as any other anti-cancer or anti-viral drug. By dint of the nature of the protocol, this process was termed preactivation. The preactivated compound(s) could then be tested for anti-tumor or anti-viral activity without further dependence on light.

At the time we developed this concept, we were involved in studying the photodynamic potential of the lipophilic polymethine dye merocyanine 540 (MC540) (36 , 37) , a photosensitizer known for its relatively high tumor selectivity (36 , 38 39 40 41) . Studies showed that MC540 was an excellent photodynamic agent against leukemia and lymphoma cells with minimal nonspecific cytotoxicity (40 , 42 43 44) . Hence, our initial studies to investigate preactivation were carried out with MC540 exposed to 514 nm (close to the absorption maximum) of laser light. Preactivated MC540 (pMC540) was then mixed in the dark with tumor cells or normal cells to determine the anti-proliferative activity. The cytotoxicity of pMC540 was significantly higher (70-90%) against a variety of tumor cell lines than normal peripheral blood mononuclear cells (<20%), and the electron micrographs showed a progression toward apoptosis in majority of the cells (10) , with minimal toxicity to normal blood cells in vitro and in vivo (10 , 45) . In addition, the life span of L1210 leukemia-bearing mice treated with pMC540 was prolonged as compared to the control group administered the native (nonactivated) MC540. pMC540 was also effective in almost complete inactivation of cell-free herpes simplex and human immunodeficiency viruses (11 , 46) . In addition, the anti-tumor activity of pMC540 was mediated by intracellular caspases (47) , thus highlighting the apoptotic potential of the photoactivated mixture. Thus, contrary to the general belief that the activity of the photosensitizer was dependent on the close proximity of the biological target at the time of irradiation of the sensitizer, the preactivated chromophore still retained anti-tumor activity without further dependence on light.

Although the preactivated mixture of MC540 contained detectable levels of reactive oxygen species, such as hydrogen peroxide (48) , the biological activity of pMC540 was retained for up to 30 days when stored in the dark at -80°C, thus making the requirement of 1O2 in the cytotoxic activity superfluous; the half-life and diffusion range of 1O2 in aqueous media are extremely short (18) . However, the activity of pMC540 was significantly reduced (~50%) on light exposure in the absence of molecular oxygen, thus suggesting that reactive oxygen, though not required for the biological activity, was necessary during the process of preactivation. Photochemical studies revealed that the triplet formed by direct photo-excitation of MC540 was quenched by molecular oxygen with the resultant formation of 1O2 (49 50 51) ; however, there was a lack of correlation between 1O2 yields and the photodynamic effectiveness of MC540 (52) . Thus, in view of the inherent photolability of some photosensitizers, cyanines in particular, the likely scenario is a complete destruction of the dye by 1O2-mediated photo-oxidation (51 , 53) . Consistent with this scenario, spectral analysis of the preactivated MC540 mixture showed a complete shift of the absorption maximum from 568 nm (MC540) to 280 nm (10) , suggesting complete photo-degradation (bleaching) of the parent sensitizer MC540, which could be triggered by reaction with excited oxygen. Further analysis of the pMC540 mixture by high-performance liquid chromatography showed that the elution profile was completely different from the parent molecule (MC540), strongly suggesting the breakdown of the parent compound (10) . These findings agree with reports that 1O2 or other reactive oxygen species produced on photoactivation could ‘back attack’ the photosensitizer molecule itself (51) , leading to rapid and irreversible oxidation of the compound.

The photochemical transformation of MC540 was further investigated by Franck and Schneider. They identified three novel photo-oxidation products on irradiation of MC540 in methanol, namely, merodantoin, merocil, and meroxazole (53) . Their study provided direct evidence that chemically reactive 1O2 was sufficiently available to trigger photo-oxidation of MC540. According to their model the central polymethine chain of MC540 was attacked by 1O2, leading to the generation of intermediates and subsequently to the new photoproducts. These results provide further impetus to the hypothesis that 1O2 produced during conventional PDT or preactivation could result in oxidative degradation of the sensitizer molecule, and the resultant photoproducts may account for the observed biological activity. A probable scenario is outlined in Fig. 1 whereby direct exposure of a photosensitive chromophore to light results in the generation of a triplet state of the chromophore. The triplet formed by light excitation can be quenched by molecular oxygen with the direct transfer of energy and the resultant formation of reactive oxygen species (such as 1O2); this energy transfer reaction results in the decay of the triplet state chromophore back to the ground state. The activated oxygen thus formed could attack the chromophore, resulting in the breakdown of the parent compound to generate novel photoproducts. This hypothesis is in line with the studies demonstrating light-induced bleaching or photo-oxidation of MC540 and the subsequent generation of the photoproducts (51 , 53) .



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  		Figure 1. Photo-exposure of the sensitizer molecule leads to the generation of photoexcited triplet sensitizer (sesitizer*). The excited sensitizer then reacts with molecular oxygen to generate singlet oxygen (3O2) or other reactive oxygen radicals (?), which can back attack and photo-oxidize the sensitizer, resulting in novel biologically active photo products.

It is now well established that caspase activation, induction of MPT, and release of cytochrome c are essential components of the apoptotic pathway (34 , 54 , 55) ; hence, the realization that drugs that directly activate caspases and/or target mitochondrial structures could have potential for use as chemotherapeutic agents to trigger effective apoptosis in tumor cells. Although the involvement of the apoptotic pathway in conventional PDT-induced tumor cell lysis was reported as early as 1991 by Agarwal et al. (56) , subsequent studies have demonstrated that mitochondrial events may be critical in the execution of PDT-induced apoptosis (33 , 57) . The photo-oxidized mixture of MC540 and two of its recently purified photoproducts, C1 (identical to merodantoin) and C2 (identical to merocil), induce caspase-dependent apoptosis in human tumor cell lines (47 , 58) . Both C1 and C2 as well as a third intermediate product C5 trigger the cytosolic translocation of cytochrome c from mitochondria by mechanism(s) dependent (C1 and C5) or independent (C2) of the MPT(59) . It is plausible that in addition to the local effect of conventional PDT explained by the light-dependent production of reactive oxygen, the generation of light-induced breakdown products could account for the observed anti-tumor activity of the photosensitizer. Thus, at least in the case of MC540, and perhaps other lipophilic agents with predilection for mitochondrial membrane structures, light exposure of cells loaded with the photosensitizer could result in direct toxicity due to 1O2 production and in part to 1O2-dependent breakdown of the chromophore to generate novel compounds with the ability to trigger molecular events associated with apoptosis.


   THE ISSUE OF TARGET SPECIFICITY?
TOP
 ABSTRACT
 BACKGROUND
 THE PHOTODYNAMIC REACTION
 THE CONCEPT OF PREACTIVATION...
 THE ISSUE OF TARGET...
CONCLUDING REMARKS
 REFERENCES
 
You may wonder as to my use of the [mark of interrogation] here. Indeed, the biggest challenge in effective anti-cancer drug design and development is to achieve a high degree of anti-tumor effect with minimal damage to the healthy tissues. The overall objective is to identify relatively small molecules with predilection for molecular target(s) truly specific for malignant cells. It is well established, though poorly understood, that photosensitizers used in conventional PDT exhibit a higher degree of selectivity for tumor tissues, though not entirely innocuous to normal tissues (60) . This has been attributed to leaky vasculature of tumor cells, a high amount of lipid favoring lipophilic sensitizers (61) , a decreased pH in tumor tissues (62) , and a slower rate of clearance of hydrophobic sensitizers due to reduced lymphatic drainage in tumor tissues (63) . The ultimate effect after light activation is therefore closely related to the localization of the sensitizer (28 , 64 , 65) .

In light of this, it would be logical to assume that prior photo-oxidation of the sensitizer could abrogate the enhanced tumor localization observed with conventional PDT. At least in the case of MC540, it is interesting that a photo-oxidized mixture of MC540 still exhibited relatively higher cytotoxicity against tumor cells in both in vitro and in vivo systems (10 , 45) . The precise mechanism of this preferential activity is not well understood, but it should be pointed out that the process of photo-oxidation leads to the generation of novel small molecules that may have the same therapeutic potential as any other natural or synthetic anti-cancer agent. Indeed, the purification of three photoproducts of MC540 and their ability to activate effector components of the cell’s suicide program already suggest that this novel modality could be exploited for the generation of potential candidate compounds. First, once a biologically active agent is identified, derivatives of the active compounds could be developed that display more desirable pharmacological properties with minimal side effects. This scheme of events was successfully used in the development of first-, second-, and third-generation vinca alkaloids, antifolates, and alkylating agents. Second, with the tremendous advancement in technologies aimed at enhancing the pharmacodistribution properties of anticancer drugs vis à vis drug delivery systems (66) , a significantly enhanced targeting of cytotoxic drugs to tumor tissues could be accomplished (67 , 68) . Indeed, such delivery vehicles have already been successfully used in conventional PDT for selective loading of photosensitizers in tumor tissues (69 , 70) . Liposome-associated photosensitizers exhibit greater efficiency and tumor specificity, and hence some second-generation photosensitizers are formulated in lipid-based delivery systems (6) . In addition, the increased proliferation rate of tumor cells is known to selectively sensitize tumor cells with a high growth fraction to chemotherapeutic agents. Thus, the innovative use of a well-known concept of photoexcitation for the generation of biologically active molecules and an investigation of their potential for clinical use could definitely add to our repertoire of weapons in the battle, not only against cancer but other life-threatening diseases, such as HIV/AIDS.


   CONCLUDING REMARKS
TOP
 ABSTRACT
 BACKGROUND
 THE PHOTODYNAMIC REACTION
 THE CONCEPT OF PREACTIVATION...
 THE ISSUE OF TARGET...
 CONCLUDING REMARKS
REFERENCES
 
Our studies have successfully advanced the hypothesis that novel biologically active compounds could be generated by photo-oxidative degradation of a photosensitizer. Although, the bulk of our studies has been performed with MC540 and its photoproducts, the concept is applicable to sensitizers that yield appreciable amounts of 1O2 or other reactive intermediates upon light exposure. In this respect, Photofrin II (6) , which yields significantly high amounts of 1O2 upon light exposure, has been successfully preactivated (71) ; however, the reactive intermediates have yet to be identified. Similarly, another photosensitizer, naphthalimide, has been reported to generate reactive photoproducts with anti-viral activity in cells infected with HIV or HTLV-1 (72) . More recently, our preliminary data strongly support a similar mechanism for another potential photodynamic agent, hypericin (St. John’s wort) (73 , 74) . Whereas hypericin in the dark is minimally toxic to tumor cells, upon photo-induced preactivation the anti-tumor activity is significantly enhanced (S. Pervaiz et al. unpublished results). These findings suggest a possible common mechanism applicable to some chromophores, whereby exposure to light results in the generation of biologically active intermediates upon breakdown of the parent compound with potential for use as chemotherapeutic agents. Photo-oxidation does not only provide a novel means for the generation of biologically active molecules, but the identification of breakdown products could also explain for the mechanism of conventional PDT. It is likely that the light-dependent breakdown of the chromophore to generate novel active compounds, in addition to reactive oxygen species, contributes to the photodynamic damage observed on simultaneous exposure of the chromophore and target tissue to light during PDT.


   ACKNOWLEDGMENTS
 
I would like to acknowledge the contributions of so many whose work could have been inadvertently left out and to thank Dr. Kirpal S. Gulliya for his contributions to the concept and with whom I shared many years of excellent working relationship. I also deeply appreciate Professor Barry Halliwell and Dr. Marie-Veronique Clément for useful comments and discussions.


   REFERENCES
TOP
 ABSTRACT
 BACKGROUND
 THE PHOTODYNAMIC REACTION
 THE CONCEPT OF PREACTIVATION...
 THE ISSUE OF TARGET...
 CONCLUDING REMARKS
 REFERENCES
 

  1. Fridovich, I. (1978) The biology of oxygen radicals. Science 201,875-880[Abstract/Free Full Text]
  2. Freeman,, B. A. (1994) Armstrong, D.et al eds. Free Radicals in Molecular Biology, Aging, and Disease Raven Press New York.
  3. Halliwell, B., Gutteridge, J. M. C. (1999) Free Radicals in Biology and Medicine 3rd Clarendon Press Oxford, England.
  4. Ochsner, M. (1997) Photophysical and photobiological processes in the photodynamic therapy of tumours. J. Photochem. Photobiol. B. 39,1-18[Medline]
  5. Oleinick, N. L., Evans, H. H. (1998) The photobiology of photodynamic therapy: cellular targets and mechanisms. Radiat. Res. 150,S146-S156
  6. Dougherty, T. J., Gomer, C. J., Henderson, B. W., Jori, G., Kessel, D., Korbelik, M., Moan, J., Peng, Q. (1998) Photodynamic therapy. J. Natl. Cancer Inst. 90,889-905[Abstract/Free Full Text]
  7. Gomer, C. J., Rucker, N., Ferrario, A., Wong, S. (1989) Properties and applications of photodynamic therapy. Radiat. Res. 120,1-18[Medline]
  8. Hsi, R. A., Rosenthal, D. I., Glatstein, E. (1999) Photodynamic therapy in the treatment of cancer: current state of the art. Drugs 57,725-734[Medline]
  9. Kessel, D. (1992) Photodynamic therapy and neoplastic disease. Oncol. Res. 4,219-225[Medline]
  10. Gulliya, K. S., Pervaiz, S., Dowben, R. M., Matthews, J. L. (1990) Tumor cell specific dark cytotoxicity of light-exposed merocyanine 540: implications for systemic therapy without light. Photochem. Photobiol. 52,831-838[Medline]
  11. Gulliya, K. S., Chanh, T., Newman, J., Pervaiz, S., Matthews, J. L. (1990) Preactivation–a novel antitumour and antiviral approach. Eur. J. Cancer 26,551-553
  12. Raab, O. (1900) Uber die Wirkung Fluoreszierender Stoffen auf Infusoria. Z. Biol. 39,524-526
  13. von Tappeiner, H., Jodlbauer, A. (1904) Uber die Wirkung der photodynamische (fluorescierenden) Stoffe auf Protozoen und Enzyme. Deutsches. Arc. Klin. Med. 39,427-487
  14. Blum, H. F. (1941) Photodynamic Action and Diseases Caused by Light Reinhold New York.
  15. Vogelmann, E., Kramer, H. E. (1976) Indication of fast triplet formation in bimolecular quenching of excited singlet states studied by conventional flash photolysis. Photochem. Photobiol. 24,595-597[Medline]
  16. Pathak, M. A. (1982) Molecular aspects of drug photosensitivity with special emphasis on psoralen photosensitization reaction. J. Natl. Cancer Inst. 69,163-170
  17. Vermeersch, G., Ronfard–Haret, J. C., Bazin, M., Carillet, V., Morliere, P., Santus, R. (1991) Type I and type II photosensitization by the antibacterial drug nalidixic acid. A laser flash photolysis study. Photochem. Photobiol. 54,661-666[Medline]
  18. Moan, J., Berg, K. (1991) The photodegradation of porphyrins in cells can be used to estimate the lifetime of singlet oxygen. Photochem. Photobiol. 53,549-553[Medline]
  19. Jesionek, A., von Tappeiner, H. (1903) Muench. Med. Wochschs. 47,20420
  20. Schwartz, S., Absolon, K., Vermund, H. (1955) Some relationships of porphyrins, x-rays, and tumors. Univ. Minnesota Med. Bull. 7,7-13
  21. Lipson, R., Aldes, E., Olsen, A. (1961) The use of a derivative of hematoporphyrin in tumor detection. J. Natl. Cancer Inst. 1,1-11
  22. Garbo, G. M. (1996) Purpurins and benzochlorins as sensitizers for photodynamic therapy. J. Photochem. Photobiol. B. 34,109-116[Medline]
  23. Diwu, Z., Lown, J. W. (1994) Phototherapeutic potential of alternative photosensitizers to porphyrins. Pharmacol. Ther. 63,1-35[Medline]
  24. Anderson, C., Hrabovsky, S., McKinley, Y., Tubesing, K., Tang, H. P., Dunbar, R., Mukhtar, H., Elmets, C. A. (1997) Phthalocyanine photodynamic therapy: disparate effects of pharmacologic inhibitors on cutaneous photosensitivity and on tumor regression. Photochem. Photobiol. 65,895-901[Medline]
  25. Delaey, E., van Laar, F., De Vos, D., Kamuhabwa, A., Jacobs, P., de Witte, P. (2000) A comparative study of the photosensitizing characteristics of some cyanine dyes. J. Photochem. Photobiol. B. 55,27-36[Medline]
  26. Pandey, R. K., Bellnier, D. A., Smith, K. M., Dougherty, T. J. (1991) Chlorin and porphyrin derivatives as potential photosensitizers in photodynamic therapy. Photochem. Photobiol. 53,65-72[Medline]
  27. Henderson, B. W., Dougherty, T. J. (1992) How does photodynamic therapy work?. Photochem. Photobiol. 55,145-157[Medline]
  28. Peng, Q., Moan, J., Nesland, J. M. (1996) Correlation of subcellular and intratumoral photosensitizer localization with ultrastructural features after photodynamic therapy. Ultrastruct. Pathol. 20,109-129[Medline]
  29. Das, M., Mukhtar, H., Greenspan, E. R., Bickers, D. R. (1985) Photoenhancement of lipid peroxidation associated with the generation of reactive oxygen species in hepatic microsomes of hematoporphyrin derivative-treated rats. Cancer Res 45,6328-6330[Abstract/Free Full Text]
  30. Davies, K. J. (1987) Protein damage and degradation by oxygen radicals. I. general aspects. J. Biol. Chem. 262,9895-9901[Abstract/Free Full Text]
  31. Dahle, J., Steen, H. B., Moan, J. (1999) The mode of cell death induced by photodynamic treatment depends on cell density. Photochem. Photobiol. 70,363-367[Medline]
  32. Villanueva, A., Dominguez, V., Polo, S., Vendrell, V. D., Sanz, C., Canete, T. M., Juarranz, A., Stockert, J. C. (1999) Photokilling mechanisms induced by zinc(II)-phthalocyanine on cultured tumor cells. Oncol. Res. 11,447-453[Medline]
  33. Kessel, D., Luo, Y. (1999) Photodynamic therapy: a mitochondrial inducer of apoptosis. Cell Death Differ 6,28-35[Medline]
  34. Kroemer, G., Zamzami, N., Susin, S. A. (1997) Mitochondrial control of apoptosis. Immunol. Today 18,44-51[Medline]
  35. Mulroney, C. M., Gluck, S., Ho, A. D. (1994) The use of photodynamic therapy in bone marrow purging. Semin. Oncol. 21,24-27
  36. Valinsky, J. E., Easton, T. G., Reich, E. (1978) Merocyanine 540 as a fluorescent probe of membranes: selective staining of leukemic and immature hemopoietic cells. Cell 13,487-499[Medline]
  37. Sieber, F. (1987) Merocyanine 540. Photochem. Photobiol. 46,1035-1042[Medline]
  38. Schlegel, R. A., Phelps, B. M., Waggoner, A., Terada, L., Williamson, P. (1980) Binding of merocyanine 540 to normal and leukemic erythroid cells. Cell 20,321-328[Medline]
  39. Smith, O. M., Gaffney, D. K., Anderson, M. S., McOlash, L., Schober, S. L., Sieber, F. (1991) Plasma membrane properties regulating the sensitivity of leukemia, lymphoma, and solid tumor cells to merocyanine 540-sensitized photoirradiation. Exp. Hematol. 19,785-788[Medline]
  40. Gulliya, K. S., Pervaiz, S. (1989) Elimination of clonogenic tumor cells from HL-60, Daudi, and U-937 cell lines by laser photoradiation therapy: implications for autologous bone marrow purging. Blood 73,1059-1065[Abstract/Free Full Text]
  41. Meagher, R. C., Rothman, S. A., Paul, P., Koberna, P., Willmer, C., Baucco, P. A. (1989) Purging of small cell lung cancer cells from human bone marrow using ethiofos (WR-2721) and light-activated merocyanine 540 phototreatment. Cancer Res 49,3637-3641[Abstract/Free Full Text]
  42. Sieber, F., Stuart, R. K., Rowley, S. D., Sharkis, S. J., Sensenbrenner, L. L. (1987) Dye-mediated photolysis of normal and neoplastic hematopoietic cells. Leukoc. Res. 11,43-49
  43. Qiu, K., Sieber, F. (1992) Merocyanine 540-sensitized photoinactivation of leukemia cells: effects of dose fractionation. Photochem. Photobiol. 56,489-493[Medline]
  44. Itoh, T., Messner, H. A., Jamal, N., Tweeddale, M., Sieber, F. (1993) Merocyanine 540-sensitized photoinactivation of high-grade non-Hodgkin’s lymphoma cells: potential application in autologous BMT. Bone Marrow Transplant 12,191-196[Medline]
  45. Pervaiz, S., Battaglino, M., Matthews, J. L., Gulliya, K. S. (1993) Biodistribution and toxicity of photoproducts of merocyanine 540. Cancer Chemother. Pharmacol. 31,467-474[Medline]
  46. Tran, C. C., Allan, J. S., Pervaiz, S., Matthews, J. L., Trevino, S. R., Gulliya, K. S. (1992) Preactivated merocyanine 540 inactivates HIV-1 and SIV: potential therapeutic and blood banking applications. J. AIDS 5,188-195
  47. Pervaiz, S., Hirpara, J. L., Clement, M.-V. (1998) Caspase proteases mediate apoptosis induced by anti-cancer agent preactivated MC540 in human tumor cell lines. Cancer Lett 127,1-12[Medline]
  48. Pervaiz, S., Harriman, A., Gulliya, K. S. (1992) Protein damage by photoproducts of merocyanine 540. Free Radic. Biol. Med. 12,389-396[Medline]
  49. Kalyanaraman, B., Feix, J. B., Sieber, F., Thomas, J. P., Girotti, A. W. (1987) Photodynamic action of merocyanine 540 on artificial and natural cell membranes: involvement of singlet molecular oxygen. Proc. Natl. Acad. Sci. USA 84,2999-3003[Abstract/Free Full Text]
  50. Davila, J., Harriman, A., Gulliya, K. S. (1991) Photochemistry of merocyanine 540: the mechanism of chemotherapeutic activity with cyanine dyes. Photochem. Photobiol. 53,1-11[Medline]
  51. Singh, R. J., Feix, J. B., Kalyanaraman, B. (1992) Photobleaching of merocyanine 540: involvement of singlet molecular oxygen. Photochem. Photobiol. 55,483-489[Medline]
  52. Singh, R. J., Feix, J. B., Pintar, T. J., Girotti, A. W., Kalyanaraman, B. (1991) Photodynamic action of merocyanine 540 in artificial bilayers and natural membranes: action spectra and quantum yields. Photochem. Photobiol. 53,493-500[Medline]
  53. Franck, B., Schneider, U. (1992) Photooxidation products of merocyanine 540 formed under preactivation conditions for tumor therapy. Photochem. Photobiol. 56,271-276[Medline]
  54. Thornberry, N. A., Lazebnik, Y. (1998) Caspases: enemies within. Science 281,1312-1316[Abstract/Free Full Text]
  55. Green, D. R., Reed, J. C. (1998) Mitochondria and apoptosis. Science 281,1309-1312[Abstract/Free Full Text]
  56. Agarwal, M. L., Clay, M. E., Harvey, E. J., Evans, H. H., Antunez, A. R., Oleinick, N. L. (1991) Photodynamic therapy induces rapid cell death by apoptosis in L5178Y mouse lymphoma cells. Cancer Res 51,5993-5996[Abstract/Free Full Text]
  57. Kessel, D., Luo, Y. (1998) Mitochondrial photodamage and PDT-induced apoptosis. J. Photochem. Photobiol. B. 42,89-95[Medline]
  58. Pervaiz, S., Seyed, M. A., Hirpara, J. L., Clement, M. V., Loh, K. W. (1999) Purified photoproducts of merocyanine 540 trigger cytochrome C release and caspase 8-dependent apoptosis in human leukemia and melanoma cells. Blood 93,4096-4108[Abstract/Free Full Text]
  59. Hirpara, J. L., Seyed, M. A., Loh, K. W., Dong, H., Kini, R. M., Pervaiz, S. (2000) Induction of mitochondrial permeability transition and cytochrome C release in the absence of caspase activation is insufficient for effective apoptosis in human leukemia cells. Blood 95,1773-1780[Abstract/Free Full Text]
  60. Nauta, J. M., van Leengoed, H. L., Star, W. M., Roodenburg, J. L., Witjes, M. J., Vermey, A. (1996) Photodynamic therapy of oral cancer. A review of basic mechanisms and clinical applications. Eur. J. Oral Sci. 104,69-81
  61. Freitas, I. (1990) Lipid accumulation: the common feature to photosensitizer-retaining normal and malignant tissues [news]. J. Photochem. Photobiol. B. 7,359-361[Medline]
  62. Barrett, A. J., Kennedy, J. C., Jones, R. A., Nadeau, P., Pottier, R. H. (1990) The effect of tissue and cellular pH on the selective biodistribution of porphyrin-type photochemotherapeutic agents: a volumetric titration study. J. Photochem. Photobiol. B. 6,309-323[Medline]
  63. Dougherty, T. J. (1987) Photosensitizers: therapy and detection of malignant tumors. Photochem. Photobiol. 45,879-889[Medline]
  64. Kessel, D., Woodburn, K., Gomer, C. J., Jagerovic, N., Smith, K. M. (1995) Photosensitization with derivatives of chlorin p6. J. Photochem. Photobiol. B. 28,13-18[Medline]
  65. Kessel, D., Woodburn, K., Henderson, B. W., Chang, C. K. (1995) Sites of photodamage in vivo and in vitro by a cationic porphyrin. Photochem. Photobiol. 62,875-881[Medline]
  66. Mayer, L. D. (1998) Future developments in the selectivity of anticancer agents: drug delivery and molecular target strategies. Cancer Metastasis Rev 17,211-218[Medline]
  67. Huang, S. K., Mayhew, E., Gilani, S., Lasic, D. D., Martin, F. J., Papahadjopoulos, D. (1992) Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing C-26 colon carcinoma. Cancer Res 52,6774-6781[Abstract/Free Full Text]
  68. Mayer, L. D., Dougherty, G., Harasym, T. O., Bally, M. B. (1997) The role of tumor-associated macrophages in the delivery of liposomal doxorubicin to solid murine fibrosarcoma tumors. J. Pharmacol. Exp. Ther. 280,1406-1414[Abstract/Free Full Text]
  69. Ricchelli, F., Gobbo, S., Jori, G., Moreno, G., Vinzens, F., Salet, C. (1993) Photosensitization of mitochondria by liposome-bound porphyrins. Photochem. Photobiol. 58,53-58[Medline]
  70. Jori, G. (1996) Tumour photosensitizers: approaches to enhance the selectivity and efficiency of photodynamic therapy. J. Photochem. Photobiol. B. 36,87-93[Medline]
  71. Chang, P. H., Pervaiz, S., Battaglino, M., Matthews, J. L., Clark, C., Day, J., Preskitt, J., Vanderpool, D., Gulliya, K. S. (1991) Synergy between preactivated photofrin-II and tamoxifen in killing retrofibroma, pseudomyxoma and breast cancer cells. Eur. J. Cancer 27,1034-1039
  72. Chanh, T. C., Lewis, D. E., Judy, M. M., Sogandares-Bernal, F., Michalek, G. R., Utecht, R. E., Skiles, H., Chang, S. C., Matthews, J. L. (1994) Inhibition of retrovirus-induced syncytium formation by photoproducts of a brominated 1,8-naphthalimide compound. Antiviral Res 25,133-146[Medline]
  73. Vantieghem, A., Assefa, Z., Vandenabeele, P., Declercq, W., Courtois, S., Vandenheede, J. R., Merlevede, W., de Witte, P., Agostinis, P. (1998) Hypericin-induced photosensitization of HeLa cells leads to apoptosis or necrosis. Involvement of cytochrome c and procaspase-3 activation in the mechanism of apoptosis. FEBS Lett. 440,19-24[Medline]
  74. Vandenbogaerde, A. L., Cuveele, J. F., Proot, P., Himpens, B. E., Merlevede, W. J., de Witte, P.A. (1997) Differential cytotoxic effects induced after photosensitization by hypericin. J. Photochem. Photobiol. B. 38,136-142[Medline]



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