NEWSANDVIEWS
223
4 R. W. Gsnge, A. D. Blackett, E. A. Matzinger, B. M. Sutherland and I. E. Kochevar, Comparative protection efficiency of UVA and WB-induced tans against erythema and formation of endonuclease-sensitivesites in DNA by UVB in humanskin,J. Invest. DennatoL, 85 (1985) 362-364. 5 B. L. Diffey, P. M. Farr and A. M. Oakley, Quantitative studies on UVA-induced erythema in human skin, Br. J. DermaioL, I17 (1987) 67-66. 6 P. M. Farr, J. M. Marks, B. L. Diffey and P. Ince, Skin fragility and blistering due to use of sunbeds, Br. Med. J., 296 (1988) 1708-1709. 7 S. K. Jones, H. Moseley and R. M. MacKie, WA-induced melsnocytic lesions, Br. J. DermutoL, I17 (1987) 111-115. 8 M. S. Devgun, B. E. Johnson and C. R. Paterson, Tanning, protection against sunburnand vitamin D formation with a W-A ‘sunbed’, Br. J. DermuZoL, I07 (1982) 275-284. 9 J. K. Rivers, P. G. Norris, G. M. Murphy, A. C. Chu, G. MidgIey et uI., UVA sunbeds: tanning,photoprotection, acute adverse effects and immunologicaIchanges& J. DermatoL, I20 (1989) 767-777. 10 P. M. Farr and B. L. Diffey, Adverse effects of sunscreens in photosensitive subjects, Lancet, i (1989) 429-431. 11 D. L. Bissett, D. P. Hannon and T. V. Orr, Wavelength dependence of histologicaL physical and visible changes in chronicalIy W-irradiated hairlessmouse skin,Photo&em. PhotobioL, 50 (1989) 763-769. 12 H. J. C. M. Sterenborg, Investigations on the action spectrum of tumorigenesisby ultraviolet radiation, Ph.D. Thesis, Utrecht, 1987. 13 L. Roza, R. A. Baan, J. C. van der Leun and L. Kligman, UVA hazards in skin associated with the use of tanning equipment, J. Photochem PhotobioL B: BioL, 3 (1989) 281-287. 14 H. J. C. M. Sterenborg and J. C. van der Leun, Tumorigenesis by a long wavelength UVA source, Photo&em. Photobiol., (1990) 325-330. 15 A. J. Swerdiow, J. S. C. English, R. M. Ma&e, C. J. O’Doherty, J. A. A. Hunter et al., Fluorescent lights, ultraviolet lamps, and risk of cutaneous melanoma, Br. Med. J., 297 (1988) 647-650. 16 A. J. Sober, Solar exposure in the etiology of cutaneous melanoma, Photodennatolo~, 4 (1987) 23-31. 17 B. W. Loggie and J. A. Eddy, Solar considerations in the development of cutaneous melanoma, Se&n. Chzcol., 15 (1988) 494-499.
Of what value is a highly absorbing photosensitizer
in PDT?
T. J. Dougherty and W. R. Potter Department of Radiation Medicine, RosweU Park Cancer Center, Elm and Carlton Streets, B@ii, IVY 14263-OOOI (U.S-4.j
An excellent recent review by Spikes [ 1] prompts us to emphasize a point previously made but perhaps not well appreciated regarding development of new photosensitizers for photodynamic therapy. In his article, Spikes states “HpD [haematoporphyrin derivative] absorbs poorly in the red region where tissue penetration by light is great. As a result, several other types of sensitizers have been examined that absorb more strongly and at longer wavelengths in the red, . . .“.
224
NEwsANDvIEws
A large extinction coefficient (i.e. stronger absorption relative to Photofrin at a given tissue level) can be a considerable detriment to achieving a greater depth of necrosis in PDT. It has been noted, first by Wilson et al. [2] and then by Potter [ 31, that sensitizers which produce significant additional absorption in tissue (tumors) can induce considerable opacity to such tissue and in fact completely negate (or worse) any advantage gained by their longer wavelength absorption compared with Photofrin. This point needs to be appreciated because many, if not most, of the newer photosensitizers being studied fit into this category; take, for example, the aluminum sulfonated phthalocyanine AlSPc reported by Bown et al. [4] and described by Wilson (21. As Wilson notes, for Photofrin in tissue at clinically relevant doses, space irradiance at even five attenuation lengths (lo-15 mm) for a typical tissue would be reduced by only about 5% beyond that of the tissue absorption itself. However, AlSPc, for whatever reasons, requires essentially the same tumor levels as does Photofrin in order to achieve any semblance of tumor control in spite of its approximately 20 times larger absorption coefficient [5]. This reduces the effective penetration depth at 675 nm by about 20% resulting in almost a 50% drop in space irradiance at five attenuation lengths compared with the dye-free tissue (in each case a “typical” inherent tissue absorption of lo- ’ mm- ’ was used for comparison, producing an effective penetration depth of about 2 mm, eg. bovine muscle [2]). Thus, while 675 nm light could increase the effective penetration depth by about 15-20% [ 61, this is completely negated by the need to use relatively high tissue levels of the sensitizer in order to achieve the desired photosensitization. In order to take advantage of the increased penetration depth in tissue at increasing wavelengths throughout the red and near IR spectrum, photosensitizers should preferably induce little or no more opacity to the tissue at the activating wavelength than Photofrin does, i.e. if the absorption coefficient is 20 times larger, it should be biologically effective at about 0.05 of the tissue level compared with Photofrin. Only a few photosensitizers appear to be able to meet this criterion. Among them is the hexyl ether derivative of methyl pheophorbide-a, which has an absorption coefficient at 658 run approximately ten times that of disaggregated Photofrin at 630 nm and produces a tumor response in the SMT-F mammary tumor in mice at tissue levels of about 0.1-0.067 that of Photofrin [7]. The purpurin SnET2 [8] and zinc phthalocyanine [91 may be similar. The greater challenge appears to be finding photosensitizers with not only advantageous optical characteristics, but also proper pharmacokinetics and photobleaching properties, about which we know essentially nothing.
1 J. D. Spikes, New trends in photobiology. Chlorins as photosensitizers in biology and medicine, J. Photochmz. Photobid. B: Bid., 6 (1990) 269-274. 2 B. C. Wilson, M. S. Patterson and D. M. Burns, Effect of photosensitizer concentration in tissue on the penetration depth of photoactivating light, Lasers in Med. Sci, 1 (1986) 235-244.
NEWSANDVIEWS
225
3 W. R. Potter, The theory of photodynamic dosimetry: consequences of photodestruction of sensitizer, Proc. SPZE, 712 (1986) 124-129. 4 S. G. Bown, C. J. Traulau, P. D. Coleridge Smith, D. Akdemir, T. J. Wieman, Photodynamic therapy with porphyrin and phthalocyanine sensitization - quantitative studies in normal rat liver, Br. J. Cancer, 54 (1986) 43-52. 5 W. S. Chan, J. F. Marshall, G. Y. F. Lam and I. R. Hart, Tissue uptake, distribution and patency of photoactivatable dye chloroahuninumsulfonated phthalocyaninein mice bearing transplantable tumors, Cancer Res., 48 (1988) 3040-3044. 6 S. Wan, R. R. Anderson and J. A. Parrish, Analytical modelling for the optical properties of the skin with in vitro and in vivo applications,Photochem. Photobid., 34 (1981) 493-499. 7 T. J. Dougherty and R. K. Pandey, unpublished results, 1990. 8 A. R. Morgan, G. M. Garbo, R. W. Keck and S. H. Sehnan, New photosensitizers for photodynamic therapy. Combined effects of metallopurpurinderivatives and light on transplantable bladder tumors, Cancer Res., 48 (1988) 194-198. 9 E. G. Reddi, R. B. LoCastro and G. Jori, Pharmacokineticstudiesof zinc(RI) - phthalocyanine in tumor-bearing mice, Br. .I Cancer, 56 (1987) 597-600.
223
4 R. W. Gsnge, A. D. Blackett, E. A. Matzinger, B. M. Sutherland and I. E. Kochevar, Comparative protection efficiency of UVA and WB-induced tans against erythema and formation of endonuclease-sensitivesites in DNA by UVB in humanskin,J. Invest. DennatoL, 85 (1985) 362-364. 5 B. L. Diffey, P. M. Farr and A. M. Oakley, Quantitative studies on UVA-induced erythema in human skin, Br. J. DermaioL, I17 (1987) 67-66. 6 P. M. Farr, J. M. Marks, B. L. Diffey and P. Ince, Skin fragility and blistering due to use of sunbeds, Br. Med. J., 296 (1988) 1708-1709. 7 S. K. Jones, H. Moseley and R. M. MacKie, WA-induced melsnocytic lesions, Br. J. DermutoL, I17 (1987) 111-115. 8 M. S. Devgun, B. E. Johnson and C. R. Paterson, Tanning, protection against sunburnand vitamin D formation with a W-A ‘sunbed’, Br. J. DermuZoL, I07 (1982) 275-284. 9 J. K. Rivers, P. G. Norris, G. M. Murphy, A. C. Chu, G. MidgIey et uI., UVA sunbeds: tanning,photoprotection, acute adverse effects and immunologicaIchanges& J. DermatoL, I20 (1989) 767-777. 10 P. M. Farr and B. L. Diffey, Adverse effects of sunscreens in photosensitive subjects, Lancet, i (1989) 429-431. 11 D. L. Bissett, D. P. Hannon and T. V. Orr, Wavelength dependence of histologicaL physical and visible changes in chronicalIy W-irradiated hairlessmouse skin,Photo&em. PhotobioL, 50 (1989) 763-769. 12 H. J. C. M. Sterenborg, Investigations on the action spectrum of tumorigenesisby ultraviolet radiation, Ph.D. Thesis, Utrecht, 1987. 13 L. Roza, R. A. Baan, J. C. van der Leun and L. Kligman, UVA hazards in skin associated with the use of tanning equipment, J. Photochem PhotobioL B: BioL, 3 (1989) 281-287. 14 H. J. C. M. Sterenborg and J. C. van der Leun, Tumorigenesis by a long wavelength UVA source, Photo&em. Photobiol., (1990) 325-330. 15 A. J. Swerdiow, J. S. C. English, R. M. Ma&e, C. J. O’Doherty, J. A. A. Hunter et al., Fluorescent lights, ultraviolet lamps, and risk of cutaneous melanoma, Br. Med. J., 297 (1988) 647-650. 16 A. J. Sober, Solar exposure in the etiology of cutaneous melanoma, Photodennatolo~, 4 (1987) 23-31. 17 B. W. Loggie and J. A. Eddy, Solar considerations in the development of cutaneous melanoma, Se&n. Chzcol., 15 (1988) 494-499.
Of what value is a highly absorbing photosensitizer
in PDT?
T. J. Dougherty and W. R. Potter Department of Radiation Medicine, RosweU Park Cancer Center, Elm and Carlton Streets, B@ii, IVY 14263-OOOI (U.S-4.j
An excellent recent review by Spikes [ 1] prompts us to emphasize a point previously made but perhaps not well appreciated regarding development of new photosensitizers for photodynamic therapy. In his article, Spikes states “HpD [haematoporphyrin derivative] absorbs poorly in the red region where tissue penetration by light is great. As a result, several other types of sensitizers have been examined that absorb more strongly and at longer wavelengths in the red, . . .“.
224
NEwsANDvIEws
A large extinction coefficient (i.e. stronger absorption relative to Photofrin at a given tissue level) can be a considerable detriment to achieving a greater depth of necrosis in PDT. It has been noted, first by Wilson et al. [2] and then by Potter [ 31, that sensitizers which produce significant additional absorption in tissue (tumors) can induce considerable opacity to such tissue and in fact completely negate (or worse) any advantage gained by their longer wavelength absorption compared with Photofrin. This point needs to be appreciated because many, if not most, of the newer photosensitizers being studied fit into this category; take, for example, the aluminum sulfonated phthalocyanine AlSPc reported by Bown et al. [4] and described by Wilson (21. As Wilson notes, for Photofrin in tissue at clinically relevant doses, space irradiance at even five attenuation lengths (lo-15 mm) for a typical tissue would be reduced by only about 5% beyond that of the tissue absorption itself. However, AlSPc, for whatever reasons, requires essentially the same tumor levels as does Photofrin in order to achieve any semblance of tumor control in spite of its approximately 20 times larger absorption coefficient [5]. This reduces the effective penetration depth at 675 nm by about 20% resulting in almost a 50% drop in space irradiance at five attenuation lengths compared with the dye-free tissue (in each case a “typical” inherent tissue absorption of lo- ’ mm- ’ was used for comparison, producing an effective penetration depth of about 2 mm, eg. bovine muscle [2]). Thus, while 675 nm light could increase the effective penetration depth by about 15-20% [ 61, this is completely negated by the need to use relatively high tissue levels of the sensitizer in order to achieve the desired photosensitization. In order to take advantage of the increased penetration depth in tissue at increasing wavelengths throughout the red and near IR spectrum, photosensitizers should preferably induce little or no more opacity to the tissue at the activating wavelength than Photofrin does, i.e. if the absorption coefficient is 20 times larger, it should be biologically effective at about 0.05 of the tissue level compared with Photofrin. Only a few photosensitizers appear to be able to meet this criterion. Among them is the hexyl ether derivative of methyl pheophorbide-a, which has an absorption coefficient at 658 run approximately ten times that of disaggregated Photofrin at 630 nm and produces a tumor response in the SMT-F mammary tumor in mice at tissue levels of about 0.1-0.067 that of Photofrin [7]. The purpurin SnET2 [8] and zinc phthalocyanine [91 may be similar. The greater challenge appears to be finding photosensitizers with not only advantageous optical characteristics, but also proper pharmacokinetics and photobleaching properties, about which we know essentially nothing.
1 J. D. Spikes, New trends in photobiology. Chlorins as photosensitizers in biology and medicine, J. Photochmz. Photobid. B: Bid., 6 (1990) 269-274. 2 B. C. Wilson, M. S. Patterson and D. M. Burns, Effect of photosensitizer concentration in tissue on the penetration depth of photoactivating light, Lasers in Med. Sci, 1 (1986) 235-244.
NEWSANDVIEWS
225
3 W. R. Potter, The theory of photodynamic dosimetry: consequences of photodestruction of sensitizer, Proc. SPZE, 712 (1986) 124-129. 4 S. G. Bown, C. J. Traulau, P. D. Coleridge Smith, D. Akdemir, T. J. Wieman, Photodynamic therapy with porphyrin and phthalocyanine sensitization - quantitative studies in normal rat liver, Br. J. Cancer, 54 (1986) 43-52. 5 W. S. Chan, J. F. Marshall, G. Y. F. Lam and I. R. Hart, Tissue uptake, distribution and patency of photoactivatable dye chloroahuninumsulfonated phthalocyaninein mice bearing transplantable tumors, Cancer Res., 48 (1988) 3040-3044. 6 S. Wan, R. R. Anderson and J. A. Parrish, Analytical modelling for the optical properties of the skin with in vitro and in vivo applications,Photochem. Photobid., 34 (1981) 493-499. 7 T. J. Dougherty and R. K. Pandey, unpublished results, 1990. 8 A. R. Morgan, G. M. Garbo, R. W. Keck and S. H. Sehnan, New photosensitizers for photodynamic therapy. Combined effects of metallopurpurinderivatives and light on transplantable bladder tumors, Cancer Res., 48 (1988) 194-198. 9 E. G. Reddi, R. B. LoCastro and G. Jori, Pharmacokineticstudiesof zinc(RI) - phthalocyanine in tumor-bearing mice, Br. .I Cancer, 56 (1987) 597-600.
