PHTHALOCYANINE PHOTODYNAMIC THERAPY - DISPARATE EFFECTS OF PHARMACOLOGICAL INHIBITORS ON CUTANEOUS PHOTOSENSITIVITY AND ON TUMOR-REGRESSION

The phthalocyanines are promising second-generation photosensitizers t hat are being evaluated for the photodynamic therapy (PDT) of malignan t tumors, In vivo studies with the silicon phthalocyanine Pc 4 have sh own that it is highly effective at causing regression of RIF-1 tumors in C3H/HeN mice in PDT protocols, Because cutaneous photosensitivity i s the major complication of photosensitizers used for PDT, experiments were performed to evaluate the effect of inhibitors of the inflammato ry response (cyproheptadine, dexamethasone, pentoxifylline, and tumor necrosis factor alpha [TNF-alpha] antibodies) on Pc 4-induced cutaneou s photosensitivity and tumor regression, The C3H/HeN mice were injecte d with either Pc 4 or Photofrin and were exposed to 86 J/cm(2) of filt ered radiation emitted from a solar simulator, Animals were irradiated at 1, 3, 7, 10, 14 and 28 days postinjection, Cutaneous photosensitiv ity was assessed using the murine ear-swelling response. Cyproheptadin e, dexamethasone, pentoxifylline and TNF-alpha antibodies were adminis tered prior to illumination to assess their ability to block Pc 4-indu ced cutaneous photosensitivity and to evaluate,whether such treatment adversely influenced Pc 4 PDT-induced tumor regression, Compared to Ph otofrin, Pc 4 produced cutaneous photosensitivity that was transient, resolving within 24 h, and that could be elicited for only 10 days aft er administration, In contrast, Photofrin caused photosensitivity that required 4 days to resolve and could be elicited for at least 1 month after it was administered, The Pc 4-induced cutaneous photosensitivit y could be blocked by corticosteroids and an inhibitor of vasoactive a mines (cyproheptadine), The TNF-or gene transcription was found to inc rease in keratinocytes following treatment with Pc 4 and light, The an ti-TNF-a antibodies and pentoxifylline, an inhibitor of cytokine trans cription, also prevented cutaneous photosensitivity, implicating TNF-a lpha in the pathogenesis of Pc 4-induced cutaneous photosensitivity. N one of these agents had any effect on Pc 4 PDT-induced tumor regressio n, Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibod ies may be valuable pharmacologic agents in the management of cutaneou s photosensitivity associated with PDT without altering the efficacy o f this new therapeutic modality, The findings suggest that it should b e possible to devise PDT protocols that block cutaneous photosensitivi ty without impairing the anti-tumor response to the agents.