Phthalocyanine Photodynamic Therapy: Disparate Effects of Pharmacologic Inhibitors on Cutaneous Photosensitivity and on Tumor Regression

Abstract

The phthalocyanines are promising second-generation photosensitizers that are being evaluated for the photodynamic therapy (PDT) of malignant tumors. In vivo studies with the silicon phthalocyanine Pc 4 have shown that it is highly effective at causing regression of RIF-1 tumors in C3H/HeN mice in PDT protocols. Because cutaneous photosensitivity is the major complication of photosensitizers used for PDT, experiments were performed to evaluate the effect of inhibitors of the inflammatory response (cyproheptadine, dexamethasone, pentoxifylline, and tumor necrosis factor alpha [TNF-alpha] antibodies) on Pc 4-induced cutaneous photosensitivity and tumor regression. The C3H/HeN mice were injected with either Pc 4 or Photofrin and were exposed to 86 J/cm2 of filtered radiation emitted from a solar simulator. Animals were irradiated at 1, 3, 7, 10, 14 and 28 days postinjection. Cutaneous photosensitivity was assessed using the murine ear-swelling response. Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibodies were administered prior to illumination to assess their ability to block Pc 4-induced cutaneous photosensitivity and to evaluate whether such treatment adversely influenced Pc 4 PDT-induced tumor regression. Compared to Photofrin, Pc 4 produced cutaneous photosensitivity that was transient, resolving within 24 h, and that could be elicited for only 10 days after 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 photosensitivity could be blocked by corticosteroids and an inhibitor of vasoactive amines (cyproheptadine). The TNF-alpha gene transcription was found to increase in keratinocytes following treatment with Pc 4 and light. The anti-TNF-alpha antibodies and pentoxifylline, an inhibitor of cytokine transcription, also prevented cutaneous photosensitivity, implicating TNF-alpha in the pathogenesis of Pc 4-induced cutaneous photosensitivity. None of these agents had any effect on Pc 4 PDT-induced tumor regression. Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibodies may be valuable pharmacologic agents in the management of cutaneous photosensitivity associated with PDT without altering the efficacy of this new therapeutic modality. The findings suggest that it should be possible to devise PDT protocols that block cutaneous photosensitivity without impairing the anti-tumor response to the agents.

Intracellular signaling mechanisms in photodynamic therapy

“…Accordingly, TNF-a gene transcription increased in keratinocytes sensitized with Pc 4 [258], and thioglycolateelicited murine macrophages released TNF when subjected to PDT with Photofrin II [259]. Photodynamic activation of the monocyte cell line U937 differentiated into macrophages (U937A cells) with mTHPC (FoscanR) also induced a dosedependent production of TNF-a [167].…”

“…Photodynamic activation of the monocyte cell line U937 differentiated into macrophages (U937A cells) with mTHPC (FoscanR) also induced a dosedependent production of TNF-a [167]. However, although anti-TNF-a antibodies and pentoxifylline, an inhibitor of cytokine transcription, prevented cutaneous photosensitivity in adult C3H/HeN mice injected with Pc 4, none of these agents affected Pc 4 PDT-induced tumor (RIF-1 radiationinduced fibrosarcoma) regression [258].…”

Photodynamic therapy for superficial bladder cancer under local anaesthetic

“…indomethacin) have been shown to reduce the cytotoxicity of PDT [30]. However, in contrast, a recent study in mice evaluating dexamethasone in conjunction with PDT reported fewer adverse effects for PDT, with unaffected cytotoxicity [31]. Further work is required to evaluate the potential of such adjuvant treatments in combination with clinical ALA PDT.…”

Expression of IL-10, TGF-β1and TNF-α in Cultured Keratinocytes (HaCaT Cells) after IPL Treatment or ALA-IPL Photodynamic Treatment

“…It is an important mediator of cutaneous inflammation and is produced by keratinocytes after stimulation, such as with UV light. In previous studies, TNF-α gene transcription was found to increase in the keratinocytes of mice treated with phthalocyanine and light 13 , and the expression of TNF-α protein was reported to increase up to 2.3-fold in cultured keratinocytes treated with sublethal doses of ALA and red light 5 .…”