Anderson C, Hrabovsky S, McKinley Y, Tubesing K, Tang H P, Dunbar R, Mukhtar H, Elmets C A
Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.
Photochem Photobiol. 1997 May;65(5):895-901. doi: 10.1111/j.1751-1097.1997.tb01940.x.
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.
酞菁类是很有前景的第二代光敏剂，目前正用于恶性肿瘤的光动力疗法（PDT）评估。对硅酞菁Pc 4进行的体内研究表明，在PDT方案中，它能非常有效地使C3H/HeN小鼠体内的RIF-1肿瘤消退。由于皮肤光敏性是用于PDT的光敏剂的主要并发症，因此开展了实验来评估炎症反应抑制剂（赛庚啶、地塞米松、己酮可可碱和肿瘤坏死因子α [TNF-α]抗体）对Pc 4诱导的皮肤光敏性和肿瘤消退的影响。给C3H/HeN小鼠注射Pc 4或卟吩姆钠，然后使其暴露于太阳模拟器发出的86 J/cm2的滤过辐射下。在注射后第1、3、7、10、14和28天对动物进行照射。使用小鼠耳部肿胀反应评估皮肤光敏性。在光照前给予赛庚啶、地塞米松、己酮可可碱和TNF-α抗体，以评估它们阻断Pc 4诱导的皮肤光敏性的能力，并评估这种治疗是否会对Pc 4 PDT诱导的肿瘤消退产生不利影响。与卟吩姆钠相比，Pc 4产生的皮肤光敏性是短暂的，在24小时内消退，并且在给药后仅10天内可引发。相比之下，卟吩姆钠引起的光敏性需要4天才能消退，并且在给药后至少1个月内可引发。Pc 4诱导的皮肤光敏性可被皮质类固醇和血管活性胺抑制剂（赛庚啶）阻断。在用Pc 4和光照处理后，发现角质形成细胞中的TNF-α基因转录增加。抗TNF-α抗体和细胞因子转录抑制剂己酮可可碱也可预防皮肤光敏性，这表明TNF-α参与了Pc 4诱导的皮肤光敏性的发病机制。这些药物均对Pc 4 PDT诱导的肿瘤消退没有任何影响。赛庚啶、地塞米松、己酮可可碱和TNF-α抗体可能是治疗与PDT相关的皮肤光敏性的有价值的药物，而不会改变这种新治疗方式的疗效。这些发现表明，应该有可能设计出在不损害药物抗肿瘤反应的情况下阻断皮肤光敏性的PDT方案。
