PHOTODYNAMIC THERAPY OF B16F10 MURINE MELANOMA WITH LUTETIUM TEXAPHYRIN

Photodynamic therapy (PDT) of pigmented melanoma has generally been un successful because of insufficient light penetration in such tissues. In this study, the responsiveness of the heavily pigmented B16F10 muri ne melanoma to lutetium texaphyrin (PCI-0123), a water-soluble sensiti zer with strong absorbance in the near infrared (700-760 nm), was exam ined. These studies were carried out in both normal and ApoE deficient C57BL/6 mice. The latter strain exhibits a lipoprotein profile more l ike humans (low density lipoprotein > high density lipoprotein) than r odents thigh density lipo-Protein much greater than low density lipopr otein). Under optimal conditions of drug dose, Light dose, and interva l between drug administration and irradiation - the median survival ti me of C57BL/6 tumor bearing mice was approximately doubled (29 d) comp ared with tumor bearing control animals (13 d). The life-span of the A poE knockout mice was greater (33 d) than the C57BL/6 animals (23 d) w hen irradiation occurred 3 h after administration of a 10 mu mol per k g drug dose. The greater efficacy of PDT in the ApoE deficient mice wa s associated with more rapid clearance of drug from the blood, greater accumulation of sensitizer in tumor tissue, and substantially greater drug binding to the very low density lipoprotein/low density lipoprot ein plasma fraction. Confocal laser scanning microscopy showed that th e predominant subcellular site of photosensitizer binding was to melan osomes; costaining was performed with Mel-5. Melanosomes are susceptib le to oxidative stress. Photooxidation, mediated by PCI-0123 PDT, coul d potentially overload an already highly oxidized stressed state leadi ng to cell death. The good tissue penetration depth achieved by PCI-02 13 mediated PDT and the activation of melanosomes makes PDT of pigment ed melanoma, for the first time, clinically relevant.