Photodynamic therapy of B16F10 murine melanoma with lutetium texaphyrin.
Photodynamic therapy (PDT) of pigmented melanoma has generally been unsuccessful because of insufficient light penetration in such tissues. In this study, the responsiveness of the heavily pigmented B16F10 murine melanoma to lutetium texaphyrin (PCI-0123), a water-soluble sensitizer with strong absorbance in the near infrared (700-760 nm), was examined. These studies were carried out in both normal and ApoE deficient C57BL/6 mice. The latter strain exhibits a lipoprotein profile more like humans (low density lipoprotein > high density lipoprotein) than rodents (high density lipoprotein >> low density lipoprotein). Under optimal conditions of drug dose, light dose, and interval between drug administration and irradiation--the median survival time of C57BL/6 tumor bearing mice was approximately doubled (29 d) compared with tumor bearing control animals (13 d). The life-span of the ApoE knockout mice was greater (33 d) than the C57BL/6 animals (23 d) when irradiation occurred 3 h after administration of a 10 micromol per kg drug dose. The greater efficacy of PDT in the ApoE deficient mice was 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 lipoprotein plasma fraction. Confocal laser scanning microscopy showed that the predominant subcellular site of photosensitizer binding was to melanosomes; costaining was performed with Mel-5. Melanosomes are susceptible to oxidative stress. Photo-oxidation, mediated by PCI-0123 PDT, could potentially overload an already highly oxidized stressed state leading to cell death. The good tissue penetration depth achieved by PCI-0213 mediated PDT and the activation of melanosomes makes PDT of pigmented melanoma, for the first time, clinically relevant.
Woodburn
K W
KW
Pharmacyclics, Inc., Sunnyvale, California, USA.
Fan
Q
Q
Kessel
D
D
Luo
Y
Y
Young
S W
SW
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D005260:Female; D008136:Longevity / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008665:Metalloporphyrins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution
D001057:Apolipoproteins E; D001798:Blood Proteins; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; C102825:motexafin lutetium; C437683:motexafin gadolinium