Hyperthermia potentiates antitumor effect of thermosensitive-liposome-encapsulated melphalan and radiation in murine melanoma.

Malignant melanoma are chemoresistent tumors with poor prognosis. The aim of this study was to determine whether multimodality therapy of murine melanoma involving a combination of radiation with thermosensitive-liposome-encapsulated melphalan and local hyperthermia would result in enhancement of therapeutic efficacy for a more effective management of melanoma. Melphalan was entrapped in thermosensitive liposomes prepared from natural lipids: egg phosphatidyl choline, cholesterol and ethanol to show phase transition at 42 +/- 0.5 degrees C and used in combination with localized heating of B16F10 murine melanoma transplanted into the legs of C57B1/6 mice for selective drug targeting at the tumors and/or radiation for treatment of melanoma. Murine melanoma transplanted into C57B1/6 mice were subjected to bimodality treatments involving a combination of radiation, hyperthermia or melphalan. Partial tumor regression was observed in mice receiving a combination of hyperthermia and radiation (median tumor volume 427.3 mm3) or a combination of free melphalan and radiation (512.1 mm3) as compared to untreated controls (630.9 mm3). Each group consisted of 18 animals, and the results are expressed as median tumor volume +/- SD. Animals receiving multimodality therapy comprising irradiation followed by injection of thermosensitive liposomal melphalan and hyperthermic treatment of the tumor-bearing leg at 42 +/- 0.5 degrees C for 1 h showed marked tumor regression in comparison with untreated controls or animals treated with a combination of radiation and hyperthermia or radiation and free-drug melphalan. Animals receiving thermoradiochemotherapy also showed prolonged survival; 70% of animals survived for more than 3 months. The study shows greater tumor cell killing, tumor growth delay and prolonged survival produced by a combination of radiation, thermosensitive-liposome-entrapped melphalan and hyperthermia compared with animals receiving single-modality or bimodality treatments. It is concluded that this multimodality approach will be potentially useful for more effective management of melanoma.