Malignant melanoma are chemoresistant tumors with poor prognosis. The aim of this study was to determine whether multimodality therapy of murine melanoma involving a combination of radiation with thermosen-sitive-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° 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°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-entrap-ped 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.
Thermosensitive liposomes prepared from synthetic lipids such as dipalmitoyl phosphatidylcholine, distearoyl phosphatidyl choline and cholesterol (Ch) have been tried for local drug release in response to hyperthermia for achieving tumour drug targeting. Herein we report a novel method of preparation of temperature-sensitive liposomes using natural lipids egg phosphatidylcholine (PC):Ch (7:1 molar ratio) and ethanol 6% (v/v) having a transition temperature of 43 degrees C, temperature attainable by local hyperthermic treatment of tumours. The anticancer drug decarbazine [5-(3,3'-dimethyl-1-triazino) imidazole-4-carboxamide] was entrapped in these liposomes. The in vivo efficacy of temperature-sensitive unilamellar vesicles encapsulated decarbazine in combination with hyperthermia was determined in murine fibrosarcomas. These PC:Ch liposomes are biodegradable, non-toxic and more cost effective in comparison with liposomes prepared from synthetic lipids for use in multimodality cancer therapy.
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