Clinical and preclinical pharmacology of liposomal vincristine

Vincristine is one of the most commonly administered anticancer drugs and i s active in a wide range of indications including non-Hodgkin's lymphomas, acute lymphocytic leukemias and lung cancer. Administration of vincristine in long-circulating liposomes may be expected to result in increased accumu lation of drug at tumor sites due to ''passive targeting'' or ''disease-sit e targeting'' effects arising from the more permeable vasculature in these regions. Further, for liposomes with appropriate drug release characteristi cs, extended exposure of tumor cells to vincristine would result from lipos omal delivery. The combination of increased drug delivery and extended dura tion of drug exposure may be expected to result in increased efficacy, part icularly because vincristine is a cell-cycle specific drug. It is shown tha t vincristine can be encapsulated in large unilamellar vesicles (diameter s imilar to 100 nm) using a pH gradient (interior acidic) approach. Further, the efficacy of liposomal formulations of vincristine in animal models is h ighly sensitive to the drug release rate in vivo. A liposomal formulation w ith drug retention characteristics such that more than 50% of the vincristi ne is retained in the carrier 24 h following i.v. injection exhibits signif icantly improved antitumor efficacy in A431 xenograft and P388 murine tumor models in comparison to either free drug or leakier liposomal formulations . The clinical activity of liposomal vincristine has been investigated in r elapsed or refractory non-Hodgkin's lymphoma patients at a dose level of 2 mg/m(2) every two weeks. Of 83 registered patients, there were 24 responses in 68 evaluable patients. The responses according to histology are: Indole nt-13%; Transformed-42%; Aggressive-45%. There were no serious cases of mye losuppression or any toxic deaths. It is concluded that liposomal vincristi ne can be given at high doses, is active and well tolerated and is rarely n eurotoxic or myelosuppressive in these heavily pretreated patients. It appe ars that the benefits of low toxicity and enhanced efficacy noted in the tu mor models are also observed in the clinical setting. A multicenter pivotal Phase II trial of liposomal vincristine in relapsed and refractory non-Hod gkin's lymphoma has been approved by the US FDA and is ongoing.