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The difference in the effectiveness of Vincristine and Vindesine against B16 melanoma proliferation was examined by treating the tumor tissue in vitro prior to subcutaneous implantation in adult mice and by treating cells in culture with the drugs. Vindesine caused greater inhibition of tumor growth than Vincristine when the tumor tissue was incubated with 50 microM drugs for 2 h prior to implantation. At nanomolar concentrations Vindesine retarded the proliferation of cells in culture to a greater extent than Vincristine. The greater effectiveness of Vindesine was also observed when cells were incubated with micromolar concentrations of the drugs followed by removal and recovery of the cell growth in vitro or in mice. The rate of drug uptake and amount of drug retained by either tumor pieces or cells in culture were similar for both Vinca alkaloids. It appears, therefore, that differences in drug uptake and retention by the tumor cells do not explain the greater effectiveness of Vindesine in inhibiting the proliferation of B16 melanoma cells.