Antitumour Effects and Pharmacokinetics of Combination of Vinblastine with a Staurosporine Derivative, NA-382, in P388/ADR-bearing Mice

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Abstract
The effects of a staurosporine derivative, N‐ethoxycarbonyl‐7‐oxostaurosporine (NA‐382), on the pharmacokinetics of vinblastine were evaluated, compared with those of verapamil, in multidrug‐resistant P388/ADR‐bearing mice. At first, the in‐vitro experiments indicated that NA‐382 permeated into the cells better and were more effective in combined cytotoxicity with vinblastine and on accumulation of vinblastine than with verapamil in P388/ADR cells. In combined intraperitoneal injection with vinblastine (200 μ kg−1) into P388/ADR‐bearing mice, NA‐382 in a suspension form (10 mg kg−1) prolonged the life‐span of the mice near to that of P388/S‐bearing mice treated with vinblastine alone, but verapamil even at the maximum tolerated dosage (30 mg kg−1) barely affected the in‐vivo antitumour effect of vinblastine. When simultaneously administered with vinblastine to P388/ADR‐bearing mice, NA‐382 maintained significantly higher vinblastine levels in the tumour cells for 24 h and gave a larger area under the time‐intracellular vinblastine concentration curve (0 to 24 h) than those receiving vinblastine alone, with long retention of the agent in ascitic fluid. Verapamil increased the cellular vinblastine content for only 6 h, accompanying a rapid elimination of the agent from the ascitic fluid. This study indicates that NA‐382 is more effective against multidrug‐resistance than verapamil, and its suspension is also advantageous for cancer chemotherapy of multidrug‐resistant tumours.