Abstract
Purpose: In contrast to Adriamycin (ADR), the novel olivacine derivative S16020-2 has demonstrated potent antitumor activity in vitro and in vivo against cell lines displaying the P-glycoprotein (Pgp)-mediated multidrug-resistance phenotype (MDR), suggesting that this compound is not transported by Pgp. The purpose of this work was to study the accumulation of S16020-2 in Pgp-overexpressing cells. Methods: The kinetics of accumulation and retention of radiolabeled S16020-2 and ADR in sensitive KB-3-1, P388, and S1 cells and their resistant counterparts KB-A1, P388/VCR-20, and S1/tMDR cells were investigated. Results: The rates of efflux of S16020-2 and ADR were similar and were higher in KB-A1 cells than in KB-3-1 cells. A modulator of MDR, S9788, inhibited the efflux of both compounds only in KB-A1 cells. These results demonstrate that S16020-2 is effectively transported by Pgp overexpressed by KB-A1 cells with an efficiency close to that of ADR. A similar conclusion was obtained with the P388/VCR-20 cell line. In addition, the initial rate of uptake and the accumulation of S16020-2 were markedly higher than those of ADR in the cell lines tested. Conclusions: The cytotoxic potency of S16020-2 toward tumor cells overexpressing Pgp is thus likely to be due to its rapid rate of uptake, which bypasses Pgp and thus leads to a high cellular accumulation.
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Received: 16 March 1998 / Accepted: 2 June 1998
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Pierré, A., Léonce, S., Pérez, V. et al. Circumvention of P-glycoprotein-mediated multidrug resistance by S16020-2: kinetics of uptake and efflux in sensitive and resistant cell lines. Cancer Chemother Pharmacol 42, 454–460 (1998). https://doi.org/10.1007/s002800050845
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DOI: https://doi.org/10.1007/s002800050845