ISSN:
1432-0843
Keywords:
Key words Accumulation
;
Adriamycin
;
Efflux
;
MDR
;
P-glycoprotein
;
S16020-2 uptake
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s002800050845
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