Circumvention of P-glycoprotein-mediated multidrug resistance by S16020-2: kinetics of uptake and efflux in sensitive and resistant cell lines.
OBJECTIVE
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.
Pierré
A
A
Institut de Recherches Servier, Division de Cancérologie Expérimentale, Suresnes, France.
Léonce
S
S
Pérez
V
V
Atassi
G
G
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D002455:Cell Division / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004611:Ellipticines / Q000494:pharmacology*; D007941:Leukemia P388 / Q000378:metabolism / Q000473:pathology; D051379:Mice; D014316:Tritium; D014407:Tumor Cells, Cultured
D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D002250:Carbon Radioisotopes; D004611:Ellipticines; C101591:S 16020-2; D014316:Tritium