In vitro anti-multidrug resistance activities of acyclic and cyclic disulfonamides in murine leukemia cells.
We synthesized seven acyclic ethylenedisulfonamides and twelve cyclic disulfonamides, 1, 5-bis(arenesulfonyl)-1, 3, 5-triazacycloheptanes, and compared their in vitro anti-multidrug resistance effects in P388/ADR multidrug-resistant cells which overexpress the multidrug transporter P-glycoprotein (P-gp). Acyclic disulfonamides with 4-methoxyphenyl, pyridyl, quinolyl, or isoquinolyl groups hardly influenced the sensitivity of P388/ADR cells to vinblastine (VLB), and cyclic disulfonamides with these aryl groups only slightly increased the sensitivity to VLB. Acyclic or cyclic disulfonamides with 4-chlorophenyl or naphthyl groups moderately potentiated the effect of VLB. The maximum effect was observed with 1, 5-bis(1-naphthale-nesulfonyl)-1, 3, 5-triazacycloheptan (B3). B3 enhanced the effects of vincristine, adriamycin, daunomycin and actinomycin D in P388/ADR cells, but not in sensitive P388 cells. B3 increased intracellular concentrations of VLB and adriamycin in P388/ADR cells. The expression of P-gp in P388/ADR cells was not affected by cultivation with B3 for 72 hours. These results indicated that the anti-multidrug resistance activities of B3 were dependent on its inhibitory effect on P-gp.
Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Japan.
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Wakusawa
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Sawanishi
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Hayashi
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology; D003508:Cycloheptanes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005030:Ethylenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D003508:Cycloheptanes; D005030:Ethylenes; D013449:Sulfonamides; D014747:Vinblastine