title: Overcoming of multidrug resistance by VA-033, a novel derivative of apovincaminic acid ester.
abstract: We have studied the effects of a novel derivative of apovincaminic acid ester, VA-033, on the resistance of tumors to chemotherapeutic agents. VA-033 increased the sensitivity of drug-resistant cell lines (P388/VCR, P388/ADM, AD10, and K562/ADM) to adriamycin or vincristine. The potency of VA-033 was stronger than verapamil. The drug lengthened the survival time of the P388/VCR-implanted mice treated with vincristine. VA-033 increased the intracellular accumulation of vincristine in the tumor cells, and the photolabeling of P-glycoprotein by [3H]azidopine was inhibited by VA-033. VA-033 showed a slight inhibitory effect on the L-type Ca2+ current in the ventricular myocytes, and had less effect on the cardiovascular parameters such as blood pressure, contractile force and atrio-ventricular conduction time than verapamil when administered systemically in the dog. These results suggest that VA-033 may become a beneficial compound as a modifier to the neoplastic cell resistant to multidrugs.
authors.affiliation: Research Center, Taisho Pharmaceutical Co., Ltd., Ohmiya, Saitama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nanaumi
authors.forename: K
authors.initials: K
authors.lastname: Tsuchida
authors.forename: S
authors.initials: S
authors.lastname: Nakaike
authors.forename: T
authors.initials: T
authors.lastname: Yamagishi
authors.forename: T
authors.initials: T
authors.lastname: Ichihara
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Watajima
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Naito
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D019337:Hematologic Neoplasms / Q000188:drug therapy; D007941:Leukemia P388; D051379:Mice; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
chemical_list: C107224:VA 033; D014748:Vinca Alkaloids; D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil