Suppression of replication of multidrug-resistant HIV type 1 variants by combinations of thymidylate synthase inhibitors with zidovudine or stavudine

作     者：Gao, WY Johns, DG Tanaka, M Mitsuya, H 

作者机构：NCI Expt Retrovirol Sect Med Branch Div Clin SciNIH Bethesda MD 20892 USA NCI Med Chem Lab Div Basic Sci NIH Bethesda MD 20892 USA 

出 版 物：《MOLECULAR PHARMACOLOGY》 (分子药理学)

年 卷 期：1999年第55卷第3期

页      面：535-540页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：抗HIV药/药理学 抗代谢药/药理学 药物相互作用 抗药性 微生物 抗药性 多药 氟尿苷/药理学 氟尿嘧啶/药理学 HIV-1/药物作用 HIV-1/分离和提纯 突变 逆转录酶抑制剂/药理学 司他夫定/药理学 胸苷酸合酶/拮抗剂和抑制剂 胸腺嘧啶核苷酸类/代谢 病毒复制/药物作用 齐多夫定/药理学 人类 

摘      要：The replication of recombinant multidrug-resistant HIV-I clones modeled on clinically derived resistant HIV-I strains from patients receiving long-term combination therapy with zidovudine (AZT) plus 2 ,3 -dideoxycytidine was found to regain sensitivity to AZT and stavudine (D4T) as a consequence of a pharmacologically induced decrease in de novo dTMP synthesis. The host-cell system used was phytohemagglutinin-stimulated peripheral blood mononuclear cells;dTMP and dTTP depletion were induced by single exposures to a low level of the thymidylate synthase inhibitor 5-fluorouracil (5-FU) or its deoxynucleoside, 2 -deoxy-5-fluorouridine. The host-cell response to the latter was biphasic: a very rapid decrease in the rate of de novo dTMP formation and, consequently, in intracellular dTTP pools, followed by slower recovery in both indices over 3 to 24 h. With the additional presence of AZT or D4T, however, replication of the multidrug-resistant HIV-I strains remained inhibited, indicating dependence of HIV DNA chain termination by AZT-5 -monophosphate or 2 ,3 -didehydro-2 ,3 -dideoxythymidine-5 -monphosphate in these resistant strains on simultaneous inhibition of host-cell de novo synthesis of thymidine nucleotides. No effect on viability of control (uninfected) phytohemagglutinin-stimulated/peripheral blood mononuclear cells was noted on 6-day exposures to 5-FU or 2 -deoxy-5-fluorouridine alone or in combination with AZT or D4T, even at drug levels severalfold higher than those used in the viral inhibition studies. These studies may provide useful information for the potential clinical use of AZT/5-FU or D4T/5-FU combinations for the prevention or reversal of multidrug resistance associated with long-term dideoxynucleoside combination therapy.