Zhu Q Y, Scarborough A, Polsky B, Chou T C
Molecular Pharmacology and Therapeutics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
AIDS Res Hum Retroviruses. 1996 Apr 10;12(6):507-17. doi: 10.1089/aid.1996.12.507.
Reference strains of HIV-1 from the NIH AIDS Research and Reference Reagent Program, including wild-type IIIB, G762-3, and AZT resistant with RT 215T-->Y (G910-11/AZT); 67D-->N, 70K-->R, 215T-->F, 219K-->Q (G691-2/AZT); as well as nevirapine (NEV) resistant with 181Y-->C (N119/NEV); and 103K-->N, 181Y-->C (A17/NEV), were subjected to quantitative parametric efficacy analysis using AZT, stavudine (D4T), and nevirapine (NEV) singly or in combinations in MT4 or MT2 cells. The median-effect principle and combination index (CI) method of Chou-Talalay (see Ref. 26) have been used, which take into account both the potency (Dm value or EC50) and the shape of the dose-effect curve (m value). Under standardized assay conditions, G910-11 and G691-2 strains showed 600- and 7800-fold resistance to AZT, and N119 and A17 strains showed 3600- and 1000-fold resistance to NEV at the EC50 level, respectively. AZT-resistant strains exhibited slight cross-resistance to D4T. Computerized analysis indicates that IIIB gave sigmoidal dose-effect curves (m = 2.8, 3.4, and 3.1 for AZT, D4T, and NEV, respectively) whereas drug-resistant strains showed negative sigmoidicity toward the corresponding AZT or NEV, with m = 0.27-0.73. Therefore, the degrees of drug resistance are drastically different at classic EC50 and at therapeutically more relevant EC95 levels (ranging from severalfold to several log orders). Combinations of AZT+NEV and AZT+NEV+D4T showed synergism against IIIB, G762-3 (wild type) and A17/NEV, G910-11/AZT strains. D4T+NEV and AZT+D4T showed nearly additive or moderate antagonism. Synergism or additive effect leads to a favorable dose-reduction index (DRI). The present study on RT inhibitors provides quantitative assessment of the combinations of AZT, NEV, and D4T against HIV infections involving drug-sensitive and drug-resistant HIVs.
来自美国国立卫生研究院艾滋病研究和参比试剂项目的HIV-1参比毒株，包括野生型IIIB、G762-3，以及对AZT耐药（RT 215T→Y，即G910-11/AZT）；67D→N、70K→R、215T→F、219K→Q（即G691-2/AZT）的毒株；还有对奈韦拉平（NEV）耐药（181Y→C，即N119/NEV）；以及103K→N、181Y→C（即A17/NEV）的毒株，在MT4或MT2细胞中单独或联合使用AZT、司他夫定（D4T）和奈韦拉平（NEV）进行定量参数疗效分析。采用了Chou-Talalay的中位效应原理和联合指数（CI）方法（见参考文献26），该方法同时考虑了效力（Dm值或EC50）和剂量效应曲线的形状（m值）。在标准化检测条件下，G910-11和G691-2毒株在EC50水平对AZT分别表现出600倍和7800倍的耐药性，N119和A17毒株在EC50水平对NEV分别表现出3600倍和1000倍的耐药性。AZT耐药毒株对D4T表现出轻微的交叉耐药性。计算机分析表明，IIIB呈现S形剂量效应曲线（AZT、D4T和NEV的m值分别为2.8、3.4和3.1），而耐药毒株对相应的AZT或NEV呈现负S形，m值为0.27 - 0.73。因此，在经典的EC50和治疗上更相关的EC95水平，耐药程度差异极大（从几倍到几个对数级）。AZT + NEV以及AZT + NEV + D4T联合用药对IIIB、G762-3（野生型）和A17/NEV、G910-11/AZT毒株表现出协同作用。D4T + NEV以及AZT + D4T表现出近乎相加或中度拮抗作用。协同作用或相加效应导致有利的剂量降低指数（DRI）。本项关于逆转录酶抑制剂的研究对AZT、NEV和D4T联合用药针对涉及药物敏感和耐药HIV的HIV感染情况进行了定量评估。
