Schinazi R F, Sommadossi J P, Saalmann V, Cannon D L, Xie M Y, Hart G C, Smith G A, Hahn E F
Veterans Affairs Medical Center, Decatur, Georgia 30033.
Antimicrob Agents Chemother. 1990 Jun;34(6):1061-7. doi: 10.1128/AAC.34.6.1061.
The relative antiviral potencies of five nucleotide heterodimers of 3'-azido-3'-deoxythymidine (AZT), 3'-azido-3'-deoxythymidilyl-(5',5')-2'-3'-dideoxy-5'-adenylic acid (AZT-P-ddA), 3'-azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-inosinic acid (AZT-P-ddI), and the corresponding 2-cyanoethyl congeners AZT-P(CyE)-ddA and AZT-P(CyE)-ddI, were determined in primary human peripheral blood mononuclear cells infected with human immunodeficiency virus type 1. The homodimer 3'-azido-3'-deoxythymidilyl-(5',5')-3'-azido-3'-deoxythymidilic acid (AZT-P-AZT) was also included for comparison. The potencies of the compounds were AZT-P-ddA greater than or equal to AZT-P-ddI greater than AZT-P(CyE)-ddA greater than or equal to AZT-P(CyE)-ddI greater than or equal to AZT greater than AZT-P-AZT. Whereas AZT-P-ddA and AZT-P-ddI had in vitro therapeutic indices greater than that of AZT, the homodimer of AZT had a low therapeutic index. AZT-P-ddI exhibited the lowest toxicity in peripheral blood mononuclear, Vero, or CEM cells. Combination studies between AZT and 2',3'-dideoxyinosine (ddI) at nontoxic concentrations indicated a synergistic interaction at a drug ratio of 1:100. At higher ratios (1:500 and 1:1,000), the interactions were synergistic only at concentrations that produced up to 75% virus inhibition. At higher levels of antiviral effects, this combination was antagonistic, as determined by the multiple drug effect analysis method. AZT-P-ddI was about 10-fold less toxic than AZT to human granulocyte-macrophage progenitor cells. However, no significant difference was apparent when the compounds were evaluated against cells of the erythroid lineage. The greater antiviral activity and lower toxicity of this compound could not be attributed to the extracellular decomposition of the dimer in media at physiological temperature and pH. However, in acidic solutions, AZT-P-ddI decomposed in a pH-dependent manner. Advanced preclinical studies with this heterodimer of two clinically effective antiretroviral agents should be considered.
测定了3'-叠氮基-3'-脱氧胸苷（AZT）的五种核苷酸异二聚体，即3'-叠氮基-3'-脱氧胸苷酰基-(5',5')-2'-3'-二脱氧-5'-腺苷酸（AZT-P-ddA）、3'-叠氮基-3'-脱氧胸苷酰基-(5',5')-2',3'-二脱氧-5'-肌苷酸（AZT-P-ddI）以及相应的2-氰基乙基类似物AZT-P(CyE)-ddA和AZT-P(CyE)-ddI，在感染人免疫缺陷病毒1型的原代人外周血单核细胞中的相对抗病毒效力。还纳入了同二聚体3'-叠氮基-3'-脱氧胸苷酰基-(5',5')-3'-叠氮基-3'-脱氧胸苷酸（AZT-P-AZT）用于比较。这些化合物的效力为AZT-P-ddA≥AZT-P-ddI＞AZT-P(CyE)-ddA≥AZT-P(CyE)-ddI≥AZT＞AZT-P-AZT。虽然AZT-P-ddA和AZT-P-ddI的体外治疗指数高于AZT，但AZT的同二聚体治疗指数较低。AZT-P-ddI在外周血单核细胞、Vero细胞或CEM细胞中表现出最低的毒性。在无毒浓度下对AZT和2',3'-二脱氧肌苷（ddI）进行的联合研究表明，在药物比例为1:100时存在协同相互作用。在更高比例（1:500和1:1000）下，仅在产生高达75%病毒抑制的浓度下相互作用才是协同的。通过多药效应分析方法确定，在更高水平的抗病毒作用下，这种组合是拮抗的。AZT-P-ddI对人粒细胞-巨噬细胞祖细胞的毒性比AZT低约10倍。然而，当用这些化合物评估红系细胞时，没有明显差异。该化合物更高的抗病毒活性和更低的毒性不能归因于其在生理温度和pH值的培养基中细胞外的分解。然而，在酸性溶液中，AZT-P-ddI以pH值依赖的方式分解。应该考虑对这种由两种临床有效的抗逆转录病毒药物组成的异二聚体进行深入的临床前研究。
