Zhen Y S, Taniki T, Weber G
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
Oncol Res. 1992;4(2):73-8.
Azidothymidine (AZT), inhibiting thymidine kinase (EC 2.7.1.21) (Weber, G. et al., Cancer Commun. 2:129-133, 1990) and dipyridamole, inhibiting nucleoside transport (Zhen, Y.-s. et al., Cancer Res. 43:1616-1619, 1983) exert blocking action on the activities of salvage pathways of nucleotide biosynthesis. Determined by clonogenic assay in human colon cancer HT-29 cells, the cell survivals for AZT, 10 microM, dipyridamole, 5 microM, and methotrexate (MTX), 0.025 microM, were 90, 82, and 62%, respectively; while the combinations of AZT + MTX, dipyridamole + MTX and AZT + dipyridamole + MTX, reduced survivals to 36, 4.3, and 0.7%. AZT or dipyridamole was synergistic with MTX, whereas AZT plus dipyridamole showed an even more marked potentiation of MTX activity. The survivals for 5-fluorouracil (5-FU), 0.5 microM, alone, AZT + 5-FU, dipyridamole + 5-FU, and AZT + dipyridamole + 5-FU were 86, 47, 29 and 5.1%, respectively. Similar results were observed in human pancreatic carcinoma BxPC-3 and PANC-1 cells. AZT markedly enhanced the inhibitory effect of dipyridamole in reversing the thymidine-hypoxanthine rescue from MTX cytotoxicity. AZT inhibited [14C]thymidine incorporation into DNA in HT-29 cells and strongly enhanced the effect of dipyridamole. The results indicate that combinations composed of AZT, dipyridamole, and antimetabolites, such as MTX and 5-FU, are potentially effective in the chemotherapy of human neoplasias.
叠氮胸苷（AZT）可抑制胸苷激酶（EC 2.7.1.21）（韦伯，G.等人，《癌症通讯》2:129 - 133，1990），双嘧达莫可抑制核苷转运（甄，Y.-s.等人，《癌症研究》43:1616 - 1619，1983），它们对核苷酸生物合成的补救途径的活性具有阻断作用。通过对人结肠癌细胞HT - 29进行克隆形成试验测定，10微摩尔的AZT、5微摩尔的双嘧达莫和0.025微摩尔的甲氨蝶呤（MTX）处理后的细胞存活率分别为90%、82%和62%；而AZT + MTX、双嘧达莫 + MTX以及AZT + 双嘧达莫 + MTX组合则将存活率降低至36%、4.3%和0.7%。AZT或双嘧达莫与MTX具有协同作用，而AZT加双嘧达莫对MTX活性的增强作用更为显著。0.5微摩尔的5 - 氟尿嘧啶（5 - FU）单独处理、AZT + 5 - FU、双嘧达莫 + 5 - FU以及AZT + 双嘧达莫 + 5 - FU处理后的细胞存活率分别为86%、47%、29%和5.1%。在人胰腺癌BxPC - 3和PANC - 1细胞中也观察到了类似结果。AZT显著增强了双嘧达莫逆转MTX细胞毒性所致的胸苷 - 次黄嘌呤补救作用的抑制效果。AZT抑制HT - 29细胞中[14C]胸苷掺入DNA，并强烈增强了双嘧达莫的作用。结果表明，由AZT、双嘧达莫和抗代谢物（如MTX和5 - FU）组成的联合用药在人类肿瘤化疗中可能有效。
