Adams E G, Badiner G J, Bhuyan B K
Cancer and Viral Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Cancer Res. 1988 Jan 1;48(1):109-16.
CC-1065 is a very potent antitumor antibiotic which selectively binds in the minor groove of DNA with alkylation at N-3 of adenine. Since therapeutic doses of CC-1065 caused delayed deaths in mice, analogues were synthesized, some of which had significant antitumor activity. The effects of several of these analogues on inhibition of CHO cell survival, cell progression, and their phase-specific toxicity are reported. CC-1065, U-66,664, U-66,819, U-66,694, and U-71,184 all have a left hand segment with an intact cyclopropyl group but have different tail segments. Lethality of these compounds after 2 h drug exposure was in the following order (50% lethal dose in nM in parentheses): CC-1065 (0.06) greater than U-71,184 (1.3) greater than U-66,694 (3.2) greater than U-68,819 (171) greater than U-66,664 (greater than 1200). In general, these compounds did not inhibit progression from G1 to S but slowed progression through S and blocked cells in G2-M. The phase-specific toxicity of U-71,184 and U-66,694 was different from that of CC-1065. CC-1065 was most cytotoxic to cells in M and early G1 and toxicity decreased as cells entered late G1 and S. In contrast, U-66,694 and U-71,184 were most toxic to cells in late G1. The biochemical and cellular effects of U-71,184 were then studied in detail since it was the most active among these analogues. After a 2-h exposure to 3 ng/ml U-71,184, 90% cell kill or growth inhibition was observed whereas 100 ng/ml was needed for similar inhibition of DNA and RNA synthesis. This discrepancy between the doses suggested that inhibition of nucleic acid synthesis may not be causally related to lethality. Further studies showed that when drug was removed after 2 h exposure, DNA synthesis continued to be inhibited whereas RNA and protein synthesis reached levels higher than the control. Therefore, it is likely that at cytotoxic doses the low level of inhibition of DNA synthesis combined with the stimulation of RNA and protein synthesis leads to unbalanced growth and cell death.
CC - 1065是一种强效抗肿瘤抗生素，它能选择性地结合于DNA的小沟，并使腺嘌呤的N - 3位发生烷基化。由于CC - 1065的治疗剂量会导致小鼠延迟死亡，因此合成了一些类似物，其中一些具有显著的抗肿瘤活性。本文报道了其中几种类似物对抑制中国仓鼠卵巢（CHO）细胞存活、细胞进程及其阶段特异性毒性的影响。CC - 1065、U - 66,664、U - 66,819、U - 66,694和U - 71,184都有一个带有完整环丙基的左手片段，但尾部片段不同。这些化合物在药物暴露2小时后的致死率顺序如下（括号内为50%致死剂量，单位为纳摩尔）：CC - 1065（0.06）＞U - 71,184（1.3）＞U - 66,694（3.2）＞U - 68,819（171）＞U - 66,664（＞1200）。一般来说，这些化合物不会抑制从G1期到S期的进程，但会减缓S期进程并使细胞阻滞在G2 - M期。U - 71,184和U - 66,694的阶段特异性毒性与CC - 1065不同。CC - 1065对处于M期和G1早期的细胞毒性最大，随着细胞进入G1晚期和S期，毒性降低。相比之下，U - 66,694和U - 71,184对处于G1晚期的细胞毒性最大。由于U - 71,184是这些类似物中活性最高的，因此对其生化和细胞效应进行了详细研究。在暴露于3纳克/毫升的U - 71,184 2小时后，观察到90%的细胞死亡或生长抑制，而抑制DNA和RNA合成则需要100纳克/毫升。这两个剂量之间的差异表明，核酸合成的抑制可能与致死率没有因果关系。进一步的研究表明，在暴露2小时后去除药物，DNA合成仍被抑制，而RNA和蛋白质合成达到高于对照的水平。因此，在细胞毒性剂量下，DNA合成的低水平抑制与RNA和蛋白质合成的刺激相结合，可能导致生长失衡和细胞死亡。
