Xu M J, Alberts D S, Liu R, Leibovitz A, Liu Y
Department of Medicine, College of Medicine, University of Arizona, Tucson 85724.
Cancer Chemother Pharmacol. 1989;25(2):89-94. doi: 10.1007/BF00692345.
Doxorubicin, cisplatin, and cyclophosphamide are the three drugs most commonly used in the treatment of ovarian cancer, but no effect greater than additivity was observed for any combination of these drugs in the present study. Only a few studies have been reported concerning the degree of their additivity or their best order of sequencing. In our in vitro studies, cisplatin in combination with doxorubicin or 4-hydroperoxycyclophosphamide (4HC) was tested against seven human gynecologic tumor-cell lines in different sequences, using a double-agar layer tissue-culture system. Drug interactions with respect to inhibition of tumor clonogenicity were evaluated by isobologram and fractional survival methods. Doxorubicin and 4HC were sequenced simultaneously and at 1, 6 and 24 h after cisplatin, and cisplatin was sequenced at 1, 6 and 24 h after 4HC. The isobolograms constructed for doxorubicin or 4HC plus cisplatin revealed strict additivity between these agents against ovarian cancer clonogenicity. Both doxorubicin and 4HC showed the greatest additivity when used simultaneously and at 1 h vs 6 or 24 h after cisplatin. Although the mechanisms by which these sequencing effects occur are unknown, these studies provide new leads for the design of clinical trials with combinations of these three agents.
阿霉素、顺铂和环磷酰胺是治疗卵巢癌最常用的三种药物，但在本研究中，未观察到这些药物的任何组合有大于相加作用的效果。关于它们相加作用的程度或最佳给药顺序，仅有少数研究报道。在我们的体外研究中，采用双层琼脂组织培养系统，以不同顺序测试了顺铂与阿霉素或4-氢过氧环磷酰胺（4HC）联合对七种人妇科肿瘤细胞系的作用。通过等效线图和分数存活法评估了药物在抑制肿瘤克隆形成方面的相互作用。阿霉素和4HC在顺铂给药后1、6和24小时同时给药，4HC给药后1、6和24小时给予顺铂。为阿霉素或4HC加顺铂构建的等效线图显示，这些药物对卵巢癌克隆形成具有严格的相加作用。阿霉素和4HC在同时给药以及在顺铂给药后1小时给药时，与在顺铂给药后6或24小时给药相比，显示出最大的相加作用。尽管这些给药顺序效应发生的机制尚不清楚，但这些研究为设计这三种药物联合的临床试验提供了新线索。
