Berenbaum M C
Department of Experimental Pathology, St Mary's Hospital Medical School, London, UK.
Br J Cancer. 1990 Jan;61(1):101-9. doi: 10.1038/bjc.1990.22.
Current cancer chemotherapy regimens may involve 20-30 or more independent variables, each affecting therapeutic response and toxicity. With standard response surface modelling methods, finding the optimum combination with as few as 10 variables entails testing over 1,000 combinations, so these methods do not provide a feasible approach to such problems. However, they may be tackled by direct search methods (DSM), i.e. stepwise searches of the response surface. Experiments were carried out in advanced L1210 leukaemia treated with combinations of adriamycin with cyclophosphamide, isophosphamide with acetylcysteine and methotrexate with leucovorin. Two established DSM (Nelder-Mead and Box) were used, and a new method was designed to find consistent search paths in spite of wide biological variation. With methotrexate and leucovorin, DSM located combinations prolonging mean survival to 40-50 days (compared with 10.4 in controls) and giving high proportions of long-term survivors. These results were achieved with single injections of drugs given 7 days after injection of 10(6) leukaemic cells, i.e. 2-3 days before deaths began in untreated mice, and appear to be unprecedented with these agents. Searching for optimal combinations of established agents may be at least as rewarding as searching for new agents, and thus DSM may prove a powerful tool for improving the results of combination cancer chemotherapy.
目前的癌症化疗方案可能涉及20 - 30个或更多独立变量，每个变量都会影响治疗反应和毒性。使用标准的响应面建模方法，要找到由少至10个变量组成的最佳组合，需要测试超过1000种组合，所以这些方法无法为解决此类问题提供可行的途径。然而，可以通过直接搜索方法（DSM）来解决，即对响应面进行逐步搜索。我们对用阿霉素与环磷酰胺、异环磷酰胺与乙酰半胱氨酸、甲氨蝶呤与亚叶酸联合治疗的晚期L1210白血病进行了实验。使用了两种既定的DSM方法（Nelder - Mead法和Box法），并设计了一种新方法，以在存在广泛生物学差异的情况下找到一致的搜索路径。对于甲氨蝶呤和亚叶酸，DSM找到了能将平均生存期延长至40 - 50天（对照组为10.4天）并产生高比例长期存活者的组合。这些结果是在注射10(6)个白血病细胞7天后单次注射药物获得的，即在未治疗小鼠开始死亡前2 - 3天，而且这些药物组合似乎取得了前所未有的效果。寻找现有药物的最佳组合可能至少与寻找新药物一样有价值，因此DSM可能被证明是改善联合癌症化疗效果的有力工具。
