Looney W B, Hopkins H A, MacLeod M S
Cancer. 1979 Apr;43(4):1201-10. doi: 10.1002/1097-0142(197904)43:4<1201::aid-cncr2820430407>3.0.co;2-0.
Single, large doses of adriamycin, cyclophosphamide and 5-fluorouracil (5-FU) have been compared to the same amount of drug given in divided doses daily over a 3 or 5 day period in a solid tumor model which metastasizes to the regional lymph nodes and lungs. No significant increase in life expectancy occurred following adriamycin or cyclophosphamide. However, a significant reduction in life expectancy occurred after 5 fractionated doses of 5-FU but not after the large single dose. The increase in mortality following fractionated doses of 5-FU is attributed to the prolongation of the onset of recovery of bone marrow. Tumor volume reduction following a single dose of each agent was equal to or greater than the fractionated doses. The results of these studies on this chemotherapeutically resistant solid tumor indicate that small daily fractionated doses of adriamycin, cyclophosphamide or 5-FU result in increased morbidity and mortality without therapeutic benefit in tumor control. The time sequence of recovery of the limiting organ of the host (i.e., bone marrow) is similar to the time sequence of recovery of the tumor. Large intermittent single doses of chemotherapeutic agents given following recovery of the host from a previous treatment would be expected to be less toxic to the host and equally effective in control of tumor growth. None of the 3 chemotherapeutic agents was successful in tumor eradication. Previous studies of this series have shown that the utilization of sequential chemotherapy combined with radiotherapy can be successfully used for eradication of another solid tumor which did not metastasize. A similar therapeutic strategy using sequential combined modality therapy should also be effective in the control of the primary H-4-II-E tumor as well as its metastatic dissemination. Information gained from these experimental studies should eventually provide information which should be helpful in the clinical management of chemotherapeutically resistant solid tumors in man.
在一个可转移至局部淋巴结和肺部的实体瘤模型中，对单次大剂量阿霉素、环磷酰胺和5-氟尿嘧啶（5-FU）与在3天或5天内每日分剂量给予相同总量药物的情况进行了比较。给予阿霉素或环磷酰胺后，预期寿命没有显著增加。然而，5次分剂量的5-FU给药后预期寿命显著降低，但单次大剂量给药后未出现这种情况。5-FU分剂量给药后死亡率增加归因于骨髓恢复开始时间的延长。每种药物单次给药后肿瘤体积的缩小等于或大于分剂量给药后的缩小。这些针对这种化疗耐药实体瘤的研究结果表明，每日小剂量分剂量的阿霉素、环磷酰胺或5-FU会导致发病率和死亡率增加，而在肿瘤控制方面没有治疗益处。宿主的限制器官（即骨髓）恢复的时间顺序与肿瘤恢复的时间顺序相似。预计在宿主从上一次治疗恢复后给予大剂量间歇性单次化疗药物对宿主的毒性较小，且在控制肿瘤生长方面同样有效。这三种化疗药物均未能成功根除肿瘤。该系列之前的研究表明，序贯化疗联合放疗可成功用于根除另一种未发生转移的实体瘤。使用序贯联合治疗模式的类似治疗策略在控制原发性H-4-II-E肿瘤及其转移扩散方面也应有效。从这些实验研究中获得的信息最终应能提供有助于临床管理人类化疗耐药实体瘤的信息。
