Hahn S M, Liebmann J E, Cook J, Fisher J, Goldspiel B, Venzon D, Mitchell J B, Kaufman D
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cancer. 1993 Nov 1;72(9):2705-11. doi: 10.1002/1097-0142(19931101)72:9<2705::aid-cncr2820720930>3.0.co;2-k.
Taxol is a novel chemotherapeutic agent that promotes microtubule assembly and stabilizes tubulin polymer formation. Clinical evaluation of its antineoplastic activity as a single agent and in combination with other chemotherapeutic drugs is in progress.
To evaluate the effect of combining taxol with other commonly used antineoplastic agents, clonogenic survival of human breast cancer MCF7 cells, human lung adenocarcinoma A549 cells, and human ovarian cancer OVG1 cells were assayed after an initial exposure to taxol for 24 hours (approximately LD90 for taxol), followed by a 1-hour incubation with varying concentrations of doxorubicin or etoposide (total taxol incubation time, 25 hours).
When corrected for taxol-induced cytotoxicity, doxorubicin and etoposide caused less cell killing in the presence of taxol compared with control incubations of doxorubicin and etoposide alone. To determine if a different schedule of drug application resulted in a similar finding, MCF7, A549, and OVG1 cells were exposed to doxorubicin for 1 hour, followed by incubation with varying concentrations of taxol for 24 hours. Less-than-additive cytotoxicity for the combination of taxol and doxorubicin was found. Flow cytometry studies in MCF7 cells showed that taxol caused a G2/M cell cycle block. Fewer cells were found to be in S-phase, which is the most doxorubicin-sensitive phase of the cell cycle. The application of doxorubicin or etoposide to MCF7 cells for 1 hour resulted in partial G1 and G2/M cell cycle blocks. Fewer cells were found to be moving through the cell cycle, which is likely required for taxol cytotoxicity.
Although direct antagonism of the cytotoxicity of doxorubicin or etoposide by taxol has not been proven, there is less-than-additive in vitro cytotoxicity when taxol is combined with these chemotherapeutic agents. The clinical implications of these findings are unknown; however, these findings generate concern about the combination of these agents in clinical trials and suggest that additional studies to determine optimal scheduling are needed.
紫杉醇是一种新型化疗药物，可促进微管组装并稳定微管蛋白聚合物的形成。目前正在对其作为单一药物以及与其他化疗药物联合使用时的抗肿瘤活性进行临床评估。
为评估紫杉醇与其他常用抗肿瘤药物联合使用的效果，在人乳腺癌MCF7细胞、人肺腺癌A549细胞和人卵巢癌OVG1细胞最初暴露于紫杉醇24小时（约为紫杉醇的LD90）后，再与不同浓度的阿霉素或依托泊苷孵育1小时（紫杉醇总孵育时间为25小时），检测其克隆形成存活率。
校正紫杉醇诱导的细胞毒性后，与单独使用阿霉素和依托泊苷的对照孵育相比，在紫杉醇存在的情况下，阿霉素和依托泊苷导致的细胞杀伤较少。为确定不同的给药方案是否会得出类似结果，将MCF7、A549和OVG1细胞暴露于阿霉素1小时，随后与不同浓度的紫杉醇孵育24小时。发现紫杉醇与阿霉素联合使用时细胞毒性小于相加作用。对MCF7细胞进行的流式细胞术研究表明，紫杉醇导致G2/M期细胞周期阻滞。处于S期的细胞较少，而S期是细胞周期中对阿霉素最敏感的阶段。将阿霉素或依托泊苷应用于MCF7细胞1小时会导致部分G1期和G2/M期细胞周期阻滞。发现通过细胞周期的细胞较少，而这可能是紫杉醇细胞毒性所必需的。
虽然尚未证实紫杉醇对阿霉素或依托泊苷的细胞毒性有直接拮抗作用，但当紫杉醇与这些化疗药物联合使用时，体外细胞毒性小于相加作用。这些发现的临床意义尚不清楚；然而，这些发现引发了对这些药物在临床试验中联合使用的担忧，并表明需要进行更多研究以确定最佳给药方案。
