Johnson K R, Wang L, Miller M C, Willingham M C, Fan W
Department of Pathology, Experimental Oncology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Clin Cancer Res. 1997 Oct;3(10):1739-45.
Paclitaxel, a naturally occurring antimitotic agent, has shown efficacy in the treatment of certain solid tumors, particularly metastatic breast carcinoma and drug-refractory ovarian cancers. Recent studies have demonstrated that paclitaxel, in addition to its effects on microtubules and cell cycle arrest, possesses significant cell-killing activity in solid tumor cells by the induction of apoptosis. However, the mechanism by which paclitaxel leads to cell death and its relationship with paclitaxel-induced mitotic arrest is presently unclear. In this study, we attempted to determine whether pre-arresting tumor cells at other phases of the cell cycle could affect paclitaxel-induced apoptosis. We found that 5-fluorouracil (5-FU), another antineoplastic agent that usually arrests tumor cells at the G1-S phase of the cell cycle, could significantly repress the cell-killing activity of paclitaxel in solid tumor cells, even when it was added simultaneously with paclitaxel. Further studies indicated that 5-FU actually inhibits the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death, suggesting that 5-FU might interfere with paclitaxel cytotoxicity at an early stage, probably by preventing tumor cells from entering G2-M phase. Because recent clinical trials have used a combination of paclitaxel and 5-FU in the treatment of metastatic breast cancers, our results also suggest that the combination of these two drugs might not be as valuable in clinical chemotherapy.
紫杉醇是一种天然存在的抗有丝分裂剂，已显示出对某些实体瘤具有治疗效果，尤其是转移性乳腺癌和对药物耐药的卵巢癌。最近的研究表明，紫杉醇除了对微管和细胞周期停滞有作用外，还通过诱导凋亡在实体瘤细胞中具有显著的细胞杀伤活性。然而，紫杉醇导致细胞死亡的机制及其与紫杉醇诱导的有丝分裂停滞的关系目前尚不清楚。在本研究中，我们试图确定在细胞周期的其他阶段预先阻滞肿瘤细胞是否会影响紫杉醇诱导的凋亡。我们发现，5-氟尿嘧啶（5-FU），另一种通常使肿瘤细胞停滞在细胞周期G1-S期的抗肿瘤药物，即使与紫杉醇同时添加，也能显著抑制紫杉醇在实体瘤细胞中的细胞杀伤活性。进一步的研究表明，5-FU实际上抑制了紫杉醇对有丝分裂停滞和凋亡性细胞死亡的细胞毒性作用，这表明5-FU可能在早期干扰紫杉醇的细胞毒性，可能是通过阻止肿瘤细胞进入G2-M期。由于最近的临床试验已使用紫杉醇和5-FU联合治疗转移性乳腺癌，我们的结果还表明，这两种药物的联合在临床化疗中可能没有那么大的价值。
