Nicholson K M, Bibby M C, Phillips R M
Clinical Oncology Unit, University of Bradford, U.K.
Eur J Cancer. 1997 Jul;33(8):1291-8. doi: 10.1016/s0959-8049(97)00114-7.
Paclitaxel is a chemotherapeutic drug which has clinical activity against several solid tumours including ovarian and metastatic breast cancers. Despite extensive preclinical evaluation in several experimental models, no studies have determined the effect of taxol on multicellular spheroids, a model which closely mimics the microregions of solid tumours. MCF-7 human breast carcinoma spheroids were significantly less sensitive than monolayers with IC50 values of 14.33 +/- 4.51 microM and 0.15 +/- 0.09 microM, respectively, following a 1 h drug exposure. Similarly, DLD-1 human colon carcinoma spheroids were also more resistant (IC50 = 33.0 +/- 8.89 microM) than monolayers (IC50 = 0.36 +/- 0.14 microM) following a 1 h drug exposure. Paclitaxel was unable to penetrate DLD-1 multicell layers (22 microns in thickness), suggesting that suboptimal drug exposures to paclitaxel occur in cells which reside some distance away from the surface of the spheroid. In the case of DLD-1 spheroids, extending the exposure time to 24 h whilst maintaining the same overall concentration x time (C x T) drug exposure parameters, resulted in greater cell kill (C x T required to kill 50% of cells = 13.67 +/- 3.21 microM/h) compared with 1 h drug exposures (C x T required to kill 50% of cells = 33.00 +/- 8.89 microM/h). Similar results were obtained with MCF-7 spheroids. In monolayers cultures, dose-response curves contained a marked plateau phase (a characteristic feature of cell cycle phase specific drug) and in the case of MCF-7 cells, cell kill was proportional to T as opposed to C x T. These results support the use of prolonged infusions of paclitaxel in the clinic, as extending the duration of drug exposure not only allows more cells to enter sensitive phases of the cell cycle, but would also allow paclitaxel more time to penetrate into avascular regions of solid tumours. It is likely that paclitaxel will only be effective against cells which reside close to tumour blood vessels and combination therapy with bioreductive drugs (such as tirapazamine) may produce synergistic effects in vivo.
紫杉醇是一种化疗药物，对包括卵巢癌和转移性乳腺癌在内的多种实体瘤具有临床活性。尽管在多个实验模型中进行了广泛的临床前评估，但尚无研究确定紫杉醇对多细胞球体的影响，多细胞球体模型能紧密模拟实体瘤的微区域。在1小时药物暴露后，MCF - 7人乳腺癌球体的敏感性明显低于单层细胞，其IC50值分别为14.33±4.51微摩尔/升和0.15±0.09微摩尔/升。同样，在1小时药物暴露后，DLD - 1人结肠癌球体也比单层细胞更具抗性（IC50 = 33.0±8.89微摩尔/升），单层细胞的IC50为0.36±0.14微摩尔/升。紫杉醇无法穿透厚度为22微米的DLD - 1多细胞层，这表明在距离球体表面有一定距离的细胞中，紫杉醇的药物暴露不足。对于DLD - 1球体，将暴露时间延长至24小时，同时保持相同的总浓度×时间（C×T）药物暴露参数，与1小时药物暴露相比（杀死50%细胞所需的C×T = 33.00±8.89微摩尔/小时），导致更大的细胞杀伤（杀死50%细胞所需的C×T = 13.67±3.21微摩尔/小时）。MCF - 7球体也得到了类似结果。在单层培养中，剂量反应曲线包含一个明显的平台期（细胞周期特异性药物的特征），对于MCF - 7细胞，细胞杀伤与时间T成正比，而不是与C×T成正比。这些结果支持在临床上使用紫杉醇延长输注，因为延长药物暴露时间不仅能使更多细胞进入细胞周期的敏感阶段，还能使紫杉醇有更多时间渗透到实体瘤的无血管区域。紫杉醇可能仅对靠近肿瘤血管的细胞有效，与生物还原药物（如替拉扎明）联合治疗可能在体内产生协同作用。
