Mason K A, Milas L, Peters L J
Division of Radiotherapy, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Int J Radiat Oncol Biol Phys. 1995 Jul 30;32(5):1381-9. doi: 10.1016/0360-3016(95)00037-Y.
Paclitaxel is a potentially useful drug for augmenting the cytotoxic action of radiotherapy because it has independent cytotoxic activity against certain cancers and blocks cells in the radiosensitive mitotic phase of the cell cycle. However, all rapidly proliferating tissues, both normal and neoplastic, may be affected by this therapeutic strategy. The aim of this study was to define the in vivo response of rapidly dividing cells of the small bowel mucosa to paclitaxel given alone and in combination with radiation.
Mice were given single IV doses of 10 or 40 mg/kg paclitaxel or four doses of 10 mg/kg paclitaxel at 6, 12, or 24 h intervals. The kinetics of mitotic arrest and apoptosis in jejunal crypts of mice at 1-24 h after treatment were defined histologically. An in vivo stem cell microcolony assay was used to assess the radiosensitizing potential of paclitaxel when radiation was delivered at the peak of mitosis and at 24 h after drug treatment.
Paclitaxel blocked jejunal crypt cells in mitosis and induced apoptosis in a dose-dependent manner. Fractionating the paclitaxel dose over 1-4 days did not result in any greater accumulation of mitotically blocked cells than did a single dose. Mitosis peaked 2-4 h after paclitaxel and returned to near normal by 24 h. Apoptosis lagged several hours behind mitosis and peaked about 6 h later than mitosis. Despite these kinetic perturbations, there was little or no enhancement of radiation effect when single doses were delivered 2-4 h after paclitaxel administration. The maximum sensitizer enhancement ratio of 1.07 observed after a single paclitaxel dose of 40 mg/kg is consistent with independent crypt cell killing. Conversely, when radiation was given 24 h after paclitaxel, a significant protective effect of the drug (SER 0.89-0.92), most probably due to a regenerative overshoot induced by paclitaxel, was observed.
Stem cells of the jejunal mucosa determining radiation response were not radiosensitized by paclitaxel with the drug concentrations and dose delivery schedules used, although additive cytotoxicity was observed with the highest drug dose. A radioprotective effect was observed when radiation was given 24 h after paclitaxel administration.
紫杉醇是一种可能有助于增强放射治疗细胞毒性作用的药物，因为它对某些癌症具有独立的细胞毒性活性，并能将细胞阻滞在细胞周期中对放射敏感的有丝分裂期。然而，所有快速增殖的组织，包括正常组织和肿瘤组织，都可能受到这种治疗策略的影响。本研究的目的是确定单独给予紫杉醇以及与放疗联合使用时，小肠黏膜快速分裂细胞的体内反应。
给小鼠静脉注射单剂量10或40mg/kg紫杉醇，或按6、12或24小时间隔给予四剂10mg/kg紫杉醇。通过组织学方法确定治疗后1至24小时小鼠空肠隐窝中有丝分裂阻滞和凋亡的动力学。当在有丝分裂高峰期和药物治疗后24小时进行放射时，使用体内干细胞微集落测定法评估紫杉醇的放射增敏潜力。
紫杉醇以剂量依赖性方式阻滞空肠隐窝细胞有丝分裂并诱导凋亡。与单剂量相比，在1至4天内分次给予紫杉醇剂量并未导致有丝分裂阻滞细胞的积累增加。紫杉醇给药后2至4小时有丝分裂达到峰值，到24小时恢复到接近正常水平。凋亡比有丝分裂滞后数小时，比有丝分裂峰值晚约6小时出现。尽管存在这些动力学扰动，但在紫杉醇给药后2至4小时给予单剂量放射时，放射效应几乎没有增强。单剂量40mg/kg紫杉醇后观察到的最大增敏剂增强比为1.07，这与隐窝细胞的独立杀伤作用一致。相反，当在紫杉醇给药后24小时进行放射时，观察到该药物具有显著的保护作用（增敏比0.89 - 0.92），这很可能是由于紫杉醇诱导的再生性过冲所致。
尽管在最高药物剂量下观察到了相加的细胞毒性，但在所使用的药物浓度和给药方案下，紫杉醇并未使决定放射反应的空肠黏膜干细胞对放射增敏。在紫杉醇给药后24小时进行放射时观察到了放射保护作用。
