Hennequin C, Giocanti N, Favaudon V
Unite 350 INSERM, Institut Curie-Biologie, Orsay, France.
Cancer Res. 1996 Apr 15;56(8):1842-50.
Altered gamma-ray response by brief (1 h), concomitant exposure to paclitaxel (Taxol) or docetaxel (Taxotere) was investigated in growing HeLa and SQ20B human tumor cells in vitro. For both cell lines, both taxoids were able to reduce or enhance radiation cell killing, depending on the drug concentration. Large reduction of radiosensitivity (up to 3.3-fold reduction relative to radiation alone) was observed in HeLa cells over a wide range of drug concentrations, extending to 1.5- (paclitaxel) or 3.3- fold (docetaxel) the IC50s determined for drug alone. This antagonistic effect was also observed with SQ20B cells. It disappeared for drug concentrations exceeding 0.9 (SQ20B), 1.6 (HeLa; paclitaxel), and 3.4 (HeLa; docetaxel) IC50 equivalents, above which a drug dose-dependent, supra-additive radiation-drug interaction was observed. Reduction of radiation susceptibility in the low-drug dose range also held for mid-G1 synchronized HeLa cells, i.e., in the cell cycle compartment characterized as the most resistant one to docetaxel (C. Hennequin et al., Br. J. Cancer, 71: 1194-1198, 1995). In the case of SQ20B cells, the cytotoxicity of either drug or radiation alone was primarily dependent on the state of growth, with quiescent (G(0)) cells showing increased radiosensitivity and reduced drug toxicity compared to the growing fraction. The effect of taxoids (1-h contact) was finally investigated in sequential treatment as a function of the time elapsed between radiation and exposure to drugs. In HeLa cells, the postirradiation time-dependence of the response to combined treatment was biphasic. The radioprotecting potential of either taxoid disappeared in approximately 1.5 h following radiation. At longer postirradiation delays, radiation-induced redistribution in the cell cycle appeared to be the major determinant of HeLa cell survival, in relation to the differential cell cycle phase specificity of each drug. Pronounced paclitaxel recovery versus increased sensitivity to docetaxel occurred over 8 h after irradiation. SQ20B cells showed monophasic radiation recovery with both drugs over the same time range.
在体外培养的HeLa和SQ20B人肿瘤细胞中，研究了短暂（1小时）同时暴露于紫杉醇（泰素）或多西他赛（泰索帝）对γ射线反应的影响。对于这两种细胞系，两种紫杉烷类药物都能够根据药物浓度降低或增强辐射对细胞的杀伤作用。在HeLa细胞中，在很宽的药物浓度范围内都观察到放射敏感性大幅降低（相对于单独辐射，降低幅度高达3.3倍），该浓度范围扩展至单独药物的IC50的1.5倍（紫杉醇）或3.3倍（多西他赛）。在SQ20B细胞中也观察到这种拮抗作用。当药物浓度超过0.9（SQ20B）、1.6（HeLa；紫杉醇）和3.4（HeLa；多西他赛）IC50当量时，这种拮抗作用消失，在此浓度以上观察到药物剂量依赖性的超相加辐射-药物相互作用。在低药物剂量范围内辐射敏感性的降低在中期G1期同步化的HeLa细胞中也存在，即在细胞周期中被认为对多西他赛最具抗性的阶段（C. Hennequin等人，《英国癌症杂志》，71: 1194-1198，1995）。对于SQ20B细胞，单独的药物或辐射的细胞毒性主要取决于生长状态，与生长部分相比，静止（G(0)）细胞显示出更高的放射敏感性和更低的药物毒性。最后研究了紫杉烷类药物（1小时接触）在序贯治疗中的作用，作为辐射与药物暴露之间时间间隔的函数。在HeLa细胞中，联合治疗反应的辐射后时间依赖性是双相的。辐射后约1.5小时，两种紫杉烷类药物的放射保护潜力均消失。在更长的辐射后延迟时间，辐射诱导的细胞周期重新分布似乎是HeLa细胞存活的主要决定因素，这与每种药物不同的细胞周期阶段特异性有关。照射后8小时内，紫杉醇的恢复明显，而对多西他赛的敏感性增加。在相同的时间范围内，两种药物对SQ20B细胞均显示单相辐射恢复。
