Hei T K, Piao C Q, Geard C R, Hall E J
Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Int J Radiat Oncol Biol Phys. 1994 May 15;29(2):267-71. doi: 10.1016/0360-3016(94)90273-9.
Taxol has been shown to be clinically active against several types of human tumors. To assess the potential oncogenic effect of taxol, the in vitro cytotoxic and oncogenic transforming effects of taxol, either alone or in combination with gamma-irradiation, were examined.
Exponentially growing mouse C3H 10T1/2 cells were treated with taxol with or without concurrent gamma-irradiation. After treatment, cultures were replated for both clonogenic survival and transformation assays. To determine the effects of taxol on cell cycle kinetics, treated cells were concurrently labelled with bromodeoxyuridine coupled with fluorescein. Accumulated mitotic cells were isolated by the shake-off technique and their plating efficiency and radiosensitivity were determined.
Taxol induced a dose dependent toxicity in 10T1/2 cells. In contrast to human tumor cells in culture, the mitotic block induced by a 100 nM dose of taxol in 10T1/2 cells was only partial. While taxol was ineffective in transformant induction, it enhanced the oncogenic transforming potential of gamma-rays in a supra-additive manner. The fact that approximately 15% of taxol-induced mitotic cells were clonogenically viable and at a cell cycle stage that was most radiosensitive suggests a mechanistic basis for the observed enhancement in transformation incidence by ionizing radiation.
Taxol enhances the oncogenicity of radiation by partially blocking the 10T1/2 cells in G2/M phases of the cell cycle, phases that are most sensitive to radiation induced oncogenic transformation.
紫杉醇已被证明对多种人类肿瘤具有临床活性。为评估紫杉醇的潜在致癌作用，研究了紫杉醇单独或与γ射线联合使用时的体外细胞毒性和致癌转化作用。
对数生长期的小鼠C3H 10T1/2细胞用紫杉醇处理，同时或不同时进行γ射线照射。处理后，将细胞培养物重新接种以进行克隆存活和转化测定。为确定紫杉醇对细胞周期动力学的影响，用与荧光素偶联的溴脱氧尿苷对处理后的细胞进行同步标记。通过振荡分离技术分离累积的有丝分裂细胞，并测定其接种效率和放射敏感性。
紫杉醇在10T1/2细胞中诱导剂量依赖性毒性。与培养的人类肿瘤细胞不同，100 nM剂量的紫杉醇在10T1/2细胞中诱导的有丝分裂阻滞只是部分性的。虽然紫杉醇在诱导转化体方面无效，但它以超加成的方式增强了γ射线的致癌转化潜力。约15%的紫杉醇诱导的有丝分裂细胞具有克隆存活能力且处于对辐射最敏感的细胞周期阶段，这一事实为观察到的电离辐射转化发生率增加提供了机制基础。
紫杉醇通过使10T1/2细胞在细胞周期的G2/M期部分阻滞来增强辐射的致癌性，而G2/M期对辐射诱导的致癌转化最为敏感。
