Distelmans W, Van Ginckel R, Vanherck W, Willebrords R, De Brabander M, Wouters L, Van den Winkel P, De Backer G
Department of Life Sciences, Janssen Research Foundation, Beerse, Belgium.
Int J Radiat Oncol Biol Phys. 1989 Jan;16(1):177-82. doi: 10.1016/0360-3016(89)90026-6.
The combined effect of the microtubule inhibitor tubulozole and gamma-irradiation has been investigated in vivo in subcutaneous MO4 fibrosarcomas and Lewis Lung carcinomas. A marked interactive effect on tumor growth was observed when 160 mg/kg tubulozole was orally administered before the tumors were treated with 10 Gy radiation. Dose dependency and optimal effect were obtained on tumor growth of MO4 tumor bearing animals when the drug treatment was given 6 hr prior to the irradiation. The optimal pretreatment time coincided with the time at which a peak mitotic index in the tumor tissue was observed. An enhancing effect is also noticed at other doses of radiation in MO4 tumors pretreated 6 hr before with 160 mg/kg tubulozole. The interactive effect is maintained in a clinically relevant dose fractionation schedule whereby 8 fractions of 2 Gy each were pretreated 6 hr before with 80 mg/kg tubulozole. Tubulozole-T, the stereo-isomer of tubulozole, neither exhibits any antimicrotubular action nor exerts an antitumoral effect on its own or in combination with gamma-irradiation. The possible mechanisms of interaction between tubulozole and gamma-irradiation in tumor tissue are discussed.
在皮下MO4纤维肉瘤和Lewis肺癌的体内实验中，研究了微管抑制剂tubulozole与γ射线联合使用的效果。在用10 Gy辐射治疗肿瘤之前，口服160 mg/kg tubulozole时，观察到对肿瘤生长有显著的交互作用。当在照射前6小时给予药物治疗时，对荷MO4肿瘤动物的肿瘤生长获得了剂量依赖性和最佳效果。最佳预处理时间与在肿瘤组织中观察到有丝分裂指数峰值的时间一致。在用160 mg/kg tubulozole预处理6小时的MO4肿瘤中，在其他辐射剂量下也观察到增强作用。在临床相关的剂量分割方案中，交互作用得以维持，即在每次2 Gy共8次分割照射前6小时，用80 mg/kg tubulozole预处理。tubulozole的立体异构体Tubulozole-T既不表现出任何抗微管作用，也不单独或与γ射线联合发挥抗肿瘤作用。讨论了tubulozole与γ射线在肿瘤组织中相互作用的可能机制。
