Budach W, Budach V, Scheulen M E, Stuschke M, Chaborski P
Department of Radiation Oncology, Essen University, Federal Republic of Germany.
Cancer Chemother Pharmacol. 1993;31 Suppl 2:S169-73.
The in vivo development of radiation- and doxorubicin-induced resistance was studied in a chemosensitive and radiosensitive human neurogenic sarcoma (Essen neuroectodermal tumor line 2) xenografted in nude mice. Dose-response curves were generated for the parent tumor line, and growth delay (GD) and specific growth delay (SGD) were the study end points. An intravenous injection of doxorubicin at 10 mg/kg, the lethal dose for 10% of the study population (LD10) in nude mice, and a single dose of 12 Gy radiation were determined to be isoeffective and were thus maintained for all subsequent treatments. For the induction of resistance to both treatment modalities, regrowing tumors were transplanted into successive generations of nude mice and retreated. This procedure was repeated 13 and 9 times, respectively, for the doxorubicin and radiation treatments. The response was monitored in all passages. As compared with the parent tumor line, a 50% decrease in SGD was observed following 3.9 and 8.5 treatments with doxorubicin and radiation, respectively. Following four treatments with doxorubicin, SGD in tumors crossed over to radiation therapy declined by 50%. Radiation therapy, on the other hand, caused significant reductions in GD and SGD in tumors that were subsequently exposed to doxorubicin, but it did not induce a 50% decline in response. Overexpression of P-170-glycoprotein was not observed for either treatment modality. The data suggest that treatment with doxorubicin or radiation can potentially induce resistance to subsequent continued or crossover treatment and that this resistance develops gradually. The lack of P-170-glycoprotein over-expression in the resistant cell lines indicates the existence of alternative pathways that may lead to resistance.
在裸鼠体内异种移植的具有化学敏感性和放射敏感性的人类神经源性肉瘤（埃森神经外胚层肿瘤系2）中，研究了辐射和阿霉素诱导抗性的体内发展情况。生成了亲本肿瘤系的剂量反应曲线，生长延迟（GD）和特定生长延迟（SGD）为研究终点。确定静脉注射10 mg/kg阿霉素（裸鼠中10%研究群体的致死剂量，即LD10）和单次12 Gy辐射具有等效效果，因此在所有后续治疗中均保持该剂量。为诱导对两种治疗方式的抗性，将再生肿瘤移植到连续几代裸鼠体内并再次进行治疗。阿霉素和辐射治疗分别重复此过程13次和9次。在所有传代过程中监测反应。与亲本肿瘤系相比，阿霉素和辐射分别经过3.9次和8.5次治疗后，SGD下降了50%。阿霉素治疗四次后，对放疗的肿瘤SGD下降了50%。另一方面，放疗使随后接受阿霉素治疗的肿瘤的GD和SGD显著降低，但并未使反应下降50%。两种治疗方式均未观察到P-170糖蛋白的过表达。数据表明，阿霉素或放疗治疗可能会诱导对后续持续治疗或交叉治疗的抗性，且这种抗性是逐渐发展的。抗性细胞系中缺乏P-170糖蛋白过表达表明存在可能导致抗性的替代途径。
