Hopwood L E, Davies B M, Moulder J E
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee 53226.
Int J Radiat Oncol Biol Phys. 1990 Sep;19(3):643-50. doi: 10.1016/0360-3016(90)90491-2.
RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance.
RIF-1肿瘤含有少量对5-氟尿嘧啶、甲氨蝶呤或阿霉素耐药的细胞（每10⁶个细胞中有1至100个）。在未经治疗的单个肿瘤中，耐药细胞的频率变化很大。体内给予3至12 Gy剂量的辐射会增加对甲氨蝶呤和5-氟尿嘧啶耐药细胞的频率，但不会增加对阿霉素耐药细胞的频率。5-氟尿嘧啶和甲氨蝶呤耐药性的诱导程度表现出对辐射剂量以及照射与耐药性评估之间间隔的复杂依赖性。对于3 Gy的剂量，仅在间隔5至7天后才会出现诱导的5-氟尿嘧啶和甲氨蝶呤耐药性，而对于12 Gy的剂量，在照射后1至3天会观察到高水平的诱导耐药性。甲氨蝶呤诱导耐药性的最大绝对风险为每Gy每10⁴个细胞4个，5-氟尿嘧啶为每Gy每10⁶个细胞3个。这些结果表明，肿瘤缺氧可能在照射后出现的耐药性水平增加中起作用，并且遗传和环境因素都可能影响辐射诱导的耐药性。这些研究为肿瘤耐药性发展模型提供了重要数据，并暗示放疗后进行化疗时出现的一些耐药性可能是由辐射诱导的耐药性引起的。
