TRANSFORMATION OF MOUSE FIBROBLASTS WITH THE ONCOGENES H-RAS OR TRK IS ASSOCIATED WITH PRONOUNCED CHANGES IN DRUG SENSITIVITY AND METABOLISM
TRANSFORMATION OF MOUSE FIBROBLASTS WITH THE ONCOGENES H-RAS OR TRK IS ASSOCIATED WITH PRONOUNCED CHANGES IN DRUG SENSITIVITY AND METABOLISM
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DOI：
10.1002/ijc.2910540316
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发表时间：
1993-05-28
影响因子：
6.4
通讯作者：
PINEDO, HM
中科院分区：
文献类型：
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作者：
PETERS, GJ;WETS, M;PINEDO, HM
癌基因ras或trk的恶性激活与许多实体瘤和白血病有关。我们测定了野生型小鼠NIH-3 T3成纤维细胞和由H-ras（S2-72 1）和trk（106-632）癌基因转化的NIH-3 T3细胞系对来自不同类别的11种不同药物的化学敏感性。敏感性差异与药物蓄积和代谢有关。ras和trk转化细胞系对顺铂（CDDP）和阿霉素（DXR）的敏感性均低于野生型。表达H-ras的NIH-3 T3转化体对吲哚醌EO 9、甲氨蝶呤和阿拉伯呋喃糖基胞嘧啶的敏感性低于表达trk或野生型的转化体。未观察到长春新碱、VP-16或新型胞苷类似物2 '，2'-二氟脱氧胞苷的灵敏度存在明显差异。在ras和trk转化细胞系中，对5-FU的敏感性适度增加，但对5 '脱氧-5-氟尿苷（5' dFUR）的敏感性显著增加。只有转trk基因的NIH-3 T3对2 ′-脱氧-5-氟尿苷更敏感。P-糖蛋白的表达在3种细胞系之间没有差异，但在两种突变体中DXR的积累减少，表明敏感性的非P-糖蛋白相关差异。5 'dFUR转化为5 FU（由嘧啶核苷磷酸化酶催化）在两种突变体中比野生型高5-10倍。磷酸核糖基转移酶的活性（5 FU直接转化为FUMP）是相当的，但5 FU转化为氟尿苷（FUR）的速率在野生型中较低，5 FU通过FUR转化为FUMP的速率也较低。相反，胸苷酸合成酶的活性，氟嘧啶的靶酶，在野生型细胞中更高。嘌呤和嘧啶核苷酸的浓度在表达trk的细胞中较低。总之，转化细胞的H-ras或trk癌基因可以显着影响敏感性的几种药物，影响正常代谢和几种抗癌药物。
Malignant activation of oncogenes ras or trk is implicated in a number of solid tumors and leukemias. We determined the chemosensitivity profile of wild-type mouse NIH-3T3 fibroblasts, and that of NIH-3T3 lines transformed by the H-ras (S2-72 1) and trk (106-632) oncogenes, against 11 different drugs from various classes. Differences in sensitivity were related to drug accumulation and metabolism. Both ras- and trk-transformed cell lines were less sensitive to cisplatin (CDDP) and doxorubicin (DXR) than the wild type. NIH-3T3 transformants expressing H-ras were less sensitive than those expressing trk or the wild type to the indoloquinone EO9, methotrexate and arabino-furanosylcytosine. No clear difference in sensitivity was observed for vincristine, VP-16, or the new cytidine analog 2',2'-difluoro-deoxycytidine. In both ras- and trk-transformed cell lines sensitivity to 5FU was increased moderately, but sensitivity to 5'deoxy-5-fluorouridine (5'dFUR) was increased markedly. Only the trk-transformed line NIH-3T3 was more sensitive to 2'deoxy-5-fluorouridine. Expression of P-glycoprotein was not different between the 3 cell lines but DXR accumulation in both mutants was decreased, indicating a non-P-glycoprotein-associated difference in sensitivity. Conversion of 5'dFUR to 5FU (catalyzed by pyrimidine nucleoside phosphorylases) was 5-10 times higher in both mutants than in the wild type. The activity of the phosphoribosyl-transferase (direct conversion of 5FU to FUMP) was comparable, but the rate of conversion of 5FU to fluorouridine (FUR) was lower in the wild type, as well as that of 5FU to FUMP via FUR. In contrast, the activity of thymidylate synthase, the target enzyme for fluoropyrimidines, was higher in the wild-type cells. The concentrations of both purine and pyrimidine nucleotides were lower in cells expressing trk. In conclusion, transformation of cells with the H-ras or trk oncogenes can markedly influence sensitivity to several drugs and affect normal metabolism and that of several anti-cancer agents.