The mechanism of differential sensitivity to methotrexate of normal and malignant human epidermal cells.
The mechanism of differential sensitivity to methotrexate of normal and malignant human epidermal cells.
复制标题
正常和恶性人表皮细胞对甲氨蝶呤敏感性差异的机制。
DOI：
10.1007/bf00685506
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发表时间：
1991
影响因子：
3
通讯作者：
Wick,MM
中科院分区：
文献类型：
--
作者：
Lee,MM;Ratliff,J;FitzGerald,GB;Wick,MM
通过细胞生长测量，鳞状癌细胞对甲氨蝶呤（MTX）和5-氟脱氧尿苷（FUDR）的细胞毒性作用比正常的人角质形成细胞敏感得多（bb10 - 104倍）。在测试的药物中，发现这种现象对MTX和FUDR具有特异性，因为阿拉伯糖胞苷（ARA-C）、13-双氯乙基亚硝基脲（BCNU）和道诺霉素在正常和恶性细胞系之间的抑制没有表现出差异。药物摄取研究未显示恶性和正常表皮细胞系在60分钟时细胞内MTX水平有显著差异。通过检测3 μM TdR对mtx诱导的细胞毒性的影响来评估胸腺嘧啶（TdR）的挽救作用。停用TdR后，正常细胞的抑制水平增加了4个数量级，而鳞状细胞癌细胞的敏感性没有变化。有趣的是，不朽的非致瘤性角化细胞系（NM-110）同样没有被TdR的加入所拯救。鳞状细胞癌（SCC）和NM-110细胞对MTX的高度敏感性是由于与正常角质形成细胞相比，它们使用外源性TdR的能力显著降低，这可能表明与细胞不朽相关的生化变化。
Squamous carcinoma cells are much more sensitive (>104times) to the cytotoxic effects of methotrexate (MTX) and 5-fluorodeoxyuridine (FUDR) than are normal human keratinocytes as measured by cell growth. Among the drugs tested, this phenomenon was found to be specific for MTX and FUDR, since arabinosylcytidine (ARA-C), 13-bis-chloroethylnitrosourea (BCNU), and daunomycin failed to show differences in inhibition between the normal and malignant cell lines. Drug uptake studies did not reveal a significant difference in MTX intracellular levels between malignant and normal epidermal cell lines at 60 min. Thymidine (TdR) salvage was assessed by examining the effects of the presence of 3 μM TdR on MTX-induced cytotoxicity. On the withdrawal of TdR, normal cells demonstrated an increased level of inhibition amounting to 4 orders of magnitude, whereas the squamous-cell carcinoma cells showed no change in sensitivity. Interestingly, the immortal nontumorigenic keratinocyte line (NM-110) was similarly not rescued by the addition of TdR. The high degree of sensitivity to MTX shown by squamous-cell carcinoma (SCC) and NM-110 cells is attributable to a significant diminution of their ability to use exogenous TdR as compared with that of normal keratinocytes and might be indicative of a biochemical change associated with cellular immortality.