Elliott E M, Ling V
Cancer Res. 1981 Feb;41(2):393-400.
Melphalan (Alkeran) is an alkylating agent commonly used in the treatment of multiple myeloma and other neoplasia. We have isolated melphalan-resistant (MelR) Chinese hamster ovary cells in vitro. Stably resistant clones were observed with a frequency of about 10(-7) after a single drug exposure. Two clones, MelR1 and MelR6, were studied in detail, and their phenotypes were compared to a colchicine-resistant membrane permeability mutant (CHRC5) isolated previously by Ling and Thompson (J. Cell Physiol., 83: 103-116, 1974), which was cross-resistant to melphalan. The MelR cones were cross-resistant to the nitrogen mustard class of alkylating agents, such as melphalan, nitrogen mustard, and chlorambucil, but not to alkylating agents, such as methanesulfonic acid:ethyl ester or mitomycin C. The MelR clones differed from CHRC5 in their lack of cross-resistance to puromycin and Adriamycin. Studies with [14C]melphalan showed CHRC5, but not the MelR clones, to be defective in drug accumulation into whole cells. The mechanism of melphalan resistance in CHRC5 is attributed to reduced drug accumulation due to a plasma membrane alteration. In the MelR clones, investigation of drug distribution into cell subfractions revealed reduced accumulation into the nucleus compared to the parental cell line. We therefore propose that the mechanism of resistance in the MelR cells results from a nuclear alteration(s) specific to a subclass of alkylating agents.
美法仑（马法兰，Alkeran）是一种常用于治疗多发性骨髓瘤和其他肿瘤的烷化剂。我们在体外分离出了对美法仑耐药（MelR）的中国仓鼠卵巢细胞。单次药物暴露后，稳定耐药克隆的出现频率约为10^(-7)。对两个克隆MelR1和MelR6进行了详细研究，并将它们的表型与Ling和Thompson（《细胞生理学杂志》，83: 103 - 116, 1974）之前分离的对秋水仙碱耐药的膜通透性突变体（CHRC5）进行了比较，CHRC5对美法仑有交叉耐药性。MelR克隆对氮芥类烷化剂如美法仑、氮芥和苯丁酸氮芥有交叉耐药性，但对甲磺酸乙酯或丝裂霉素C等烷化剂没有交叉耐药性。MelR克隆与CHRC5的不同之处在于它们对嘌呤霉素和阿霉素缺乏交叉耐药性。用[14C]美法仑进行的研究表明，CHRC5在药物积累到全细胞方面存在缺陷，但MelR克隆没有。CHRC5中对美法仑耐药的机制归因于由于质膜改变导致的药物积累减少。在MelR克隆中，对药物在细胞亚组分中的分布研究表明，与亲代细胞系相比，其在细胞核中的积累减少。因此，我们提出MelR细胞的耐药机制是由特定亚类烷化剂所特有的核改变导致的。
