Foster B J, Grotzinger K R, McKoy W M, Rubinstein L V, Hamilton T C
Investigational Drug Branch, National Cancer Institute, Bethesda, MD 20892.
Cancer Chemother Pharmacol. 1988;22(2):147-52. doi: 10.1007/BF00257313.
The clinical utility of adriamycin in the treatment of patients with metastatic breast cancer is often-limited by the development of drug resistance. It has been recognized that in addition to the development of primary resistance against adriamycin, malignant cells can simultaneously develop cross-resistance to other agents. An adriamycin-resistant human breast cancer cell line (MCF 7Ad) was developed by exposing the parent line (MCF 7) to gradually increasing concentrations of adriamycin while the cells were being grown in monolayer. Using these lines in a clonogenic assay, the relative drug sensitivities to adriamycin, vinblastine, melphalan, 5-fluorouracil and methotrexate were studied. MCF 7Ad was 12.5-fold more resistant to adriamycin than MCF 7 and 500-fold cross-resistant to vinblastine. There was no cross-resistance to melphalan, 5-fluorouracil or methotrexate. The resistance of MCF 7Ad was decreased by simultaneous exposure to tamoxifen (by a factor of 3.33) or perhexiline maleate (by a factor of 7.50). This decreased resistance was evidenced by a shift to the left of the sensitivity curves. However, there was no consistent change in the sensitivity curves of MCF 7. At the selected concentration of tamoxifen and perhexiline maleate, the cloning efficiency of MCF 7 and MCF 7Ad was 80%-90% of control values in medium without tamoxifen, perhexiline maleate or cytotoxic drugs. The resistance of MCF 7Ad to adriamycin was associated with a lower accumulation of [14C]adriamycin than exhibited by the sensitive MCF 7 line. There was no consistent change in [14C]adriamycin accumulation in MCF 7 or MCF 7Ad when tamoxifen was added, but when perhexiline maleate was added the [14C] accumulation increased. These results suggest that the tamoxifen-induced change in MCF 7Ad adriamycin resistance was not due to an increase in the amount of cell-associated adriamycin, but rather to some other mechanism that increased the cytotoxicity of the adriamycin.
阿霉素在转移性乳腺癌患者治疗中的临床效用常常受到耐药性产生的限制。人们已经认识到，除了对阿霉素产生原发性耐药外，恶性细胞还能同时对其他药物产生交叉耐药性。通过在单层培养细胞时，将亲本细胞系（MCF 7）暴露于逐渐增加浓度的阿霉素中，建立了一种耐阿霉素的人乳腺癌细胞系（MCF 7Ad）。在克隆形成试验中使用这些细胞系，研究了它们对阿霉素、长春碱、美法仑、5-氟尿嘧啶和甲氨蝶呤的相对药物敏感性。MCF 7Ad对阿霉素的耐药性是MCF 7的12.5倍，对长春碱有500倍的交叉耐药性。对美法仑、5-氟尿嘧啶或甲氨蝶呤没有交叉耐药性。同时暴露于他莫昔芬（耐药性降低3.33倍）或马来酸哌克昔林（耐药性降低7.50倍）可降低MCF 7Ad的耐药性。敏感性曲线左移证明了耐药性的降低。然而，MCF 7的敏感性曲线没有一致的变化。在选定的他莫昔芬和马来酸哌克昔林浓度下，MCF 7和MCF 7Ad在不含他莫昔芬、马来酸哌克昔林或细胞毒性药物的培养基中的克隆效率为对照值的80%-90%。MCF 7Ad对阿霉素的耐药性与[14C]阿霉素的积累量低于敏感的MCF 7细胞系有关。添加他莫昔芬时，MCF 7或MCF 7Ad中[14C]阿霉素的积累没有一致的变化，但添加马来酸哌克昔林时，[14C]积累增加。这些结果表明，他莫昔芬诱导的MCF 7Ad对阿霉素耐药性的变化不是由于细胞相关阿霉素量的增加，而是由于某种其他机制增加了阿霉素的细胞毒性。
