ACQUIRED MULTICELLULAR-MEDIATED RESISTANCE TO ALKYLATING-AGENTS IN CANCER
ACQUIRED MULTICELLULAR-MEDIATED RESISTANCE TO ALKYLATING-AGENTS IN CANCER
复制标题
DOI：
10.1073/pnas.90.8.3294
复制
发表时间：
1993-04-15
影响因子：
11.1
通讯作者：
KERBEL, RS
中科院分区：
文献类型：
--
作者：
KOBAYASHI, H;MAN, S;KERBEL, RS
对环磷酰胺、顺式二氨基二氯铂(II)或N，N‘，N’‘-三乙烯硫代磷酰胺等药物进行体内序贯治疗，获得了对环磷酰胺、顺铂(II)或N，N’，N‘-三乙烯硫代磷酰胺高度耐药的EMT-6小鼠乳腺肿瘤亚系。以前的研究表明，当细胞以单层培养方式生长时，亚系的耐药表型在体外不表达。我们现在证明，当细胞在类似体内的三维条件下生长时，包括体内观察到的交叉耐药模式在内的耐药性的表达可以在体外完全概括--即多细胞肿瘤球体。此外，从所有耐药亚系产生的球体显示出更紧凑的结构。对紧凑的耐药球体经胰酶处理后释放的单个细胞立即进行药物敏感性测试，结果显示这些细胞失去了大部分抗药特性。这些结果提示，肿瘤获得性耐药的可能机制是基于细胞群体的反应(即多细胞或组织耐药)，而不是经典的(单细胞)耐药机制。
EMT-6 murine mammary tumor sublines highly resistant to cyclophosphamide, cis-diamminedichloro-platinum(II), or N,N',N''-triethylenethiophosphoramide were generated in vivo by sequential treatment of tumor-bearing mice with the respective drugs. Previous studies demonstrated the drug-resistant phenotypes of the sublines were not expressed in vitro when the cells were grown as monolayer cultures. We now show that expression of drug resistance- including patterns of cross-drug resistance observed in vivo- can be fully recapitulated in vitro when the cells are grown under in vivo-like, three-dimensional conditions-namely, as multicellular tumor spheroids. Moreover, the spheroids generated from all of the drug-resistant sublines manifested a much more compact structure. Immediate drug-sensitivity testing of single cells released by trypsin treatment from compact drug-resistant spheroids revealed that such cells lost much of their drug-resistant properties. The results suggest a possible mechanism of acquired drug resistance in tumors based on the response of a cell population (i.e., multicellular or tissue resistance) as opposed to classic (uni)cellular resistance mechanisms.