Kobayashi H, Man S, Graham C H, Kapitain S J, Teicher B A, Kerbel R S
Division of Cancer Research, Sunnybrook Health Science Centre, Toronto, ON, Canada.
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3294-8. doi: 10.1073/pnas.90.8.3294.
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.
通过用相应药物对荷瘤小鼠进行序贯治疗，在体内产生了对环磷酰胺、顺二氨二氯铂（II）或氮芥高度耐药的EMT - 6小鼠乳腺肿瘤亚系。先前的研究表明，当这些细胞作为单层培养物生长时，亚系的耐药表型在体外并不表达。我们现在表明，当细胞在类似体内的三维条件下生长，即作为多细胞肿瘤球体生长时，耐药性的表达——包括在体内观察到的交叉耐药模式——可以在体外完全重现。此外，从所有耐药亚系产生的球体表现出更紧密的结构。对通过胰蛋白酶处理从紧密的耐药球体中释放的单细胞进行即时药敏试验表明，这些细胞失去了大部分耐药特性。结果表明，与经典的（单）细胞耐药机制相反，肿瘤中获得性耐药可能基于细胞群体的反应（即多细胞或组织耐药）。
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