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. 1993 Apr 15;90(8):3294–3298. doi: 10.1073/pnas.90.8.3294

Acquired multicellular-mediated resistance to alkylating agents in cancer.

H Kobayashi 1, S Man 1, C H Graham 1, S J Kapitain 1, B A Teicher 1, R S Kerbel 1
PMCID: PMC46286  PMID: 8475071

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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