Acquired Multicellular-Mediated Resistance to Alkylating Agents in Cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 8; pp. 3294 - 3298
• Main Authors: Kobayashi, Hiroaki, Man, Shan, Graham, Charles H., Kapitain, Sean J., Teicher, Beverly A., Kerbel, Robert S.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15.04.1993; National Acad Sciences; National Academy of Sciences
• Subjects: Alkylating Agents - pharmacology; Animals; Antineoplastic agents; Antineoplastics; Biological and medical sciences; Cancer; Cell aggregates; Cell Aggregation - drug effects; Cell growth; Cell lines; Cell Survival - drug effects; Cells; Cellular biology; Cisplatin - pharmacology; Cyclophosphamide - pharmacology; Delta cells; Drug resistance; Drug Resistance - physiology; Drugs; General aspects; Mammary Neoplasms, Experimental; Medical sciences; Mice; Mice, Inbred BALB C; Pharmacology. Drug treatments; Rodents; Spheroids; Thiotepa - pharmacology; Tumor cell line; Tumor Cells, Cultured; Tumor Stem Cell Assay; Tumors; Antineoplastic agent; Rodentia; In vitro; Mechanism; Resistance; Mammary gland diseases; Vertebrata; Alkylating agent; Mammalia; Three dimensional culture; Cell population; Mouse; Animal; Tumor; Mammary gland; Tumor cell
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.8.3294

EMT-6 murine mammary tumor sublines highly resistant to cyclophosphamide, cis-diamminedichloroplatinum(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.