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In Vivo and in Vitro Mechanisms of Drug Resistance in a Rat Mammary Carcinoma Model¹

Departments of Medicine [R. L. S., A. W., M. D., G. B.] and Oncology [G. B.], The Montreal General Hospital and McGill University, Montreal, Canada H3G 1A4

Many in vitro tumor models have been examined to help understand the precise mechanisms responsible for drug resistance. The importance of these results in vivo remains uncertain. MatB 13762 is a rat mammary adenocarcinoma cell line that can be grown both in vitro and as a solid tumor in Fischer 344 rats, thus permitting the examination of tumor cell drug resistance under both conditions. Two cell lines have been selected in vitro for resistance to Adriamycin (Adr^R) and melphalan (Mln^R), respectively. Each subline has the following features: Adr^R, increased mdr-1 messenger RNA, a high level of cross-resistance to vincristine and atypical low level resistance to melphalan and 1,3-bis(2-chloroethyl)-1-nitrosourea, decreased cellular glutathione content, and increased expression of Yc and Yp glutathione S-transferase isozymes; Mln^R, low level drug resistance to melphalan and cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea, Adriamycin, and vincristine; increased cellular concentration of glutathione; elevated glutathione S-transferase activity; and greatly increased messenger RNA specific to the Yc and Yp glutathione-S-transferase subunits. Most of the biochemical and molecular features described above are present but significantly less prominent in tumors grown in vivo. This model provides the opportunity to examine the magnitude of expression and the clinical significance of in vitro resistance in an in vivo model.

¹ This work was supported in part by the National Cancer Institute of Canada.

² Recipient of a fellowship from the Cancer Research Society.

³ Scholar of the Medical Research Council of Canada. To whom requests for reprints should be addressed, at Montreal General Hospital, 1650 Cedar Avenue, Montreal, Canada H3G1A4.

Received 3/14/90. Accepted 12/18/90.

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