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Selection of Metastatic Variants with Identifiable Karyotypic Changes from a Nonmetastatic Murine Tumor after Treatment with 2'-Deoxy-5-azacytidine or Hydroxyurea: Implications for the Mechanisms of Tumor Progression¹

Departments of Cell Biology [P. F., B. H.], Medicine [P. F.], and Cellular Genetics [S. P.], The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030, and the Division of Cancer Research [R. S. K., S. M.], Mount Sinai Hospital Research Institute, Toronto, Ontario, Canada

Experiments were undertaken to explore whether in vitro exposure of a nonmetastatic murine tumor to chemotherapeutic drugs would affect the ability of this tumor to metastasize spontaneously. The tumor chosen was an aneuploid (near-tetraploid) spontaneously arising intraductal mammary adenocarcinoma (CBA-SP1), which normally fails to give rise to microscopic or macroscopic metastases after s.c. inoculation of cells. The drugs tested were 5-aza-2'-deoxycytidine (5-aza-dCyd) and hydroxyurea. We found that the injection of 1 x 10⁵ uncloned drug-treated cells s.c. resulted in the emergence of gross and/or microscopically detectable metastases in the lungs of CBA mice. Individual clones derived from hydroxyurea-treated cells all produced metastases in a manner similar to the bulk culture injections. Clones of 5-aza-dCyd-treated cells also produced metastases, but fewer of these produced macroscopic metastases. In addition, only 9 of 15 5-aza-dCyd-treated clones produced tumor takes because of the ability of 5-Aza-dCyd to engender Imm+ variants in CBA-SP1 cells. Lung metastases obtained after the injection of uncloned cells retained their metastatic phenotype for three generations, indicating that the phenotypic change was a heritable characteristic. Although the genetic or epigenetic mechanism for this change is unknown, we observed karyotypic changes of a similar nature in the drug-treated cell lines established from micrometastases. These involved the detection of extra copies of chromosome 8. It is possible that exposure of tumors to therapeutic agents may in some cases increase their aggressiveness through genetic or epigenetic mechanisms that lead to high frequency heritable phenotypic alterations associated with distinguishable chromosomal changes.

¹ Supported in part by USPHS Grant CA 39853, the National Cancer Institute of Canada, and D & F Industries, Irvine, CA.

² To whom requests for reprints should be addressed, at Department of Cell Biology, M. D. Anderson Hospital, HMB Box 173, 1515 Holcombe Blvd., Houston, TX 77030.

³ Research Associate of the National Cancer Institute of Canada.

Received 7/15/86. Revised 12/11/86. Accepted 2/19/87.

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