Progression and enhancement of metastatic potential after exposure of tumor cells to chemotherapeutic agents

Data presented in this report indicate short-term irt vitro treatment of no nmetastatic MCF-7 breast carcinoma cells with the chemotherapeutic agents-, Adriamycin and/or 5-fluoro-2 ' -deoxyuridine (FUdR), induced changes in th e expressed phenotype, Cells treated sequentially with Adriamycin and FUdR expressed a metastatic phenotype, The results also show short-term exposure of MCF-7 cells to either Adriamycin or FUdR rapidly increases, in a dose-d ependent manner, the release of the angiogenic cytokine, interleukin-8(IL-8 ), which is released at consistently higher levels in metastatic cell lines . Cell populations surviving a single treatment with either one or both of these chemotherapeutic agents continue to stably release IL-8. Survivors of sequential treatment with Adriamycin and FUdR (MCF-7 A/F) release the most IL-8 and express the greatest phenotypic variance from the parental, MCF-7 cells. Parental MCF-7 cells and MCF-7 A/F cells both form primary tumors w hen used in an orthotopic tumor model; however, the MCF-7 A/F tumors have a more rapid initial growth phase in situ and give rise to spontaneous lung metastases within 10 weeks. A cell line that is established from lung metas tases releases more IL-8, has a higher cloning efficiency, and forms looser colonies in monolayer than do their parental cells. These experiments indi cate the in vitro exposure of tumor cells to chemotherapeutic agents either selects more aggressive cells or enhances the metastatic potential of the surviving cells.