Derivation and initial characterization of a mouse mammary tumor cell linecarrying the polyomavirus middle T antigen: Utility in the development of novel cancer therapeutics

Here we describe the derivation of novel cell lines from spontaneous mammar y tumors that arose in mouse mammary tumor virus-polyomavirus (MMTV-PyV) Mi ddle T (MidT) transgenic mice. Clonal cell lines from four mixed cell popul ations were tested for adenovirus transducibility and sensitivity to p53 tu mor suppressor gene therapy mediated by SCH58500, a :replication-deficient adenovirus that expresses human p53, The MidT2-1 cell line was selected for further characterization ill vitro and in vivo. This cell line carried the PyV MidT antigen, had wild-type p53 DNA, and was sensitive to suppression of proliferation by MMAC/PTEN tumor suppressor gene therapy. MidT2-1 cells gave rise to highly aggressive tumors in syngeneic FVB mice in both the mam mary fat pad and the peritoneal cavity. The histopathology of MidT2-1 tumor s closely resembled the histopathology of the primary transgenic tumors. Tu mor growth in vivo was inhibited by p53 gene therapy or by MMAC gene therap y. In addition, combination therapy with a number of anticancer agents had synergistic or additive efficacy in vitro. In particular, MMAC gene therapy synergized with SCH58500 or paclitaxel. In the i.p. MidT2-1 tumor model, p 53 gene;therapy enhanced the survival benefits of paclitaxel/cisplatin chem otherapy. Combination therapy has become a mainstay in cancer treatment. In this report, we use a novel transgenic mouse tumor cell line to:suggest ne w combinations that might be explored in clinical cancer care. These includ e gene therapy using the tumor suppressors MMAC and p53, chemotherapy using farnesyl transferase inhibitors, the microtubule-stabilizing taxanes, and the DNA synthesis disrupters gemcitabine and cisplatin, The precise biologi cal mechanisms by which these therapies induce their antitumor effects are not fully elucidated. However, the work presented here suggests that many o f these therapeutic approaches have synergistic antitumor activity when use d in combination.