Derivation and initial characterization of a mouse mammary tumor cell line carrying the polyomavirus middle T antigen: utility in the development of novel cancer therapeutics.
Here we describe the derivation of novel cell lines from spontaneous mammary tumors that arose in mouse mammary tumor virus-polyomavirus (MMTV-PyV) Middle T (MidT) transgenic mice. Clonal cell lines from four mixed cell populations were tested for adenovirus transducibility and sensitivity to p53 tumor suppressor gene therapy mediated by SCH58500, a replication-deficient adenovirus that expresses human p53. The MidT2-1 cell line was selected for further characterization in 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 mammary fat pad and the peritoneal cavity. The histopathology of MidT2-1 tumors closely resembled the histopathology of the primary transgenic tumors. Tumor growth in vivo was inhibited by p53 gene therapy or by MMAC gene therapy. 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 p53 gene therapy enhanced the survival benefits of paclitaxel/cisplatin chemotherapy. Combination therapy has become a mainstay in cancer treatment. In this report, we use a novel transgenic mouse tumor cell line to suggest new combinations that might be explored in clinical cancer care. These include gene therapy using the tumor suppressors MMAC and p53, chemotherapy using farnesyl transferase inhibitors, the microtubule stabilizing taxanes, and the DNA synthesis disruptors gemcitabine and cisplatin. The precise biological mechanisms by which these therapies induce their antitumor effects are not fully elucidated. However, the work presented here suggests that many of these therapeutic approaches have synergistic antitumor activity when used in combination.
Nielsen
L L
LL
Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-1300, USA. loretta.nielsen@spcorp.com
Gurnani
M
M
Shi
B
B
Terracina
G
G
Johnson
R C
RC
Carroll
J
J
Mathis
J M
JM
Hajian
G
G
D000256:Adenoviridae / Q000235:genetics; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002455:Cell Division; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase; D005260:Female; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000235:genetics; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017422:Sequence Analysis, DNA; D043823:Taxoids; D013997:Time Factors; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D000093542:Gemcitabine
D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D019384:Nucleic Acid Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C080625:taxane; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine