POSTTRANSPLANT METHOTREXATE ADMINISTRATION LEADS TO IMPROVED CURABILITY OF MICE BEARING A MAMMARY-TUMOR TRANSPLANTED WITH MARROW TRANSDUCEDWITH A MUTANT HUMAN DIHYDROFOLATE-REDUCTASE CDNA

To test the concept that protection of bone marrow progenitor cells vi a introduction of a drug resistance gene would allow larger and curati ve doses of chemotherapy to be administered, we used mice bearing a tr ansplanted breast cancer as a model system, Mice bearing the E0771 tum or were treated with lethal doses of cyclophosphamide (CPA) and rescue d from toxicity by administration of bone marrow transduced with a mut ant dihydrofolate reductase (DHFR) cDNA (Ser-31) in a retroviral const ruct, Animals receiving marrow not transduced with mutant DHFR cDNA di ed from methotrexate (MTX) toxicity, whereas mice transduced with muta nt DHFR cDNA containing marrow were able to tolerate MTX treatment pos t-transplant; 44% of the mice had no demonstrable tumor when sacrifice d on day 52. Another control group of mice treated with CPA and transp lanted but not treated with MTX post-transplant succumbed to tumor reg rowth, These data provide a strong rationale for the use of drug resis tance genes to protect marrow from drug toxicity because the increase in dose tolerated may result in an improved cure rate of chemosensitiv e tumors.