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Expression of the arg22, drug-resistant variant of dihydrofolate reductase (DHFR) in hematopoietic cells has been demonstrated to confer resistance to methotrexate (MTX) in mice, even though this variant suffers from low catalytic activity. The recently reported tyr22 variant has the advantage of higher catalytic activity combined with significant(More)
Introduction of genes conferring drug resistance into hematopoietic cells may allow for improved chemotherapy by protection of normally drug-sensitive cells from the toxic side-effects of antitumor agents. We recently reported that transplantation of murine marrow transgenic for drug-resistant dihydrofolate reductase (DHFR) protected mice from lethal doses(More)
Effective engraftment of hematopoietic cells targeted for gene transfer is facilitated by cytoreductive preconditioning such as high-dose total body irradiation (TBI). To minimize the adverse side effects associated with TBI, experiments were conducted to determine whether sublethal doses of TBI would allow sufficient engraftment of MTX-resistant(More)
Methotrexate (MTX) dose-escalation studies were conducted in two inbred lines of FVB/N transgenic mice expressing distinct drug-resistant dihydrofolate reductases (DHFRs) and in animals transplanted with transgenic marrow. Survival of animals expressing a tryptophan-31 variant DHFR transgene was only slightly improved over that of normal animals, and(More)
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