Protection of Mice From Lethal Doses of Methotrexate by Transplantation With Transgenic Marrow Expressing Drug-Resistant Dihydrofolate Reductase Activity

Marrow cells from previously established lines of transgenic mice expressing either of two different methotrexate (MTXIresistant dihydrofolate reductases (DHFRs) were transplanted into recipient animals to determine the resultant in vivo protective effect against toxicity associated with MTX administration. Sublethally irradiated, untransplanted animals were first used to establish conditions of low-dose MTX administration resulting in substantial hematopoietic toxicity with undetectable gastrointestinal toxicity. Under these conditions, low survival rates were observed for normal or transgenic animals not expressing drug-resistant DHFR activity, whereas transgenic animals expressing either the argZ2 (line 0 4 ) or trp3l (line 03) DHFR variants survived. Transplantation of lo" marrow cells from either transgenic lines 03 or 04 rescued normal FVB/N recipient animals from low-dose MTX administration, which was lethal for animals