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 expr essing either of two different methotrexate (MTX)resistant dihydrofola te reductases (DHFRs) were transplanted into recipient animals to dete rmine the resultant in vivo protective effect against toxicity associa ted with MTX administration. Sublethally irradiated, untransplanted an imals were first used to establish conditions of low-dose MTX administ ration resulting in substantial hematopoietic toxicity with undetectab le gastrointestinal toxicity. Under these conditions, low survival rat es were observed for normal or transgenic animals not expressing drug- resistant DHFR activity, whereas transgenic animals expressing either the arg22 (line 04) or trp31 (line 03) DHFR variants survived. Transpl antation of 10(6) marrow cells from either transgenic lines 03 or 04 r escued normal FVB/N recipient animals from low-dose MTX administration , which was lethal for animals transplanted with 10(6) normal FVB/N ma rrow cells. Reduced survival of transgenic line 04 marrow recipients w as observed when twofold or fourfold doses of MTX were administered, H owever, when 10(7) transgenic line 04 marrow cells were infused, the r ecipients were found to be resistant to a MTX dose that was not only l ethal for animals transplanted with 10(7) normal FVB/N marrow cells, b ut also lethal for normal, untransplanted FVB/N mice, Histologic analy sis showed protection of both marrow and gastrointestinal tissues from MTX toxicity in transgenic line 04 marrow transplant recipients. Thus , exclusive expression of MTX-resistant DHFR activity in the marrow ha d a substantial, systemic chemoprotective effect in animals, which cou ld be applied for improved utilization of MTX for antitumor chemothera py. (C) 1995 by The American Society of Hematology.