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Protection of mice from lethal doses of methotrexate by transplantation
with transgenic marrow expressing drug-resistant dihydrofolate reductase
activity
C May, R Gunther and RS McIvor
Institue of Human Genetics, University of Minnesota, Minneapolis 55455,
USA.
Marrow cells from previously established lines of transgenic mice
expressing either of two different methotrexate (MTX)-resistant
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 arg22 (line 04) or trp31 (line 03) DHFR variants
survived. Transplantation of 10(6) 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 transplanted with 10(6) normal
FVB/N marrow cells. Reduced survival of transgenic line 04 marrow
recipients was observed when twofold or fourfold doses of MTX were
administered. However, when 10(7) transgenic line 04 marrow cells were
infused, the recipients were found to be resistant to a MTX dose that was
not only lethal for animals transplanted with 10(7) normal FVB/N marrow
cells, but also lethal for normal, untransplanted FVB/N mice. Histologic
analysis 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 had a
substantial, systemic chemoprotective effect in animals, which could be
applied for improved utilization of MTX for antitumor chemotherapy.
Volume 86,
Issue 6,
pp. 2439-2448,
09/15/1995
Copyright © 1995 by The American Society of Hematology
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