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Methotrexate Preconditioning Allows Sufficient Engraftment to Confer Drug Resistance in Mice Transplanted with Marrow Expressing Drug-Resistant Dihydrofolate Reductase Activity
Methotrexate (MTX) is an effective antitumor agent that has been demonstrated to be particularly useful in the treatment of hematopoietic neoplasms but causes substantial hematologic and gastrointestinal toxicity. We previously demonstrated that transplantation with transgenic marrow expressing drug...
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Published in: | The Journal of pharmacology and experimental therapeutics 2005-08, Vol.314 (2), p.668-674 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Methotrexate (MTX) is an effective antitumor agent that has been demonstrated to be particularly useful in the treatment of
hematopoietic neoplasms but causes substantial hematologic and gastrointestinal toxicity. We previously demonstrated that
transplantation with transgenic marrow expressing drug-resistant dihydrofolate reductase (DHFR) into animals preconditioned
by irradiation substantially protected recipient mice from the toxic side effects of methotrexate administration. Here we
test the use of methotrexate itself as a preconditioning agent for engraftment of drug-resistant transgenic marrow, subsequently
conferring drug resistance upon recipient animals. Administration of methotrexate beginning 1 or 2 weeks prior to or on the
same day as transplantation with drug-resistant DHFR transgenic marrow did not allow sufficient engraftment to confer drug
resistance to most unirradiated recipients. A small number of animals were curiously protected from lethal MTX toxicity but
exhibited extremely low hematocrits and were not engrafted with stem cells, as indicated by low engraftment levels assessed
in secondary transplant recipients. However, we subsequently found that MTX preconditioning allowed sufficient engraftment
of DHFR transgenic marrow to confer drug resistance if MTX administration was withdrawn at the time of bone marrow transplantation
(BMT) and withheld until 2 weeks post-transplant. Quantitative molecular analysis of primary and secondary recipients indicated
a stem cell engraftment level of approximately 1%, consistent with previous studies demonstrating that a low level of DHFR
transgenic cell engraftment was sufficient to confer drug resistance in recipient animals. We conclude that MTX can be used
as a preconditioning agent for subsequent engraftment of hematopoietic stem cells, in this case conferring resistance to MTX. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.104.082982 |