Document Detail

Multidrug resistance in a human leukemic cell line selected for resistance to trimetrexate.
MedLine Citation:
PMID:  2573416     Owner:  NLM     Status:  MEDLINE    
Trimetrexate (TMQ) is a lipophilic antifolate shown to have antitumor activity in humans. TMQ-resistant sublines of the MOLT-3 human acute lymphoblastic leukemia cell line were developed and were designated as MOLT-3/TMQ200, MOLT-3/TMQ800, and MOLT-3/TMQ2500 based on degrees of resistance to TMQ. The TMQ resistance was accompanied by 5- to 7-fold increases in dihydrofolate reductase activity and markedly reduced cellular TMQ accumulation. Methotrexate accumulation was not impaired in TMQ-resistant cells. TMQ retention (efflux) was unchanged in these TMQ-resistant cells. Verapamil enhanced the TMQ accumulation in the resistant cells to the level seen in the parent cells but had no effects on the TMQ retention. These sublines were cross-resistant not only to methotrexate but also to vincristine, doxorubicin, daunorubicin, and mitoxantrone. There was no cross-resistance to bleomycin or cisplatin. Resistance to vincristine, doxorubicin, daunorubicin, and mitoxantrone was reversed by verapamil. TMQ resistance was only minimally reversed by verapamil and methotrexate resistance not affected at all. Both cellular accumulation and retention of vincristine and daunorubicin in the TMQ-resistant cells were markedly decreased. Verapamil enhanced both accumulation and retention of the drug. Plasma membrane fractions of the TMQ-resistant cells analyzed by urea-sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by staining with Coomassie Blue revealed the presence of a distinct band with a molecular weight of 170,000. Immunoblot analysis with 125I-labeled monoclonal antibody raised against P-glycoprotein of multidrug-resistant Chinese hamster ovary cells (C219) cross-reacted with the Mr 170,000 protein of the TMQ-resistant cells. These results show that the TMQ-resistant cells displayed not only decreased TMQ uptake and increased dihydrofolate reductase but also characteristics associated with a classical multidrug-resistant phenotype. Multidrug resistance includes lipophilic antifolate.
H Arkin; T Ohnuma; B A Kamen; J F Holland; S Vallabhajosula
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  49     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1989 Dec 
Date Detail:
Created Date:  1989-12-27     Completed Date:  1989-12-27     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  6556-61     Citation Subset:  IM    
Department of Neoplastic Diseases, Mount Sinai School of Medicine, New York, New York 10029.
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MeSH Terms
Biological Transport / drug effects
Drug Resistance*
Membrane Glycoproteins / metabolism
Methotrexate / metabolism
Quinazolines* / metabolism
Tetrahydrofolate Dehydrogenase / metabolism
Tumor Cells, Cultured
Verapamil / pharmacology
Vincristine / metabolism
Grant Support
Reg. No./Substance:
0/Membrane Glycoproteins; 0/P-Glycoprotein; 0/Quinazolines; 23214-92-8/Doxorubicin; 52-53-9/Verapamil; 52128-35-5/Trimetrexate; 57-22-7/Vincristine; 59-05-2/Methotrexate; EC Dehydrogenase

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