Mechanisms of sensitivity and natural resistance to antifolates in a methylcholanthrene-induced rat sarcoma.
A methylcholanthrene-induced rat sarcoma that can be propagated in vitro or in vivo was evaluated for resistance to antifolates and was found to be relatively resistant to methotrexate and 10-ethyl-10-deazaaminopterin but sensitive to trimetrexate. Rat sarcoma cell extracts contained low levels of dihydrofolate reductase activity, the target enzyme of methotrexate, and inhibition of this enzyme by these three antifolates was similar. Transport studies showed poor uptake of both methotrexate and 10-ethyl-10-deazaaminopterin. In contrast, trimetrexate achieved high intracellular levels. The poor uptake of methotrexate was not due to lack of polyglutamylation. Thus, the basis for natural resistance to methotrexate and 10-ethyl-10-deazaaminopterin, compared with trimetrexate, in this rat sarcoma cell line was due to decreased transport of these drugs.
Li
W W
WW
Laboratory of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Lin
J T
JT
Schweitzer
B I
BI
Bertino
J R
JR
D000630:Aminopterin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D002955:Leucovorin / Q000378:metabolism; D008727:Methotrexate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D008748:Methylcholanthrene; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D013762:Tetrahydrofolate Dehydrogenase / Q000032:analysis; D016597:Trimetrexate / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D005493:Folic Acid Antagonists; D011099:Polyglutamic Acid; D008748:Methylcholanthrene; C014085:methotrexate polyglutamate; D013762:Tetrahydrofolate Dehydrogenase; C040210:edatrexate; D000630:Aminopterin; D002955:Leucovorin; D016597:Trimetrexate; D008727:Methotrexate