Overcoming methotrexate resistance by a lipophilic antifolate (BW 301U): from theory to models to practice.
We have provided a rationale for the clinical use of a new lipid-soluble folate antagonist, BW 301U, in terms of its potential for killing several classes of methotrexate-resistant cells. As part of a Phase I evaluation of this agent we studied normal bone marrow from cancer patients and their metabolic susceptibility to either BW 301U or to MTX and then repeated the observations at the end of five days of BW 301U infusions. Both inhibitors were roughly comparable at equimolar concentrations prior to therapy, but a relative resistance developed to MTX after BW 301U treatment. Such findings were replicated in an in vitro HL-60 cell culture system that was exposed to BW 301U. Some possible mechanisms for this unusual collateral resistance are discussed.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D007942:Leukemia, Experimental / Q000378:metabolism; D008727:Methotrexate / Q000627:therapeutic use*; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D011739:Pyrimethamine / Q000031:analogs & derivatives / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; C006308:metoprine; D004247:DNA; C024530:piritrexim; D008727:Methotrexate; D011739:Pyrimethamine