Paradoxical effect of BW 301U, a lipophilic antifolate, on methotrexate-inhibitable deoxyuridine incorporation by human hematopoietic cells.
The ability of methotrexate and BW 301U, a lipophilic folate antagonist, to inhibit tritiated deoxyuridine incorporation into acid-precipitable material by human bone marrow cells was evaluated before and after five sequential daily infusions of BW 301U. After in vivo BW 301U therapy, bone marrow cells from five of the six patients exhibited significantly reduced inhibition by 1 microM methotrexate in vitro, whereas the response to 1 microM BW 301U remained unchanged. Megaloblastic marrow morphology and decreased myeloid progenitor cloning efficiency were also observed following five daily BW 301U infusions of 21 and 71 mg/sq m, respectively. A similar reduction in the ability of methotrexate to inhibit tritiated deoxyuridine incorporation was also seen in HL-60 cells, a human acute promyelocytic leukemia cell line, after incubation in vitro with cytostatic concentrations of BW 301U for 3 days. Concomitant changes in the response to BW 301U did not occur. While it is premature to infer clinical significance from this preliminary observation of BW 301U-induced asymmetry in the response to subsequent antifolates, our results augment a growing body of evidence which suggests that lipophilic folate antagonists might be effective in the treatment of methotrexate-resistant neoplasms.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003857:Deoxyuridine / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D008727:Methotrexate / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D014316:Tritium; C024530:piritrexim; D013936:Thymidine; D003857:Deoxyuridine; D008727:Methotrexate