A human leukemia cell line made resistant to two folate analogues, trimetrexate and N10-propargyl-5,8-dideazafolic acid (CB3717).

Abstract

We established a novel human acute lymphoblastic leukemia cell line made resistant to two folate analogues, trimetrexate (TMQ) and N10-propargyl-5,8-dideazafolic acid (CB3717), by sequential exposure of the 200-fold TMQ-resistant cells (MOLT-3/TMQ200) to CB3717. A 30-fold-resistant subline to CB3717 was selected from the TMQ-resistant cells and designated as MOLT-3/TMQ200-CB371730. This double-folate-resistant cell line was 15-fold more resistant to methotrexate (MTX) than MOLT-3/TMQ200; however, TMQ resistance was decreased to 10-fold as compared to MOLT-3/TMQ200. The doubly resistant cells also showed 2-fold cross-resistance to 5-fluorouracil (5-FU). Equimolar concentrations of leucovorin almost completely reversed the inhibitory effect of MTX on the doubly resistant cells and partially that of CB3717 and TMQ; on the other hand, leucovorin enhanced the inhibitory effect of 5-FU. Thymidylate synthase activities demonstrated little or no difference among these three cell lines, being consistent with no overexpression of mRNA for this enzyme in the doubly resistant cells. MOLT-3/TMQ200 cells displayed classical multidrug resistance; sequential development of CB3717 resistance in the TMQ-resistant cells resulted in an enhancement of the multidrug-resistance phenotype and a concomitant increase of MDR1 mRNA. The development of a complex resistance pattern seen in this double-folate-resistant subline indicates intricacy in the study of drug resistance after multidrug chemotherapy.

• Authors: Y Takemura, T Ohnuma, H Miyachi, S Sekiguchi
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 117 Issue 6 Pg. 519-25 ( 1991) ISSN: 0171-5216 [Print] Germany
• PMID: 1683871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Membrane Glycoproteins
• Quinazolines
• RNA, Messenger
• Dactinomycin
• Vincristine
• Etoposide
• CB 3717
• Doxorubicin
• Folic Acid
• Thymidylate Synthase
• Cisplatin
• Leucovorin
• Fluorouracil
• Trimetrexate
• Methotrexate

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents (pharmacology)
• Cell Division (drug effects)
• Cell Line
• Cisplatin (pharmacology)
• Cross Reactions
• Dactinomycin (pharmacology)
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• Drug Resistance
• Etoposide (pharmacology)
• Fluorouracil (pharmacology)
• Folic Acid (analogs & derivatives, pharmacology)
• Humans
• Leucovorin (pharmacology)
• Membrane Glycoproteins (biosynthesis)
• Methotrexate (pharmacology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, immunology)
• Quinazolines (pharmacology)
• RNA, Messenger (biosynthesis)
• Thymidylate Synthase (biosynthesis)
• Trimetrexate (pharmacology)
• Vincristine (pharmacology)