A human leukemia cell line made resistant to two folate analogues, trimetrexate and N10-propargyl-5,8-dideazafolic acid (CB3717).
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.
Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Japan.
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Y
Takemura
T
T
Ohnuma
H
H
Miyachi
S
S
Sekiguchi
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D003429:Cross Reactions; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008727:Methotrexate / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013940:Thymidylate Synthase / Q000096:biosynthesis; D016597:Trimetrexate / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D011799:Quinazolines; D012333:RNA, Messenger; D003609:Dactinomycin; D014750:Vincristine; D005047:Etoposide; C031662:CB 3717; D004317:Doxorubicin; D005492:Folic Acid; D013940:Thymidylate Synthase; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil; D016597:Trimetrexate; D008727:Methotrexate