Increased thymidylate synthase in L1210 cells possessing acquired resistance to N10-propargyl-5,8-dideazafolic acid (CB3717): development, characterization, and cross-resistance studies

Journal Article · Sun Jun 01 04:00:00 EDT 1986 · Cancer Res.; (United States)

OSTI ID:5618366

Jackman, A L; Alison, D L; Calvert, A H; Harrap, K R

The properties are described of a mutant L1210 cell line (L1210:C15) with acquired resistance (greater than 200-fold) to the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid. TS was overproduced 45-fold and was accompanied by a small increase in the activity of dihydrofolate reductase (2.6-fold). Both the level of resistance and enzyme activities were maintained in drug-free medium (greater than 300 generations). Failure of N10-propargyl-5,8-dideazafolic acid to suppress the (/sup 3/H)-2'-deoxyuridine incorporation into the acid-precipitable material of the resistant line supported the evidence that TS overproduction was the mechanism of resistance; consequently the L1210:C15 cells were largely cross-resistant to another (but weaker) TS inhibitor, 5,8-dideazafolic acid. Minimal cross-resistance was observed to the dihydrofolate reductase inhibitors methotrexate and 5-methyl-5,8-dideazaaminopterin (5- and 2-fold, respectively). L1210 and L1210:C15 cells were, however, equally sensitive to 5-fluorodeoxyuridine (FdUrd), an unexpected finding since a metabolite, 5-fluorodeoxyuridine monophosphate, is a potent TS inhibitor; however, this cytotoxicity against the L1210:C15 cells was antagonized by coincubation with 5 microM folinic acid although folinic acid potentiated the cytotoxicity of FdUrd to the N10-propargyl-5,8-dideazafolic acid-sensitive L1210 line. Thymidine was much less effective as a FdUrd protecting agent in the L1210:C15 when compared with the L1210 cells; however, a combination of thymidine plus hypoxanthine was without any additional effect (compared with thymidine alone) against the sensitive line but effectively protected L1210:C15 cells.

• Research Organization: Institute of Cancer Research, Surrey, England
• OSTI ID: 5618366
• Journal Information: Cancer Res.; (United States), Journal Name: Cancer Res.; (United States) Vol. 6; ISSN CNREA
• Country of Publication: United States
• Language: English

Related Subjects

550901* -- Pathology-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINO ACIDS
ANIMAL CELLS
ANIMALS
ANTIMETABOLITES
ANTINEOPLASTIC DRUGS
AROMATICS
AZAARENES
AZINES
BIOCHEMICAL REACTION KINETICS
CARBOXYLIC ACIDS
CHEMICAL PROPERTIES
DEOXYURIDINE
DISEASES
DRUGS
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
FOLIC ACID
HEMATINICS
HEMATOLOGIC AGENTS
HEMIC DISEASES
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
LEUKEMIA
LIGASES
MAMMALS
MICE
MUTANTS
NEOPLASMS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PTERIDINES
PYRIMIDINES
REACTION KINETICS
RIBOSIDES
RODENTS
THYMIDINE
TOLERANCE
TRACER TECHNIQUES
TRITIUM COMPOUNDS
TUMOR CELLS
URACILS
VERTEBRATES
VITAMIN B GROUP
VITAMINS