Tumor cell responses to inhibition of thymidylate synthase

Book · Sun Jan 01 04:00:00 EST 1989

OSTI ID:6321378

Keyomarsi, K

The cellular, biochemical and molecular events that occur in tumor cells treated with inhibitors of thymidylate synthase (TS) were studied. 5-Fluorouracil (5-FUra) and fluorodeoxyuridine (FdUrd) are more growth inhibitory to mouse and human tumor cells when grown in medium containing folinate. L1210 cells exposed to folinate and noncytotoxic concentrations of 5-FUra or FdUrd, resulted in a 98% to 99.98% cell kill. Exposure of L1210 cells to folinate resulted in expansion of intracellular pools of 5,10-methylenetetrahydrofolate, delayed the reappearance of catalytically active TS following FdUrd exposure, and stabilized inactive TS complexes over the same concentration range that augmented the cytotoxic effect of FdUrd and 5-FUra. In intact L1210 cells, fluorodeoxyuridylate (FdUMP) behaved as an inhibitor whose complexes with TS dissociate with a biologically significant rate. However, these complexes become functionally irreversible in cells incubated with high levels of folinate. CB 3717 eliminated TS activity in L1210 cells, yet the inactive enzyme retained the ability to bind ({sup 3}H)-FdUMP covalently, suggesting that the binding of one subunit of TS inactivates the catalytic activity of both subunits.

• Research Organization: University of Southern California, Los Angeles, CA (USA)
• OSTI ID: 6321378
• Country of Publication: United States
• Language: English

Related Subjects

550901* -- Pathology-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
ANIMALS
BIOCHEMICAL REACTION KINETICS
CELL KILLING
ENZYME ACTIVITY
ENZYME INHIBITORS
GROWTH
HYDROGEN COMPOUNDS
INHIBITION
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
MAN
MICE
PRIMATES
REACTION KINETICS
RODENTS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
TUMOR CELLS
VERTEBRATES