# CELLULAR EFFECTS OF INHIBITION OF THYMIDYLATE SYNTHASE

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 1992 · $176,421

## Abstract

Inhibition of the key enzyme thymidylate synthase (TS) is a major cause of
the activity of 5-fluorouracil (5-FU) as a cancer chemotherapeutic agent.
Newer methods of administration of 5-FU, such as combination with reduced
folates and with inhibitors of ribonucleotide reductase, have recently
improved the effectiveness of this drug against several adult carcinomas.
Hence, there is a renewed urgency to efforts aimed at understanding the
responses of normal and neoplastic stem cells to pharmacologically induced
cellular deficiencies in the supply of thymidine nucleotides. This
application proposes to study the biochemcial phenomena initiated by
inhibition of TS that cause cell death in normal and neoplastic population.
The progression of cells out of S-phase will be analyzed in cultured cells
undergoing thymidine nucleotides. This application proposes to study the
biochemical phenomena initiated by inhibition of TS that cause cell death
in normal and neoplastic populations. The progression of cells out of S-
phase will be analyzed in cultured cells undergoing thymidine nucleotide
starvation using a series of biochemical techniques. The identity of the
proteins accumulating in these cells and the appropriateness of the RNA
species to the cell cycle phase will be examfined. The significance of
discrete DNA fragments that can be detected in these cells will be pursued
and related to the irreversible committment of cells to death. The
generality of this phenomenon and its utility afor fine mapping the sequence
of S-phase will be sgudied. The mechanism of the accumulation of TS and
other proteins involved in S-phase specific events will be determined in
cells in which TS is inhibited. The mechanism whereby hydroxyurea augments
the cytotoxic activity of 5-FU will be studied. Initially, the hypothesis
that inhibition of the accumulation of dUMP is the cause of this synergism
will be investigated. The response of tumor cells to inhibition of TS by
the folate analog CB 3717 will be compared with that following 5-FU. The
role of the unnatural diastercomer of 5-formyltetrahydrofolate in limiting
the activity of the natural isomer will be studied. Likewise, the
cytotoxicity to 5-FU and folinic acid will be determined in a series of
relevant human tumor cell lines and will be correlated with the stability
of ternary complex in these cells. Finally, an explanation for the limited
increase in the host toxicity of 5-FU when folinic acid is simultaneously
administered will be sought on a biochemical level.

## Key facts

- **NIH application ID:** 3173562
- **Project number:** 5R01CA036054-10
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **SAM.gov UEI:** G88KLJR3KYT5
- **Principal Investigator:** RICHARD G MORAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $176,421
- **Award type:** 5
- **Project period:** 1983-07-01 → 1993-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3173562

## Citation

> US National Institutes of Health, RePORTER application 3173562, CELLULAR EFFECTS OF INHIBITION OF THYMIDYLATE SYNTHASE (5R01CA036054-10). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3173562. Licensed CC0.

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