# EFFECTS OF ANTIMETABOLITES ON RNA METABOLISM

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 1987 · $124,447

## Abstract

A number of antimetabolites (e.g. nucleoside analogs) have been shown to
have a chemotherapeutic effect.  Among these agents, 5-fluorouracil (FUra)
is a widely used agent whose mechanism of action is still not clear.
Numerous laboratories have demonstrated incorporation of FUra into RNA and
this is considered to be one of its three major sites of action.  The other
two major effects are 1) conversion to the deoxyribonucleotide and
inhibition of thymidylate synthetase and 2) conversion to the
deoxyribonucleoside triphosphate and possible incorporation into DNA.  This
study will concentrate on the effects of FUra due to incorporation into RNA.

Previously, the major RNA effect was considered to be inhibition of
ribosomal RNA (rRNA) maturation.  Our laboratory previously demonstrated
that miscoding of messenger RNA (mRNA) appears to occur at concentrations
of FUra where no effect on rRNA is evident.

The study is based upon the preliminary observation that FUra causes an
alteration in the properties of dihydrofolate reductase (DHFR) and several
species of RNA.  Specifically, we propose to study the following.

1) Further evaluate the effects of FUra incorporation into RNA on enzymes
synthesized from the substituted mRNA (using DHFR and DHFR mRNA as a model
enzyme and mRNA, respectively).

2) The effect of FUra on RNA processing (specifically DHFR RNA as a model)
both in vivo and in vitro.

3) The effect of FUra on small nuclear RNA (using U1 RNA as a model).

4) rRNA.

The relative importance of these four possible sites will be assessed.  The
results of this study will be able to provide means and models to study the
RNA-mediated effects of other nucleoside analogs which are incorporated
into RNA.

## Key facts

- **NIH application ID:** 3172014
- **Project number:** 5R01CA034301-05
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **SAM.gov UEI:** LCLSJAGTNZQ7
- **Principal Investigator:** BRUCE JEFFREY DOLNICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $124,447
- **Award type:** 5
- **Project period:** 1983-05-01 → 1988-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172014

## Citation

> US National Institutes of Health, RePORTER application 3172014, EFFECTS OF ANTIMETABOLITES ON RNA METABOLISM (5R01CA034301-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172014. Licensed CC0.

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