# BIOCHEMISTRY AND PATHOLOGY OF 5-FLUOROURACIL EFFECTS

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 1987 · $148,339

## Abstract

Methods have recently been developed (17,19) for detailed biochemical
analysis of tissues exposed in vivo to 5-fluorouracil (FUra).  These
include determination of 5-fluorodeoxyuridylate (FdUMP), the metabolite
that inhibits thymidylate synthetase (TS); deoxyuridylate (dUMP), which
limits this inhibition; free, non-FdUMP-bound enzyme (TSf) and total enzyme
(TStot); and assay of levels of non-radiolabeled FUra incorporated into RNA
(F-RNA) and DNA (F-DNA).  Preliminary application of the TS methods in
patients with adenocarcinomas given bolus FUra has suggested that the
degree of TS inhibition may correlate with clinical response, but this may
reflect histologic differences (18).

In this proposal, comprehensive biochemical and pathologic analyses will be
done on samples of hepatic tumor nodules and bone marrow leukocytes 24 h
following infusional or bolus intravenous FUra 500 mg/m sq.  These samples
will be obtained at laporatomy of patients with colorectal adenocarcinoma
at the University of Goteborg, Sweden, who are treated for hepatic
metastases by hepatic artery ligation and portal vein infusion with FUra.
Determinations of FdUMP, dUMP, TSf, TStot, (3H)FdUMP-binding capacity,
F-RNA, and F-DNA will be done on fresh frozen tumor samples and bone marrow
leukocytes isolated by density gradient centrifugation.  Pathologic
evaluations of paired tissue samples will include semi-quantitative
histologic scoring; quantitative cytomorphometric determinations of
cellularity, mitotic index, nuclear indices, and mucin content; and flow
cytometry analysis of relative DNA content.

Statistical analyses will be done to determine if the biochemical
mechanism(s) of action of FUra varies between adenocarcinomas and bone
marrow leukocytes or varies with the schedule of FUra administration, and
to determine fundamental correlations among biochemical, pathologic, and
clinical data.  These studies ultimately may enable identification of
mechanisms of resistance to FUra, that could be overcome by rational
biochemical approaches.

## Key facts

- **NIH application ID:** 3178856
- **Project number:** 5R01CA039629-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **SAM.gov UEI:** G88KLJR3KYT5
- **Principal Investigator:** COLIN PAUL SPEARS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $148,339
- **Award type:** 5
- **Project period:** 1985-05-01 → 1988-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178856

## Citation

> US National Institutes of Health, RePORTER application 3178856, BIOCHEMISTRY AND PATHOLOGY OF 5-FLUOROURACIL EFFECTS (5R01CA039629-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178856. Licensed CC0.

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