# SELECTIVE THERAPY FOR COLON CARCINOMA

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 1988 · $125,480

## Abstract

The enzyme thymidylate synthase provides a unique pathway for de novo
biosynthesis of dTMP in mammalian cells, and is considered an important
target in mediating the cytotoxicity of 5-fluorouracil (FUra) in human
colon carcinomas.  This application concerns three aspects of thymidylate
synthase as a target for therapy in colon carcinoma.  These are a)
modulation of the interaction of 5-fluorodeoxyuridylate (FdUMP) with
thymidylate synthase, b) the role of dThd salvage in intrinsic resistance,
and hence the significance of thymidylate synthase as a target for tumors
in situ, and c) the consequences of FUra base substitution in thymidylate
synthase mRNA.

Modulation studies will examine the consequences of the addition of
polyglutamate residues to N5, N10-methylenetetrahydrofolate
(CH2-H4PteGlu-n), in terms of affinity for thymidylate synthase purified
from human colon adenocarcinoma xenografts, and effect on the kinetics of
the catalytic reaction, the binding of FdUMP, and stability of covalent
ternary complexes.  The distribution of CH2-H4PteGlu-n in colon xenografts
and the effect of leucovorin administration will be examined.

The role of dThd salvage in determining the sensitivity of xenografts to
FUra will be examined.  Specifically, cloned colon adenocarcinoma cell
lines deficient in thymidine kinase activity (TK-) will be selected in
tissue culture and characterized by TK activity, clonogenic survival after
FUra, and drug metabolism.  In vivo models will be developed by growing
clonal parent and TK- variants in immune-deprived mice with
characterization as above.

In a cell free system, the effect of FUra substitution at specific
frequencies into thymidylate synthase mRNA will be examined with respect to
alteration of the rate and function of in vitro synthesized mRNA, and the
rate of translation and function of translated protein.

The long term objectives are to a) identify potential targets for
chemotherapeutic agents using cell free systems, and b) determine their
significance in the treatment of human colon cancer by further development
of relevant in vitro and in vivo models of human colon adenocarcinoma in
which treatment strategies and hypotheses may be tested.

## Key facts

- **NIH application ID:** 3170519
- **Project number:** 5R01CA032613-06
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **SAM.gov UEI:** JL4JHE9SDRR3
- **Principal Investigator:** JANET A. HOUGHTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $125,480
- **Award type:** 5
- **Project period:** 1983-07-01 → 1989-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3170519

## Citation

> US National Institutes of Health, RePORTER application 3170519, SELECTIVE THERAPY FOR COLON CARCINOMA (5R01CA032613-06). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3170519. Licensed CC0.

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