# SELECTIVE THERAPY FOR COLON CARCINOMA

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 1991 · $176,498

## Abstract

The objectives of the proposal are to focus on thymidylate synthase (TS)
as a therapeutic target in the treatment of colon adenocarcinoma.
Studies will examine ways of combining 5-fluorouracil (FUra) with
potential modulators of reduced folate pools, in particular leucovorin
([6RS]LV), to maximize TS inhibition and FUra cytotoxicity, and identify
sites distal to TS that may be modulated to increase the cytotoxic
effects of TS inhibition.  Xenografts of human colon adenocarcinomas,
clonal cultured cell lines derived from these, and clonal mutants
selected for deficiency in de novo (TS-) or salvage (TK-) pathways for
dTMP biosynthesis will be utilized.

Optimization of FUra-[6RS]LV in vivo will be based upon in vitro and in
vivo studies.  Experimental designs include the relationship between dose
of [6RS]LV, schedule of administration, metabolism, TS inhibition, and
expansion of pools of tetrahydrofolate polyglutamates (H4PteGlun) and
5,10-methylenetetrahydrofolates (CH2-H4PteGlun), which are important for
stabilizing the covalent ternary complex formed between 5-
flurordeoxyuridylate (FdUMP), TS and CH2-H4PteGlun.  In vivo studies will
determine intracellular events relative to plasma pharmacokinetics of
reduced folates, and will evaluate other potential precursors of CH2-
H4PteGlu.  The influence of the inactive [6R] isomer of LV on the
cellular pharmacology of active [6S]LV and cytotoxic action of FUra, and
other potential modulators of CH2-H4PteGlun and H4PteGlun pools will
initially be evaluated in vitro.  These studies will be important in
understanding critical factors that influence the modulation of FUra
activity in tumors with different metabolic characteristics of [6RS]LV
metabolism.

In human tumor xenografts and cell lines, the level and activity of TS
varies by >40-fold, and is higher in FUra-unresponsive tumors.  Turnover
and regulation of TS may therefore have therapeutic significance and will
b examined.

Lastly, it will be determined whether thymine-less death is associated
with dNTP imbalance and induction of an endonuclease activity proposed as
a general model for antimetabolite death.  Using the TS- and TK- mutants,
evaluation of possible "nonclassical" salvage in which TS+ cells may
rescue TS- cells, will be made.

These studies will design therapy to optimize FUra-folate combinations,
shown to have clinical efficacy, and will allow development and testing
of strategies that may have synergistic therapeutic efficacy with therapy
directed at the TS locus.

## Key facts

- **NIH application ID:** 3170521
- **Project number:** 5R01CA032613-09
- **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:** 1991
- **Award amount:** $176,498
- **Award type:** 5
- **Project period:** 1983-07-01 → 1994-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3170521

## Citation

> US National Institutes of Health, RePORTER application 3170521, SELECTIVE THERAPY FOR COLON CARCINOMA (5R01CA032613-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3170521. Licensed CC0.

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