# MECHANISM OF ACTION OF DIFFERENTIATION AGENTS

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 1993 · $174,519

## Abstract

Due to a lack of curative chemotherapy for many solid tumors, alternative
therapeutic approaches have received considerable attention.  One such
approach has been attempts to generate non-cytotoxic induction of
differentiation.  Most agents utilized for this approach have not been
clinically successful partly because the agents used are not effective
inducers of differentiation unless they are used at concentrations which
are marginally toxic.  Therefore, the objective of the original proposal
for this renewal application, was the identification of key
differentiation signals in tumor cells which might be elicited by
non-toxic agents.  Key signals that were identified included repression
of the competence gene c-myc and the induction of extracellular matrix
(ECM) related components.  Furthermore, it was found that the
transforming growth factor-beta's (TGF-beta's) could induce these signals
in colon carcinoma cells in the complete absence of toxicity.  However,
TGF-beta's themselves are limited as potential therapeutic products
because of the need of continuous target cell exposure, rapid clearance
from the blood and the prohibitive expense of pharmaceutical development
of protein based therapy.  However, if the expression of TGF's can be
controlled or their effects mimicked by other non-toxic agents, systemic
therapy could be circumvented.  Therefore, it is important to determine
relationships among the TGF-beta's, differentiation control and the
mechanisms which control TGF-beta activity and expression.  There is
evidence for an autoregulatory role for TGF-beta's in regulation of
proliferation and differentiation suggesting that nontoxic control of
expression of TGF-beta's would be therapeutically important.  Therefore,
the objectives of the renewal application are to provide an understanding
of the autoregulatory mechanisms involved by:
1.   Determination of the autocrine function of the various TGF-beta's in
human colon carcinoma cell lines and its potential revelance to
differentiation. 2. Characterization of the molecular basis for control
of TGF-beta expression in human colon carcinoma cell lines. 3.
Determination of the molecular basis of TGF-beta action and the basis for
the failure of some subtypes of colon carcinoma cells to respond to
TGF-beta's.

## Key facts

- **NIH application ID:** 3176225
- **Project number:** 5R01CA038173-07
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **SAM.gov UEI:** M9ACC5DQCNL6
- **Principal Investigator:** MICHAEL G BRATTAIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $174,519
- **Award type:** 5
- **Project period:** 1986-07-01 → 1996-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3176225

## Citation

> US National Institutes of Health, RePORTER application 3176225, MECHANISM OF ACTION OF DIFFERENTIATION AGENTS (5R01CA038173-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3176225. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*