# RETINOID TUMOR INHIBITORY ACTIVITY-TOXICITY PROBE

> **NIH NIH R01** · SRI INTERNATIONAL · 1989 · $52,177

## Abstract

Retinoic acid and other retinoids are able to control cellular
differentiation and, by so doing, are able to suppress or reverse the
transformation of premalignant cells to the malignant state.  Therefore,
the retinoids have potential value as therapeutic and prophylactic agents
for the treatment of cancer if their toxic side effects can be reduced.  We
propose to synthesize and screen potentially more effective retinoids to
develop drugs having an improved therapeutic index (ratio of
tumor-inhibitory activity to toxicity).  In particular, we propose
systematic structure-activity studies of analogs of four active retinoids
that we have synthesized--namely, (1)
4-[(E)-2-(4,4-dimethyl-3,4-dihydro-2H-1-benzopyran-6-yl)-propenyl]benzoic
acid, (2)
4-[(E)-2-(4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran-6-yl)-propenyl]benzoi
cacid, (3)
4-[(E)-2-(4,4-dimethyl-4,5,6,7-tetrahydro-2-benzo[b]-thienyl)propenyl]benzoi
cacid, and (4)
6-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-6-naphthyl)-2-naphthalenecarboxyli
cacid--to further determine what regions of the retinoid skeleton enhance
tumor-inhibitory activity and reduce toxicity.  Compounds will first be
tested in three rapid, preliminary screens used to assess retinoid
activity:  (1) the reversal of keratinization in retinoid-deficient
epithelial cells of hamster trachea in organ culture, (2) the inhibition of
the induction of ornithine decarboxylase in mouse epidermis treated with a
tumor promoter, and (3) the induction of differentiation of F9 murine
embryonic carcinoma cells.  Active retinoids will then be screened in two
in vivo assays to determine (1) their effectiveness in inhibiting papilloma
tumor formation in mouse epidermis treated with a carcinogen and a tumor
promoter (antipapilloma assay) and (2) their toxicity in the mouse
(hypervitaminosis A assay).  The therapeutic index will be determined from
these two assays.  This approach should lead to the design and synthesis of
more effective retinoids.

In addition, we propose the synthesis of radiolabeled,
photoaffinity-labeled retinoids to probe the biochemical mechanism and site
of retinoid action.

## Key facts

- **NIH application ID:** 3170354
- **Project number:** 3R01CA032428-07S1
- **Recipient organization:** SRI INTERNATIONAL
- **SAM.gov UEI:** SRG2J1WS9X63
- **Principal Investigator:** MARCIA I. DAWSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $52,177
- **Award type:** 3
- **Project period:** 1982-09-01 → 1990-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3170354

## Citation

> US National Institutes of Health, RePORTER application 3170354, RETINOID TUMOR INHIBITORY ACTIVITY-TOXICITY PROBE (3R01CA032428-07S1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3170354. Licensed CC0.

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