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Tobacco-related cancer prevention by Vitamin A derivatives

Institution: Molecular Medicine Research Institute
Investigator(s): Marcia Dawson, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0212A Award: $149,947
Subject Area: Cancer
Award Type: Research Project Awards

Initial Award Abstract
In spite of recent advances in surgical, radiation, and chemotherapeutic treatment of cancer, lung cancer continues to be biggest cancer killer (27%) in California. About 18,000 new cases and 14,315 deaths from lung cancer are predicted for 1997. Both prostate cancer and breast cancer are slightly more common, but lung cancer kills about four times as many victims as prostate cancer and three times as many as breast cancer. Tobacco use and exposure is the main cause of lung cancer, and more women and young people are smoking cigarettes and thus are at increased risk. Therefore, there is an urgent need for more effective methods to prevent and treat lung cancer.

1. Carcinogens in tobacco smoke cause mutations in genes that regulate the cell cycle, with a resulting loss of the controls that allow normal cell repair or apoptosis (i.e., cell death as part of the normal life cycle). These abnormal (transformed) cells then grow uncontrollably. Drugs that can reinforce control points to stop the growth of transformed cells may allow these cells to be repaired or destroyed rather than to continue their uncontrolled growth.

Although laboratory studies show that several retinoids (derivatives of vitamin A) inhibit cancer cell growth, clinical trials found that two of the most promising retinoids only delayed the appearance of new tumors in lung cancer and breast cancer patients, even at doses high enough to warrant discontinuance because of side effects. Clearly, new anticancer agents must be both more effective and less toxic.

Recent studies indicate that induction of apoptosis may enhance cancer prevention. We found that one retinoid, 6-[3-(1-adamantyl)-4-hydro-xyphenyl)]-2-naphthale-necarboxylic acid (abbreviated AHPN), inhibits lung cancer cell growth and induces lung cancer cell apoptosis. Our studies indicate that AHPN exerts its anticancer activity without interacting with the retinoid receptors, an advantage because toxic effects are less likely to cause side effects. Furthermore, AHPN is far more effective (20- to 100-fold) than other retinoids, including the natural retinoid trans-retinoic acid, in inhibiting growth of lung cancer cells in culture.

We will design and synthesize variants of AHPN that cause lung cancer cell apoptosis but do not activate cellular responses associated with side effects. Our preliminary studies with SR11389, our AHPN analog, indicate that this objective is reasonable. New compounds will first be evaluated for their ability to inhibit lung cancer cell growth compared to normal lung cell growth. Effective analogs will then be evaluated for their ability to induce cancer cell apoptosis without initiating side effects, then for their ability to lower the amount of an apoptosis inhibitor. These studies will identify the most promising analog for further development.

Final Report
Although breast and prostate cancer are slightly more common than lung cancer in California, lung cancer leads in lethality, causing four times as many deaths. Tobacco use and exposure are the main causes of lung cancer, and use among young people and women is increasing. Therefore, the need for more effective methods to prevent and treat lung cancer is urgent.

Recent studies indicate that induction of apoptosis (a natural form of cell death) in cancer cells may enhance cancer prevention and facilitate its treatment. We found that a derivative of vitamin A, a retinoid called 6-[3'-(1"-adamantyl)-4'-hydroxyphenyll-2-naphthalenecarboxylic acid (abbreviated AHPN) inhibits the growth and induces the apoptosis (programmed cell death) of lung cancer cells. Our studies indicate that AHPN exerts its anticancer activity by a mechanism uncharacteristic of standard retinoids; this is an advantage, because the toxic effects of AHPN caused by its retinoid activity may be able to be removed in new derivatives.

This final report covers the research work performed at MMRI in collaboration with the Burnham Institute. The proposed aims have been accomplished in this time period. The proposed compounds have been synthesized and evaluated against lung cancer growth. In addition, a threedimensional model that relates compound activity to compound structure has been constructed. This model was generated using the computer program MOLMOD to identify the regions of the active molecules that enable them to inhibit the growth of HL-60R human leukemia cancer cells and the distances between these regions. These cancer cells are useful for evaluating AHPN analogs because retinoid activities do not interfere with testing the ability of compounds to inhibit cancer cell growth. The second aim of evaluating the analogs prepared in the first and second years of the grant was also achieved. Of 38 compounds evaluated for their abilities to inhibit the growth of retinoid-sensitive H640 lung cancer cells and retinoid-insensitive H292 lung cancer cells, 10 were found to have high cell growth inhibitory activity. Compounds were resynthesized, if necessary, then evaluated for their ability to induce retinoid-responsive gene transcription by activating retinoid receptors. In this set of compounds, three lung cancer cell growth inhibitors were found to lack retinoid transcriptional agonist activity. In subsequent work, we propose to use these compounds to improve the model, which will then be used to assist in the design of improved candidates for evaluation as inhibitors of lung cancer. This proposed strategy should provide our collaborative research effort with the optimum opportunity of applying rational drug design to the identification and development of therapeutic agents for the treatment and prevention of lung cancer.

Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3
Periodical: Science Index Medicus:
Authors: Li H, Kolluri SK, Gu J, et al ART
Yr: 2000 Vol: 289 Nbr: 5482 Abs: Pg: 1159-1164