retinol-acetate and Mouth-Neoplasms

We conducted a double-blind placebo-controlled trial to evaluate the chemopreventive potential of either vitamin A alone or beta carotene alone in subjects with oral leukoplakia in Kerala, India. We randomised 160 fishermen and women with oral precancerous lesions to receive oral vitamin A (retinyl acetate 300,000 IU/week x 12 months, n = 50), or beta carotene (360 mg/week x 12 months, n = 55), or placebo (n = 55). Blood, saliva and urine samples were collected at baseline and at exit to study serum micronutrients and mutagenicity assays. Biopsies of the mucosal lesions at entry were performed for histopathological exclusion of malignancy. The subjects were examined once every 2 months to establish clinical response of lesions and toxicity, if any. The results are based on 43 complaint subjects on placebo, 42 on vitamin A and 46 on beta carotene. The complete regression rates were: 10% in the placebo arm, 52% with vitamin A and 33% with beta carotene (P < 0.0001). Homogeneous leukoplakias and smaller lesions responded better than non-homogeneous and larger lesions. No major toxicities were observed. Half of the responders with beta carotene and two thirds with vitamin A relapsed after stopping supplementation. Serum beta carotene concentration increased substantially with beta carotene administration while with vitamin A supplementation there was no change in serum retinol levels. In the vitamin A treated group there was a significant decrease in serum alpha tocopherol. Vitamin A administration resulted in a significant remission of oral leukoplakia without any side effects of prolonged vitamin A supplementation. The results of this study, as well as those from previous studies, appear to provide strong supporting evidence to justify long term trials with vitamin A in subjects with high-risk leukoplakias with oral cancer as an endpoint.

Topics: Adult; Anticarcinogenic Agents; beta Carotene; Diterpenes; Double-Blind Method; Female; Humans; Leukoplakia, Oral; Male; Micronutrients; Middle Aged; Mouth Neoplasms; Mutagenicity Tests; Retinyl Esters; Treatment Outcome; Vitamin A

Cyclooxygenase-2 expression is up-regulated in transformed cells and tumors. Because this enzyme catalyzes the synthesis of prostaglandins, strategies aimed at suppressing its expression may prove useful in preventing or treating cancer. We investigated the ability of retinoids to suppress phorbol ester-mediated induction of cyclooxygenase-2 in human oral epithelial cells. Treatment with phorbol myristate acetate (PMA) resulted in approximately a 3-fold increase in the production of prostaglandin E2 (PGE2). Retinoids [all-trans-retinoic acid (RA), 13-cis-RA, and retinyl acetate] markedly suppressed PMA-mediated increases in amounts of cyclooxygenase-2 (Cox-2) and the production of PGE2. Retinoids also suppressed the induction of Cox-2 mRNA by PMA. Nuclear run-offs revealed increased rates of Cox-2 transcription after treatment with PMA; this effect was inhibited by all-trans-RA. Transient transfection experiments showed that PMA caused about a 2-fold increase in Cox-2 promoter activity, an effect that was suppressed by all-trans-RA. Our data indicate that treatment of oral epithelial cells with PMA is associated with enhanced transcription of Cox-2 and increased production of PGE2. These effects of PMA were inhibited by retinoids.

Topics: Anticarcinogenic Agents; Biotransformation; Carcinoma, Squamous Cell; Cyclooxygenase 2; Dinoprostone; Diterpenes; Enzyme Induction; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Isotretinoin; Membrane Proteins; Mouth Neoplasms; Neoplasm Proteins; Peroxidases; Prostaglandin-Endoperoxide Synthases; Retinyl Esters; Tetradecanoylphorbol Acetate; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured; Vitamin A

The role of vitamin A in the induction and growth of chemically induced tumors is still controversial. While in some studies vitamin A influenced inhibition of chemically induced tumors was observed, other studies report on an enhancing influence of this substance on tumor induction. The cheek pouch epithelium of sixty five Syrian golden hamsters was exposed to DMBA and different doses of retinyl acetate, singly and in combination with DMBA. The findings suggest that 1) a significant delay occurs in tumor induction in animals treated with DMBA in combination with a higher concentration (2.0%) of retinyl acetate, 2) retinyl acetate at lower concentration (0.5 and 1.0%) does not inhibit or delay tumor induction.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Cheek; Cricetinae; Diterpenes; Female; Hyperplasia; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Retinyl Esters; Time Factors; Vitamin A

Sixty young adult Syrian hamsters were divided into five groups. Group 1 and Group 2 animals were treated with 0.25% dimethylbenz(a)anthracene (DMBA), painted on their left buccal pouches thrice weekly for 20 weeks. Starting at 12 weeks, at which time there was clinical evidence of leukoplakia and initial tumor formation, Group 2 animals received 10 mg retinyl acetate 3 times/week in a 5% solution in peanut oil, while Group 1 animals received only peanut oil. Two animals in Group 1 and two animals in Group 2 were sacrificed weekly from week 12 to week 20. Left buccal pouches were examined, tumors were counted, and tumor size was measured. Group 3 animals were untreated controls, Group 4 animals were retinyl acetate controls, and Group 5 animals received only peanut oil. It was found that DMBA-treated animals receiving retinyl acetate from week 12 to week 20 developed fewer tumors, and their average tumor size was less than that in DMBA-treated animals not receiving retinyl acetate. It appears that retinyl acetate, administered systemically, can retard tumor development even after leukoplakia has been established and tumors have begun to develop.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Squamous Cell; Cheek; Cricetinae; Diterpenes; Leukoplakia, Oral; Mesocricetus; Mouth Neoplasms; Retinyl Esters; Vitamin A