retinol-acetate and Carcinoma--Squamous-Cell

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

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Blotting, Northern; Blotting, Western; Carcinogens; Carcinoma, Squamous Cell; Cyclooxygenase 2; Dinoprostone; Diterpenes; Gene Expression Regulation, Enzymologic; Humans; Isoenzymes; Isotretinoin; Membrane Proteins; Peroxidases; Phorbol Esters; Prostaglandin-Endoperoxide Synthases; Retinoids; Retinyl Esters; Tretinoin; Tumor Cells, Cultured; Vitamin A

The analysis of clinical and immunologic findings indicate that retinol and decaris influence functional activity of immune cells at stage II of lung cancer irrespective of histological structure. In stage III, retinol induced changes in proportion of lymphocyte subpopulations, more evident in glandular cancer. Both immunomodulators lowered the number of purulent complications after surgical interventions. It is only retinol that influenced metastatic dissemination in lung cancer stage II-III.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Adult; Carcinoma, Squamous Cell; Combined Modality Therapy; Diterpenes; Humans; Levamisole; Lung Neoplasms; Lymphocyte Subsets; Male; Middle Aged; Neoplasm Metastasis; Preoperative Care; Retinyl Esters; Vitamin A

Retinoic acid and retinyl acetate induce tissue transglutaminase to high levels in cultured SCC-4 keratinocytes, increasing the enzyme specific activity over 50-fold under optimal conditions. Pretreatment of the cells for a day with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (3-MC) or benzo[a]pyrene almost completely prevented the induction observed upon subsequent treatment with retinoic acid for 2 days. Similar aromatic compounds that do not induce aryl hydrocarbon hydroxylase (pyrene, dibenzofuran) did not exhibit this suppressive effect. The concentration dependence on TCDD for induction of aryl hydrocarbon hydroxylase was nearly identical to that for its suppression of transglutaminase induction, with half-maximal effects observed at approximately 20 pM in each instance. Similarly, the concentrations of 3-MC giving half-maximal stimulation of the hydroxylase and suppression of the transglutaminase were comparable (0.9 and 0.3 microM, respectively), although this agent was almost five orders of magnitude less potent than TCDD. These observations reveal a loss of cellular sensitivity to vitamin A mediated by the Ah receptor.

Topics: Carcinoma, Squamous Cell; Cell Line; Dioxins; Diterpenes; Enzyme Induction; Humans; Kinetics; Polychlorinated Dibenzodioxins; Polycyclic Compounds; Retinyl Esters; Tetradecanoylphorbol Acetate; Transglutaminases; Tretinoin; Vitamin A

Growth of SCC-13 squamous carcinoma cultures in the presence of retinoids considerably reduced the expression of two differentiation markers, the cellular capability to form cross-linked envelopes, and the enzyme transglutaminase required for cross-linking. A limited survey of retinoids showed that all-trans retinoic acid, 13-cis retinoic acid, and arotinoid Ro 13-6298 were highly effective in the absence of hydrocortisone and were only slightly antagonized by its presence in the medium. In contrast, retinyl acetate, retinol, and retinol bound to its plasma binding protein were quite active in the absence of hydrocortisone but were essentially inactive in its presence. Dexamethasone was also highly effective in antagonizing the suppressive action of retinyl acetate on envelope formation, while the corticosteroid antagonists cortexolone and progesterone were inactive. These results suggest that there are separate pathways, which are differentially regulated by hydrocortisone, for either the metabolism or action of retinol and retinoic acid in SCC-13 cells.

Topics: Acyltransferases; Carcinoma, Squamous Cell; Cell Line; Cell Membrane; Diterpenes; Humans; Hydrocortisone; Kinetics; Retinoids; Retinyl Esters; Structure-Activity Relationship; Transglutaminases; Tretinoin; Vitamin A

A number of recent studies have indicated that the expression of keratins is altered upon malignant transformation of human epithelial cells. We have shown that the altered expression of 67-kDa and 40-kDa keratins in established squamous cell carcinoma lines from tongue and epidermis stems largely from a difference in their sensitivity to vitamin A apparently acquired during tumorigenesis. When the vitamin A concentration in the medium is raised, the 40-kDa keratin is produced at increased levels. Conversely, when the amount of vitamin is reduced, the 67-kDa keratin is synthesized and the cells undergo stratification and terminal differentiation. However, even when vitamin A is quantitatively removed from the medium, the maximal degree of differentiation attained by each squamous cell carcinoma cell as judged by the synthesis of 67-kDa keratin was still less than that of the normal keratinocytes. These findings suggest that the altered patterns of keratins observed for some tissues upon malignant transformation arise from a complex mixture of intracellular changes in the differentiative pathway in addition to changes in the responsiveness of cells to extracellular regulators of keratin gene expression.

Topics: Animals; Carcinoma, Squamous Cell; Carrier Proteins; Cell Differentiation; Cell Line; Diterpenes; Dose-Response Relationship, Drug; Epithelium; Fluorescent Antibody Technique; Humans; Infant, Newborn; Keratins; Male; Rabbits; Receptors, Retinoic Acid; Retinyl Esters; RNA, Messenger; Vitamin A; Vitamin A Deficiency

Involucrin accumulation and ionophore-assisted envelope formation, markers of keratinocyte differentiation, were found to be highly dependent on culture conditions in the malignant epidermal keratinocyte line, SCC-13, derived from a human squamous cell carcinoma. In confluent cultures, approximately one-half of the cells were competent to form envelopes when grown in medium without hydrocortisone or retinyl acetate supplementation. Addition of hydrocortisone to the medium during growth resulted in up to 90% competence, while addition of retinyl acetate instead resulted in as low as 10% competence. Hydrocortisone partially antagonized the effect of retinyl acetate when both agents were added together. Involucrin levels, measured by radioimmunoassay, were modulated essentially in parallel with envelope competence under the various conditions tested. When the cells were grown in medium supplemented with hydrocortisone, the levels shortly after confluence were over 50-fold higher than in sparse cultures. Regardless of hydrocortisone or retinyl acetate addition, less than 1% of the cells were competent in sparse cultures of growing cells, but up to 90% exhibited this property after growth arrest in serum-free medium containing hydrocortisone. High levels of competence were correlated with cessation of cell division but not with loss of colony-forming efficiency; under optimal conditions, two-thirds of the cells were capable of both envelope formation and colony initiation. Normal human epidermal cells showed a 4- to 5-fold increase in envelope competence from sparse to confluent culture but were insensitive to the suppressive effect of retinyl acetate. The results suggest that some potential differentiated character of malignant keratinocytes may be suppressed in vivo by physiological agents such as vitamin A.

Topics: Carcinoma, Squamous Cell; Cell Division; Cell Line; Cell Membrane; Diterpenes; Humans; Hydrocortisone; Keratins; Protein Precursors; Radioimmunoassay; Retinyl Esters; Skin; 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

Serially propagated SCC-13 keratinocytes, derived from a human squamous cell carcinoma, are greatly influenced by culture conditions in their ability to form ionophore-inducible cross-linked envelopes. Supplementation of the growth medium with fetal bovine serum at concentrations ranging from 0.5 to 20 percent had little effect on competence to form envelopes in confluent cultures. At each serum concentration, however, addition of hydrocortisone to the medium led to an increase in competence of almost fourfold, from approximately 20 to nearly 80 percent. With the serum supplementation held at 5 percent, addition of retinyl acetate to the medium suppressed competence in a concentration-dependent manner over the range of 1 to 100 ng/ml. At the highest concentration employed, competence was reduced over fourfold in the presence of hydrocortisone and virtually eliminated in its absence. When the cells were grown using serum depleted of endogenous vitamin A, a majority were competent in the absence of hydrocortisone. Under this condition, retinyl acetate suppressed competence over fivefold in the absence of hydrocortisone, but not at all in its presence. We conclude that hydrocortisone stimulates envelope competence primarily by antagonizing the suppressive effect of vitamin A. The SCC-13 cell line may prove valuable in studying mechanisms of retinoid and corticosteroid therapeutic action on diseased human keratinocytes.

Topics: Carcinoma, Squamous Cell; Cells, Cultured; Diterpenes; Humans; Hydrocortisone; Retinyl Esters; Vitamin A

Virgin female C3H/He mice (275) were fed a ration that included 0.1 per cent N-4-(5-nitro-2-furyl)-2-thiazolyl formamide (FANFT) and retinyl acetate. The mice were divided into five groups with Groups 1 through 4 receiving 300, 600, 1200, and 2400 IU of retinyl acetate per kilogram of feed plus FANFT respectively. Group 5 received 300 IU per kg of feed and no FANFT as a control. After 45 weeks the bladders were removed and inspected for neoplasms. There were no tumors found in any of the mice from Group 5. It was found that retinyl acetate significantly inhibited the formation of squamous cell tumors at all levels and inhibited transitional cell carcinoma when given as 600 IU per kilogram of feed.

Topics: Animal Feed; Animals; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Diet; Diterpenes; FANFT; Female; Mice; Retinyl Esters; Urinary Bladder Neoplasms; Vitamin A