retinol-palmitate and Hyperplasia

Laryngeal leukoplakia can be a premalignant precursor of squamous cell carcinoma, is often tobacco-related and can usually be readily monitored by indirect laryngoscopy. One of the main motivations for using retinyl palmitate in patients with persistent leukoplakia was to avoid general anesthesia for elderly patients, who are considered to be high-risk patients when direct larynoscopy is required for possible tissue biopsy. Our study was the first to investigate the effectiveness and toxicity of high-dose retinyl palmitate in the treatment of laryngeal leukoplakia. Treatment was divided into two phases. In the first phase, all patients underwent induction therapy with 300,000 IU/day of retinyl palmitate for the 1st week, which was then adjusted up to 1,500,000 IU/day in the 5th week in patients with resistant lesions. Patients whose lesions progressed during this period were withdrawn from the study. In the second phase, patients whose lesions responded to treatment or remained stable were assigned to a maintenance therapy of 150,000 IU/day. Complete remission was observed in 15 of 20 patients (75% of cases). Partial response was seen in the remaining 5 patients, with 3 of the patients relapsing. The median duration of treatment and follow-up was 18 months (range, 12-24 months). These results indicate that retinyl palmitate has substantial activity in laryngeal leukoplakias. Since only minor side effects were seen, the medication is an excellent candidate as a preventive agent for laryngeal cancer.

Topics: Aged; Aged, 80 and over; Alcohol Drinking; Anticarcinogenic Agents; Biopsy; Carcinoma in Situ; Carcinoma, Squamous Cell; Disease Progression; Diterpenes; Female; Follow-Up Studies; Humans; Hyperplasia; Laryngeal Neoplasms; Laryngoscopy; Leukoplakia; Male; Middle Aged; Neoplasm Recurrence, Local; Precancerous Conditions; Remission Induction; Retinyl Esters; Smoking; Vitamin A

The formation of all-trans retinoic acid is an oxidative process whereby retinol is converted to retinaldehyde and then to retinoic acid. Because retinol causes qualitative molecular changes similar to those produced by retinoic acid, we compared potency of retinol, retinaldehyde, and retinyl palmitate to retinoic acid and assessed the effects of occlusion. Retinoids were prepared in an experimental vehicle of 95% ethanol:propylene glycol (7:3) with anti-oxidant. Induction of retinoic acid 4-hydroxylase activity was the end point for comparison. Retinoic acid concentrations from 0.001% to 0.05% under occlusion produced a linear dose-response induction of 4-hydroxylase activity. The concentrations of the other retinoids under occlusion required to achieve significant induction of enzyme activity were 0.6% retinyl palmitate, 0.025% retinol, and 0.01% retinaldehyde. The linear dose-response was lost with retinoid concentrations in excess of 0.25% retinol or 0.5% retinaldehyde. Statistical analyses showed no difference in 4-hydroxylase activity between unoccluded and occluded retinol treated sites. By contrast, however, unoccluded sites treated with retinoic acid or retinyl palmitate had less induction of 4-hydroxylase activity than occluded sites. Retinol, retinaldehyde, and retinyl palmitate did not produce erythema but did increase epidermal thickness. Although retinol is a weaker retinoid than retinoic acid, the increased penetration of unoccluded retinol in comparison to unoccluded retinoic acid with this prototypic vehicle confers on retinol a more effective delivery of a retinoidal effect than unoccluded retinoic acid. Retinol at 0.25% may be a useful retinoid for application without occlusion because it does not irritate but does induce cellular and molecular changes similar to those observed with application of 0.025% retinoic acid.

Topics: Administration, Topical; Adult; Anticarcinogenic Agents; Antioxidants; Cell Membrane Permeability; Cytochrome P-450 Enzyme System; Diterpenes; Dose-Response Relationship, Drug; Enzyme Activation; Erythema; Humans; Hyperplasia; Retinoic Acid 4-Hydroxylase; Retinyl Esters; Skin; Tretinoin; Vitamin A

The effects of four different hyperplastic agents and of the carcinogen DMBA on cytokeratin expression in hamster cheek pouch epithelia were compared. Reversible hyperplasia was produced by the application of either oil of turpentine, vitamin A or TPA. No hyperplastic changes were produced by application of EPP. Apart from the transient appearance of a 45 kDa cytokeratin in one group treated with vitamin A, the immunohistochemical staining patterns and immunoblot profiles of cytokeratins from cheek pouches treated with each of the hyperplastic agents were identical to controls. Following application of DMBA, the cytokeratins stained with increased intensity in the spinous and granular cell layers. This was associated with increased amounts of 42-56 kDa cytokeratins and decreased production of 62-75 kDa cytokeratins. Monoclonal antibody AE1 detected a 45 kDa cytokeratin in extracts of DMBA-treated epithelia that was not detected in untreated epithelial extracts. Monoclonal antibody AE3 detected an additional 54 kDa cytokeratin band in extracts of DMBA-treated epithelia. These cytokeratin changes were present in preneoplastic epithelia and maintained in neoplastic epithelia.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alkynes; Animals; Cricetinae; Diterpenes; Epithelium; Gene Expression Regulation, Neoplastic; Hyperplasia; Immunoblotting; Immunohistochemistry; Keratins; Male; Molecular Weight; Mouth Mucosa; Mouth Neoplasms; Precancerous Conditions; Retinyl Esters; Tetradecanoylphorbol Acetate; Turpentine; Vitamin A

Hyperplasia in the hamster cheek pouch was examined using 4 different hyperplastic agents: oil of turpentine 50% v/v in liquid paraffin; vitamin A palmitate 10% w/v in liquid paraffin; 12-O-tetradeconyl-phorbol-13-acetate 16nM in acetone; and ethylphenylpropiolate 0.04mM in acetone. Acetone, paraffin and untreated control groups were also examined. Cheek pouches were painted 3 times a week for up to 4 weeks with each solution. Samples were removed and prepared for light microscopy 24 hours after 2 weeks of painting and 24 hours, 6, 12 and 18 weeks after 4 weeks of painting. Hyperplasia was produced by application of turpentine, vitamin A and TPA after 2 weeks of application. Further increases in epithelial width occurred after 4 weeks of painting in the turpentine and vitamin A groups but a decrease was seen in the TPA group. Six weeks (vitamin A and TPA groups) or 12 weeks (turpentine group) after the completion of treatment the epithelium had a normal histological appearance. No differences between the control or EPP treated cheek pouch mucosa could be detected. Turpentine and vitamin A can be used as models of reversible hyperplasia in the hamster cheek pouch.

Topics: Alkynes; Animals; Cell Nucleus; Connective Tissue; Cricetinae; Cytoplasmic Granules; Diterpenes; Epithelium; Hyalin; Hyperplasia; Keratins; Male; Mouth Mucosa; Retinyl Esters; Tetradecanoylphorbol Acetate; Time Factors; Turpentine; Vitamin A

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Bufonidae; Diterpenes; Female; Hyperplasia; Male; NAD; Retinyl Esters; Skin; Vitamin A