retinol-palmitate and Carcinoma--Squamous-Cell

Head and neck squamous cell carcinoma affects >45,000 Americans annually. Patients who are successfully treated for their primary tumor are at high risk of developing a second primary tumor, making effective preventive strategies highly desirable for this disease. Although a landmark study in 1990 suggested some benefit of high-dose retinoids in head and neck cancer prevention, subsequent trials using more tolerable doses have shown limited clinical success. Newer preventive strategies have included bioadjuvant therapy combining retinoids with interferon and alpha-tocopherol, combinations of molecularly targeted agents, and oncolytic viruses. Furthermore, considerable evidence has supported a cancer protective role for several nutrients, including green tea and curcumin analogs. Natural compounds such as these with favorable long-term safety profiles might be particularly suited to the cancer prevention setting, in which patients will usually tolerate only moderate risk and toxicity.

Topics: Adenoviridae; Anticarcinogenic Agents; Carcinoma, Squamous Cell; Cyclooxygenase 2 Inhibitors; Diterpenes; ErbB Receptors; Etretinate; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Neoadjuvant Therapy; Randomized Controlled Trials as Topic; Retinoids; Retinyl Esters; Viral Vaccines; Vitamin A

Topics: Acetylcysteine; Antineoplastic Agents; Carcinoma, Squamous Cell; Diterpenes; Europe; Head and Neck Neoplasms; Humans; Mouth Neoplasms; Neoplasms, Second Primary; Research Design; Retinyl Esters; Risk Factors; Vitamin A

The risk of malignant transformation of oral preneoplastic lesion (OPL) is difficult to assess. DeltaNp63 is an early oncoprotein associated with mucosal tumorigenesis. The purpose of this study was to assess DeltaNp63 expression in OPL and its role as a marker of oral cancer risk.. DeltaNp63 expression was determined using immunohistochemistry in 152 OPL patients included in a clinical trial comparing retinyl palmitate alone or plus beta-carotene with low-dose 13-cis-retinoic acid. The associations between DeltaNp63 expression as well as DeltaNp63 expression with other potential risk factors for oral cancer development were analyzed.. DeltaNp63 expression was positive in 41 (27%) patients, clusters of intraepithelial inflammatory cells (EIC) were noted in 37 (26%) patients, and podoplanin (previously reported) was positive in 56 (37%) patients. Significantly more patients whose lesions were DeltaNp63 positive or exhibited EIC developed oral cancers. In the multicovariate analysis including age, treatment, and histologic status as cofactors, positive DeltaNp63 expression was associated with an increased hazard ratio of 3.308 (95% confidence interval, 1.663-6.580; P = 0.0007). Patients whose lesions showed positive DeltaNp63, podoplanin, and EIC had the highest oral cancer risk with a hazard ratio of 4.372 (95% confidence interval, 1.912-9.992; P = 0.0005) and 61% oral cancer development rate at 5 years compared with 15% of other OPL patients (P < 0.0001).. DeltaNp63 overepression in OPL is associated with increased oral cancer risk. Together, DeltaNp63, podoplanin, and EIC may be used as biomarkers to identify OPL patients with substantially high oral cancer risk.

Topics: Antineoplastic Combined Chemotherapy Protocols; beta Carotene; Biomarkers, Tumor; Carcinoma, Squamous Cell; Diterpenes; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Inflammation; Isotretinoin; Leukoplakia, Oral; Male; Membrane Glycoproteins; Middle Aged; Mouth Neoplasms; Prognosis; Retinyl Esters; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins; Up-Regulation; Vitamin A

Vitamin A and related compounds, also known as retinoids are thought to play a role in the development of head and neck cancer. We measured levels of the major retinoids, retinol, all-trans retinoic acid, 13-cis retinoic acid and 13-cis-4-oxo retinoic acid in plasma of head and neck cancer patients in comparison with controls without cancer. No differences were found between plasma levels of these retinoids between 25 head and neck cancer patients and 21 controls. Mean baseline levels for the patients were 2458. 6.0, 6.4 and 8.6 nM for retinol, all-trans retinoic acid, 13-cis retinoic acid and 13-cis-4-oxo retinoic acid, respectively. In addition, we selected 10 patients from the chemoprevention trial Euroscan and measured the effect on retinoid levels of 300,000 I.U. daily retinyl palmitate intake during 1 month. Medication caused significant elevations in retinol levels (1.2 fold), all-trans retinoic acid (2.2 fold) and its metabolites 13-cis retinoic acid (5.8 fold) and 13-cis-4-oxo retinoic acid (8.9 fold). Because of its high increase in levels, 13-cis-4-oxo retinoic acid seems a good candidate to serve as a suitable marker to monitor patient compliance in future chemo-prevention trials involving retinoids. No relations were found between the occurrence of side-effects of retinyl palmitate and retinoid levels during treatment. However, the two patients who developed side-effects had the highest pre-treatment levels of 13-cis retinoic acid and 13-cis-4-oxo retinoic acid, suggesting that retinoid toxicity is associated with relatively high basal retinoid metabolism.

Topics: Anticarcinogenic Agents; Carcinoma, Squamous Cell; Chromatography, High Pressure Liquid; Diterpenes; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Retinoids; Retinyl Esters; Vitamin A

Two chemoprevention randomized clinical trials were begun in 1984 to evaluate retinoids in the prevention of skin cancers. Moderate risk subjects with a history of at least 10 actinic keratoses and at most two prior skin cancers were enrolled in the SKICAP-AK trial and randomized to 25,000 IU retinol or placebo daily for 5 years. High risk subjects with a history of at least four prior skin cancers were enrolled in the SKICAP-S/B trial and randomized to receive 25,000 IU retinol, 5-10 mg isotretinoin or placebo daily for 3 years. Data from the SKICAP-AK trial indicate that retinol reduces incidence of first new squamous cell skin cancers but had no effect on the incidence of first new basal cell skin cancer. The effect of retinoids had no significant benefit on squamous or basal cell skin cancers in the high risk subjects on the SKICAP-S/B trial, although intervention duration was less than planned. Daily retinol was effective in preventing squamous cell cancers in moderate risk subjects.

Topics: Aged; Anticarcinogenic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Female; Humans; Male; Middle Aged; Nevus; Retinoids; Retinyl Esters; Skin Neoplasms; Vitamin A

Cosmetic products that contain retinyl palmitate are popular as antiaging skin treatments; however, recent studies suggest a risk for enhanced skin tumor development with topical retinyl palmitate applications and exposure to solar ultraviolet radiation (UVR). In this study, we investigated the potential of retinyl palmitate to enhance UVR-induced photo-co-carcinogenesis. Groups of 36 male and 36 female SKH-1 hairless mice were exposed to simulated solar light (SSL) and treated with the control cream or creams containing retinyl palmitate, 5 days per week for 40 weeks. Other groups of mice were exposed to SSL and received no cream treatment or received cream treatments and were exposed to ultraviolet-A or ultraviolet-B. Mice were monitored for the development of skin tumors, and the incidences and multiplicities of squamous cell neoplasia were determined by histopathology. In both the absence and presence of SSL, mice administered the control cream developed skin tumors earlier and had higher incidences and multiplicities of skin squamous cell neoplasms than mice that received no cream treatment. Compared to the control cream groups, mice exposed to SSL and administered the retinyl palmitate creams demonstrated earlier onsets of skin tumors and had increased incidences and multiplicities of squamous cell skin neoplasms.

Topics: Administration, Topical; Animals; Carcinoma, Squamous Cell; Cocarcinogenesis; Diterpenes; Female; Male; Mice, Hairless; Neoplasms, Radiation-Induced; Retinyl Esters; Skin Neoplasms; Sunlight; Ultraviolet Rays; Vitamin A

Topical retinoids, compounds that are metabolites, analogues, or derivatives of retinol and possess biological vitamin A activity, are among the most used adjunctive agents for the mitigation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of photodamaged and chronically aged skin. Retinoic acid (RA) is the most active biological form of vitamin A and remains the medical treatment of choice for photoaged skin. Retinyl palmitate (RP) is the major storage form of vitamin A in the skin and, because RP is also the most stable of available vitamin A esters, it is readily incorporated into the oil phase of cosmetic creams or lotions. Therefore, the topical application of RP is a practical strategy for increasing the levels of vitamin A in the skin. Usual cosmetic product concentrations of RA range from 0.025% to 0.1% and those of RP range from 0.1% to 5%. With a maximum absorbance around 325 nm, RA and RP absorb both ultraviolet A and B radiation (UVA and UVB) in incident sunlight. A 1-year study was conducted in mice to determine whether RA and RP would alter the photocarcinogenicity of broad-UV spectrum light generated by xenon arc lamps, termed simulated solar light (SSL), or narrow spectrum UV light generated by UVA and UVB lamps.

Topics: Administration, Topical; Animals; Antineoplastic Agents; Carcinogenicity Tests; Carcinoma, Squamous Cell; Diterpenes; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred Strains; Mice, Nude; Retinyl Esters; Skin; Skin Neoplasms; Sunlight; Tretinoin; Vitamin A

Epidemiological studies have shown an inverse relationship between dietary vitamin A intake and the risk of developing lung cancer. The aim of this study was to investigate the vitamin A status in patients with lung cancer, by determining the serum levels of retinoic acid, retinol and retinyl palmitate.. In total, 36 patients with lung cancer and 27 controls were assessed. Of the patients 14 had squamous cell carcinoma, 3 adenocarcinoma, 15 non-small cell lung cancer and 4 small cell lung cancer. Serum retinoic acid, retinol and retinyl palmitate levels were determined with HPLC and UV detection, after liquid extraction.. Serum retinol levels did not differ between patients (733.5 +/- 326.4 ng/mL) and controls (734.5 +/- 337.1 ng/mL). The retinyl palmitate concentration tended to be lower in patients (14.3 +/- 9.7 ng/mL) than in controls (16.7 +/- 13.7 ng/mL). The serum retinoic acid levels were significantly lower in patients (1.9 +/- 0.6 ng/mL) than in controls (2.5 +/- 1.1 ng/mL, P < 0.05). A positive correlation was observed between the retinol and retinoic acid levels and retinyl palmitate and retinoic acid levels.. The lower levels of retinoic acid in patients with lung cancer suggest there may be a deficiency or impairment in retinol metabolism in these patients. Further studies with larger numbers of patients are needed to evaluate the possible relationship between serum retinoid levels and lung cancer.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chromatography, High Pressure Liquid; Disease Progression; Diterpenes; Female; Humans; Lung Neoplasms; Male; Prognosis; Retinyl Esters; Risk Factors; Tretinoin; Vitamin A

The influence of excess retinol palmitate on induction of tumors in the oral region was examined histopathologically. Sixty-three weanling Syrian golden hamsters were divided into five groups and received either 0.2% N-methylnitrosourea (MNU) (1 mg/100 g body weight) or retinol palmitate (RP) (25,000 IU/100 g body weight) twice a week for 16 weeks, singly or in combination. Animals received RP intraperitoneally or intragastrically and then, 6 hours later, the animals received intragastric administration of MNU. To accelerate the cell activity of the incisal tooth buds, intentional disocclusion of the left upper and lower incisor of all hamsters was carried out by repeated cutting with cooled diamond disks to a level just above the inter-dental papilla twice a week for 12 weeks. The right incisors were left in occlusion. In all animals exposed to RP + MNU, while the induction of squamous cell carcinomas of the gingiva and forestomach were prevented, the notable findings were a significantly increased incidence of odontogenic tumors in cut incisal regions of the animals with intragastric administration of RP + MNU and an induction of maxillary neurogenic tumors. The incidence of MNU-induced disturbances in odontogenesis in the incisors was reduced but marked disturbances were increased. RP seemed to have opposite effects of prevention and enhancement for development of neoplastic changes in the oral region.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Carcinoma, Squamous Cell; Cricetinae; Diterpenes; Drug Antagonism; Drug Synergism; Gingival Neoplasms; Mesocricetus; Methylnitrosourea; Mouth Neoplasms; Odontogenic Tumors; Retinoids; Retinyl Esters; Vitamin A

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 retinol and retinyl ester concentrations in human xenografted squamous cell carcinomas, with various concentrations of cellular retinol-binding protein (CRBP), were studied, as well as the in vivo uptake and esterification in these tumours of labelled retinol, presented as a complex with plasma RBP. The mean retinol concentration in the different tumours was in the range 3.7-6.2 nmol/g protein, and the mean CRBP concentration was between 16 and 69 nmol/g protein. There was a statistically significant correlation between the retinol and the CRBP concentrations in the same tumour (P less than 0.001; r = 0.622). Calculation of the maximal extent of retinol-saturation of CRBP showed low values (range: 9-26%). Retinyl palmitate, the predominant retinyl ester, comprised approx. 70% of the retinyl esters in the tumours. There was no correlation between the concentration of CRBP and that of retinyl palmitate. The uptake of [3H]retinol from intravenously injected retinol-RBP complex was similar in the four human squamous cell carcinomas studied, and not related to their CRBP concentration. 20% of the radioactivity in tumour specimens was lipid soluble, as compared to 96% in liver specimens, showing that in the former a higher fraction metabolised to polar compounds. Taken together, our results suggest that in these squamous carcinoma cells, factors other than cellular CRBP content are the major determinants of net cellular uptake and esterification of retinol. The cellular retinol concentration, on the other hand, appears proportional to CRBP content.

Topics: Carcinoma, Squamous Cell; Diterpenes; Epidermis; Humans; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Retinol-Binding Proteins, Plasma; Retinyl Esters; Tumor Cells, Cultured; Vitamin A

This paper reports a study on the influence of excess of vitamin A palmitate on the induction and maintenance of oral tumors. Sixty four weanling Syrian hamsters were divided in four groups and painted three times a week, either with 0.5% DMBA or 15% vitamin A palmitate, singly or in combination. A possible mild immune response evoked by vitamin A palmitate is considered responsible for the delayed induction of the tumors. In all animals exposed to carcinogen + vitamin A the induced tumors were small in size and histologically verified as well differentiated epidermoid carcinomas. In control group with sole vitamin A palmitate application the cheek pouch showed considerably increased keratinization.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Basement Membrane; Benz(a)Anthracenes; Carcinoma, Squamous Cell; Cheek; Cricetinae; Diterpenes; Epithelium; Female; Male; Mesocricetus; Microscopy, Electron; Mouth Neoplasms; Retinyl Esters; Time Factors; Vitamin A