retinol-palmitate and Precancerous-Conditions

Lung cancer is the major cause of death in industrialized western societies. Its link to tobacco abuse is well established and efforts should be made to eliminate this potent environmental carcinogen. The concept of chemoprevention, the use of agents to inhibit and reverse lung cancer carcinogenesis, has great appeal. The CARET study, conducted in 18,000 high-risk smokers in the US, found that a combination of beta-carotene and retinyl palmitate resulted in a 28% increase in the incidence of lung cancer. A similar study conducted in Finland, the ATBC trial utilizing alpha tocopherol and beta-carotene, had similar findings for the group taking beta-carotene. These two trials have caused a rethinking of the use of natural compounds as chemoprevention agents. These agents should no longer be regarded as harmless, but as having potential toxicities. A new approach in the chemoprevention of cancer has been the concept of surrogate endpoints, biological changes that are on the pathway to cancer. Trials are underway to determine what are appropriate surrogate endpoints for lung cancer chemoprevention trials.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Anticarcinogenic Agents; beta Carotene; Carotenoids; Chromosomes, Human, Pair 3; Clinical Trials as Topic; Cocarcinogenesis; Cytochrome P-450 CYP1A1; Diterpenes; Female; Flavonoids; Genetic Predisposition to Disease; Glutathione Transferase; Humans; Inactivation, Metabolic; Incidence; Lung Neoplasms; Lycopene; Male; Middle Aged; Polymorphism, Genetic; Precancerous Conditions; Retinoids; Retinyl Esters; Risk Factors; Selenium; Smoking; Smoking Prevention; Trace Elements; Treatment Outcome; Vitamin A; Vitamin E

To investigate whether retinyl palmitate (RP) alone or plus beta-carotene (BC) would be as effective and less toxic than low-dose 13-cis retinoic acid (13cRA) in treating oral premalignant lesions (OPLs) and reducing the risk of oral cancer.. Initially, patients were randomly assigned to receive low-dose 13cRA or BC plus RP for 3 years (plus 2 years follow-up). After other randomized trials established an adverse effect of BC on lung cancer incidence/mortality, BC was dropped (patients randomly assigned to 13cRA or RP alone). The primary end point was OPL clinical response at 3 months.. We randomly assigned 162 eligible patients. The 3-month clinical response rate of the combined BC plus RP and RP alone arm (32.5%) was not statistically equivalent to that of 13cRA (48.1%). The clinical response rate of RP alone (20.0%) was significantly lower than that of BC plus RP (42.9%; P = .03). Similar oral cancer-free survival rates were observed across all arms. There was no significant association between 3-month OPL response and subsequent oral cancer development (P = .11). Grades 2 and higher adverse events were more common in the 13cRA than other groups (P < .0001).. This large chemoprevention trial did not establish the equivalence of RP plus BC or RP alone with low-dose 13cRA in reducing the long-term risk of oral cancer. At present, 13cRA, BC plus RP, and RP alone cannot be recommended for chemoprevention, and new, better agents are needed in this setting. Our results did not establish short-term OPL response as a surrogate end point for oral cancer-free survival.

Topics: Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; beta Carotene; Disease-Free Survival; Diterpenes; Female; Humans; Isotretinoin; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Retinyl Esters; Treatment Outcome; Vitamin A; Vitamins

The objective of this preliminary uncontrolled study was twofold: First, to assess the feasibility of retinyl palmitate inhalation and second, to analyze the changes of metaplastic lesions of the respiratory epithelium (metaplasia or dysplasia) following retinyl palmitate inhalation. The response to a daily dose of 18.000 I.U. retinyl palmitate by inhalation over a period of 3 month was assessed in 11 subjects (9 smokers, 2 ex-smokers). Using white-light bronchoscopy combined with autofluorescence bronchoscopy, bronchial biopsies were taken before and after a 3 month-period. The biopsy samples were evaluated blind by a referee lung pathologist. The overall response rate (remission or partial remission) was 56% (95% CI 0.30 0.79; p<0.05). These data suggest that inhalation of retinyl esters could be a promising therapeutical approach for chemoprevention of lung cancer. Vitamin A; chemoprevention; lung cancer; squamous metaplasia; dysplasia; retinoids

Topics: Administration, Inhalation; Aerosols; Biopsy; Bronchi; Bronchoscopy; Diterpenes; Female; Fluorescence; Hoarseness; Humans; Male; Metaplasia; Middle Aged; Pilot Projects; Precancerous Conditions; Prospective Studies; Remission Induction; Respiratory Mucosa; Retinyl Esters; Smoking; Treatment Outcome; Vitamin A

Epidemiologic studies have demonstrated that individuals who eat more fruits and vegetables and/or have high levels of serum beta-carotene have a lower risk of cancer, especially lung cancer. However, recent human intervention studies using beta-carotene supplements have shown an increase in the risk of lung cancer among smokers and asbestos workers. In this study, we used an animal model system to evaluate the hazard associated with a combination of high-dose beta-carotene supplementation and tobacco smoking.. Ferrets were given a beta-carotene supplement, exposed to cigarette smoke, or both for 6 months. Cell proliferation and squamous metaplasia in lung tissue were assessed by examination of proliferating-cell nuclear antigen expression and histopathologic examination, respectively. beta-Carotene and retinoid concentrations in lung tissue and plasma samples were analyzed by high-performance liquid chromatography. Expression of genes for retinoic acid receptors (RARs) and activator protein-1 (encoded by the c-Jun and c-Fos genes) in lung tissue specimens was examined by western blotting.. A strong proliferative response in lung tissue and squamous metaplasia was observed in all beta-carotene-supplemented animals, and this response was enhanced by exposure to tobacco smoke. When compared with control groups, all three treatment groups had statistically significantly lower concentrations of retinoic acid in lung tissue, and they exhibited 18%-73% reductions in RARbeta gene expression; however, RARalpha and RARgamma gene expression was not reduced. Ferrets given a beta-carotene supplement and exposed to tobacco smoke had threefold to fourfold elevated expression of the c-Jun and c-Fos genes.. Diminished retinoid signaling, resulting from the suppression of RARbeta gene expression and overexpression of activator protein-1, could be a mechanism to enhance lung tumorigenesis after high-dose beta-carotene supplementation and exposure to tobacco smoke.

Topics: Animals; beta Carotene; Cell Division; Cocarcinogenesis; Diterpenes; Down-Regulation; Environmental Exposure; Ferrets; Gene Expression Regulation; Genes, fos; Genes, jun; Humans; Lung; Lung Neoplasms; Male; Metaplasia; Nicotiana; Plants, Toxic; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Receptors, Retinoic Acid; Retinyl Esters; Signal Transduction; Smoke; Transcription Factor AP-1; Tretinoin; 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 inhibitory effects of beta-carotene or vitamin A on preneoplastic lesions induced in rats were compared, when specifically administered during early promotion of hepatocarcinogenesis. Initiation was performed by diethylnitrosamine. During the selection/promotion period 2-acetylaminofluorene was administered, and a partial hepatectomy was performed. Afterwards, the rats were divided into 3 groups. To two groups, beta-carotene or vitamin A were given for five weeks. Another group served as control and received corn oil. At the end of the study, beta-carotene reduced the incidence and total number of hepatocyte nodules. Vitamin A rats exhibited a lower number of nodules, but the incidence was 100%. Moreover, beta-carotene reduced the total number of gamma GT-positive preneoplastic lesions, as well as the morphometric parameters of persistent gamma GT-positive lesions. In contrast, morphometric parameters of persistent lesions remained almost unaffected in vitamin A animals. Furthermore, beta-carotene significantly increased the number of remodeling gamma GT-positive preneoplastic lesions. Vitamin A administration, however, resulted only in a small increase in the number of remodeling lesions. These results suggest that the inhibitory effects of beta-carotene during early promotion of hepatocarcinogenesis can be attributed not only to an inhibitory effect on persistent lesions, but also to a striking stimulatory activity on remodeling gamma GT-positive lesions.

Topics: Animals; Anticarcinogenic Agents; beta Carotene; Diterpenes; gamma-Glutamyltransferase; Liver; Liver Neoplasms; Male; Precancerous Conditions; Rats; Rats, Wistar; Retinyl Esters; Vitamin A

The purpose of this study was to determine the effects of dietary vitamin A on the tumor promoting effect of 3,3',4,4'-TCB and 2,2',4,4',5,5'-HCB in a two-stage rat hepatocarcinogenesis model with diethylnitrosamine (DEN, 150 mg/kg) as the initiator. Two weeks after DEN injection rats were fed a purified diet containing either 2000 or 100,000 IU of vitamin A in the form of retinyl palmitate. Rats received four biweekly injections of 3,3',4,4'-TCB, 2,2',4,4',5,5'-HCB (300 mumol/kg), or both (150 mumol/kg each) in corn oil (10 ml/kg) for 8 weeks. Control animals received vehicle only. Six rats in each group that received no DEN treatment were used as additional control animals. Ten days after the last injection the rats were killed. In rats fed the low retinyl palmitate diet, treatment with 3,3',4,4'-TCB, 2,2',4,4',5,5'-HCB or both compounds lowered hepatic retinyl palmitate content. This effect was prevented by high dietary retinyl palmitate supplementation in rats treated with 2,2',4,4',5,5'-HCB, but not 3,3',4,4'-TCB or both compounds together. Histopathological examination of the liver showed that high dietary retinyl palmitate lessened the severity of hepatocellular necrosis and fatty changes induced by 3,3',4,4'-TCB alone or in combination with 2,2',4,4',5,5'-HCB. The latter did not cause significant pathological lesions to the liver. However, high dietary retinyl palmitate was not able to prevent thymic involution caused by 3,3',4,4'-TCB. The number and volume of altered hepatic foci were increased by 2,2',4,4',5,5'-HCB and particularly 3,3',4,4'-TCB; no synergistic effect was seen. Supplementation with high dietary retinyl palmitate diminished the number and volume of foci. These results show that supplementation with high dietary retinyl palmitate protects against hepatocellular necrosis, fatty changes, and preneoplastic changes induced by 3,3',4,4'-TCB as well as against preneoplastic changes induced by 2,2',4,4',5,5'-HCB. In addition, these two agents did not synergistically induce preneoplastic changes in DEN-induced rats.

Topics: Animals; Body Weight; Cell Division; Cocarcinogenesis; Diethylnitrosamine; Diterpenes; Drug Interactions; Female; Liver; Liver Neoplasms, Experimental; Methylcholanthrene; Polychlorinated Biphenyls; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Retinyl Esters; 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

The preneoplastic skin changes usually induced by topical application of 7,12-dimethylbenz[a]anthracene (DMBA) to adult rat skin did not appear when animals were treated locally with depot im injections of high doses of retinyl palmitate (RP) prior to exposure to the carcinogen. The epidermal histology after RP-DMBA treatment was similar to that seen in areas exposed to RP alone. Keratinization was inhibited but there was no cellular atypia, evidence of cell injury, or mucous metaplasia. Other features were hyperplasia with acanthosis and thickened stratum granulosum, parakeratosis, intercellular edema, and loss of hair overlying the injection site. Ultrastructurally, the epidermal cells contained conspicuously fewer tonofibrils and increased dense chromatin, when compared to control cells. Skin changes observed following treatment of littermates with DMBA alone included the appearance of giant tumor cells, dyskeratotic cells, nuclear hyperchromatism, increased nucleocytoplasmic ratio, and pleomorphic nuclei and nucleoli. oss of desmosomes, increased tonofibrils, and defects in the basement membrane with epithelial projections into the dermis were also seen. These preneoplastic changes did not regress when application with DMBA was discontinued after 6 weeks; exposure to the carcinogen for longer than 6 weeks resulted in an exacerbation of the abnormal state. RP had profound effects on rat epidermis that interfered with the effects of a potent skin carcinogen. The mechanisms underlying the phenomenon have not been defined. The use of depot injections of the vitamin which avoids both systemic toxicity and the local irritation seen with topical exposure could serve as a model in which the anticarcinogenesis properties of retinoids could be explored.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Benz(a)Anthracenes; Diterpenes; Drug Administration Schedule; Injections, Intramuscular; Male; Neoplasms, Experimental; Palmitates; Precancerous Conditions; Rats; Retinyl Esters; Skin; Skin Neoplasms; Vitamin A