retinol-palmitate and Mouth-Neoplasms

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

Topics: Anticarcinogenic Agents; Diterpenes; Etretinate; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia; Lung Neoplasms; Mouth Neoplasms; Retinoids; Retinyl Esters; 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

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 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

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

Topics: Anticarcinogenic Agents; Diterpenes; Etretinate; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia; Lung Neoplasms; Mouth Neoplasms; Retinoids; Retinyl Esters; Vitamin A

23 patients, with advanced oral cavity cancer, radically unresectable or relapsing after surgery and/or radiotherapy, were treated with a chemotherapeutic regimen, including 5-Fluorouracil 1000 mg/m2 and cis-platinum 20 mg/m2 for 5 consecutive days. Retinol palmitate was administered at the dose of 15.000 IU b.i.d. in chemotherapy intervals. In complete or partial responders, radiotherapy was planned on primary tumor. Chemotherapy treatment was well tolerated with G3 haematological toxicity in 30% of patients and G2 gastrointestinal toxicity in 20% of patients. Seven patients (31.8%) had a complete response (CR), 7 patients had a partial response (PR) (31.8%), stable disease was observed in 3 patients (SD) (13.7), while 5 patients progressed (PD) (22.7%). Median time to treatment failure was 5.6 months. Median survival, from start of chemotherapy, was 8 months 237 days (range 8 days-4 years). 12 patients received consolidation chemotherapy on the primary disease site. No patient developed a second tumor. A combined approach, in the treatment of oral cavity cancer, may give prolonged responses, with acceptable toxicity, without interfering on the quality of life.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Diterpenes; Female; Fluorouracil; Humans; Jaw Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Neoplasm Staging; Retinyl Esters; Tongue Neoplasms; 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

In vitro changes of normal human keratinocytes (NHKs) derived from the oral mucosa after treatment with the chemical carcinogen 7,12 dimethylbenz[a]anthracene (DMBA; 5, 50, 200 ng/10 ml) were evaluated. NHKs were also treated with chemopreventive nutrient agents that previously had enhanced growth of epidermal and oral keratinocytes or suppressed growth of oral squamous cell carcinoma. These agents included the carotenoids beta-carotene and canthaxanthin and the retinoid retinyl palmitate (60 microM). Plating efficiency, growth in agarose (independent growth), viability [tetrazolium salt (MTT) assay], and proliferation ([3H]thymidine labeling) defined the growth of NHKs. The number of cornified cells and keratin expression (high-molecular-weight keratin) defined differentiation. gamma-Glutamyl transpeptidase, p53 expression, and tumorigenesis in mice defined oxidation and malignant transformation. Treatment with DMBA (50 ng/10 ml) was detected by autofluorescence; it produced an increase in pleomorphism and multinucleation and enhanced plating efficiency and the number of colonies grown in agarose. Chemopreventive treatment enhanced the number of colonies grown in agarose, but the MTT levels and [3H]thymidine incorporation-proliferation (24 h) were reduced. Chemopreventives also increased differentiation defined by the number of cornified cells and the expression of high-molecular-weight keratin-positive cells. Malignant transformation potential was depressed by reducing gamma-glutamyl transpeptidase and mutant p53 expression, whereas tumor suppressor p53 was enhanced. NHKs treated with DMBA and injected into nude mice (nu/nu: 1 x 10(6) cells/0.25 ml) produced tumor masses (3 of 3 animals), whereas the nutrient and DMBA groups produced smaller tumor masses, some with central ulcers (2 of 3 animals). Mock injection of untreated or nutrient-treated NHKs without DMBA treatment did not produce a tumor mass (0 of 3 animals). beta-Carotene, retinyl palmitate, and canthaxanthin increased differentiation and reduced transformation induced by DMBA in oral NHKs.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adult; Animals; Anticarcinogenic Agents; beta Carotene; Canthaxanthin; Carcinogens; Cell Division; Cell Transformation, Neoplastic; Chromatography, High Pressure Liquid; Diterpenes; Flow Cytometry; Gene Expression Regulation; Humans; Immunohistochemistry; Keratinocytes; Male; Mice; Mice, Nude; Mouth Mucosa; Mouth Neoplasms; 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

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