beta-carotene and Leukoplakia

Oral cancer is often preceded by precancerous lesions, the most common of which is leukoplakia. Several treatment modalities are available: elimination of the possible cause, cold knife, laser, or cryosurgery, and topical application of bleomycin and 5-fluorouracil. In research, oral leukoplakia is used as a model to study the value of chemoprevention as a strategy to prevent cancer, because its effect is directly visible and material for analysis is easily obtainable from the mouth. In several studies and chemoprevention trials the efficacy of retinoids, retinol and/or beta-carotene on oral leukoplakia has been demonstrated. Second primary tumors occur in 10-30% of head and neck cancer patients and 10% of lung cancer patients. Chemoprevention offers an attractive approach to combat this threat to such patients, which is bound to cast a shadow over their lives. In the last 10-15 years several chemoprevention studies with vitamin A, retinoids or agents working through other mechanisms (antioxidants) have been launched. The largest chemoprevention study in curatively treated early-stage oral cancer, laryngeal cancer and lung cancer (N = 2595) is EUROSCAN, an EORTC study initiated in 1988. End-points are second tumors, local/regional recurrence and distant metastases, and long-term survival rates. Preminary results will be available in 1998.

Topics: beta Carotene; Biomarkers, Tumor; Clinical Trials as Topic; Head and Neck Neoplasms; Humans; Leukoplakia; Lung Neoplasms; Precancerous Conditions; Retinoids; Vitamin A

Topics: Animals; Anticarcinogenic Agents; Antioxidants; beta Carotene; Carotenoids; Humans; Leukoplakia; Mouth Neoplasms; Precancerous Conditions; Retinoids; Vitamins

Bowman-Birk inhibitor is a protease inhibitor derived from soybeans that has demonstrated chemopreventive activity in a number of in vitro and animal systems. We conducted a 1-month phase IIa clinical trial of Bowman-Birk inhibitor concentrate (BBIC) in patients with oral leukoplakia. BBIC was administered to 32 subjects with oral leukoplakia for 1 month. We assessed toxicity and clinical and histological response of the lesions, and oral mucosal cell protease activity (PA) and serum micronutrient levels were measured. Clinical response was determined by measurement of pre- and posttreatment individual and total lesion areas and analysis of blinded clinical judgments of photographs. On the basis of prespecified response criteria, 31% of patients achieved a clinical response (two with complete and eight with partial responses). BBIC was nontoxic in doses up to 1066 chymotrypsin inhibitory units. The mean pretreatment total lesion area decreased from 615 to 438 mm2 after BBIC treatment (P < 0.004). A linear fit of the dose-response relationship between dose of BBIC and decrease in total lesion area was suggested (P < 0.08), and analysis of blinded clinical impression from lesion photographs confirmed this relationship (P < 0.01). Overall, at all doses tested, a 24.2% decrease in total lesion area was observed following treatment (sign rank = -142; P < 0.004). High pretreatment PA was associated with greater decreases in PA after BBIC administration (P < 0.02). BBIC demonstrated clinical activity after oral administration to patients with oral leukoplakia. These results indicate that BBIC should be investigated for chemopreventive activity in a randomized clinical trial.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Dose-Response Relationship, Drug; Endopeptidases; Female; Humans; Leukoplakia; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Protease Inhibitors; Treatment Outcome; Trypsin Inhibitor, Bowman-Birk Soybean; Trypsin Inhibitors; Vitamin A; Vitamin E

Recent reports have demonstrated that beta-carotene, a nontoxic carotenoid, is able to stimulate immune functions in humans. The purpose of this study is to understand the mechanisms of immunoenhancement by carotenoids in order to explain their anticancer effects. We have evaluated the clinical efficacy of beta-carotene, given 30 mg/day orally, for treatment of oral leukoplakia patients. Patients who responded to beta-carotene treatment showed increased plasma levels of TNF-alpha. Epithelial cells from these patients were characterized in vitro. These results may lead to a better understanding of the therapeutic use of beta-carotene in humans.

Topics: Adjuvants, Immunologic; beta Carotene; Carotenoids; Cell Adhesion Molecules; Cell Line; Cytotoxicity, Immunologic; Epithelium; HLA-DR Antigens; Humans; Intercellular Adhesion Molecule-1; Killer Cells, Natural; Leukoplakia; Mouth Mucosa; Mouth Neoplasms; T-Lymphocyte Subsets; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Leukoplakia is associated with increased risk of oral cancer and is considered a premalignant lesion. Retinoids, particularly 13-cis retinoic acid, can frequently reverse leukoplakia. However, these drugs have considerable toxicity and are not suitable for large-scale use in the prevention of oral cancer. Beta-carotene is a naturally occurring, nontoxic carotenoid with biologic properties that suggest that it might be efficacious against oral leukoplakia. In 1986, we began a randomized study of 13-cis retinoic acid (1 mg/kg/d) versus beta-carotene (30 mg/d) in leukoplakia. However, owing to the marked differences in toxicity between the two compounds outlined in the consent form, 11 of the initial 16 eligible patients refused to participate unless they were "guaranteed" beta-carotene. Therefore, the study design was changed to a phase II trial of beta-carotene in which the compound was given daily for 3 months. Responding patients were continued for another 3 months of treatment. All lesions were examined histologically at entry. Responses were monitored by bidimensional measurements and photography done at entry, then monthly while on treatment and at study completion. Twenty-four evaluable patients were treated, and 17 had major responses (two complete, 15 partial), a response rate of 71% (95% confidence limits, 53% to 89%). There was no significant toxicity requiring drug discontinuation or dose reduction. These results indicate that beta-carotene has substantial activity in oral premalignancy. Because of its lack of toxicity, it is an excellent candidate for a preventive agent for oral cancer.

Topics: Aged; Antineoplastic Agents; beta Carotene; Biopsy; Carotenoids; Drug Evaluation; Female; Humans; Leukoplakia; Male; Middle Aged; Mouth; Mouth Neoplasms; Remission Induction

In a clinical trial the effect of chemoprevention with beta-carotene, vitamin E and C on dysplastic tissue was studied. The study included 24 patients with oral leukoplakia and 24 patients after radical resection of a primary oral cancer. There was a reduction of increased cell kinetic parameters like the S-phase portion or the average number of nuclear-organizer regions (NOR) per cell nucleus, a decrease of the micronuclei portion and a normalization of the cytokeratin gene-expression. The general response was 97.5%. Stopping the alcohol and tobacco abuse the effect of the antioxidative vitamins on redifferentiation of the oral mucosa was more intense than by persistance of the alcohol and tobacco abuse, but a long term prevention seems to be ineffective.

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Biopsy; Cell Differentiation; Cohort Studies; Drug Therapy, Combination; Humans; Keratins; Leukoplakia; Mouth Mucosa; Mouth Neoplasms; Nucleolus Organizer Region; S Phase; Time Factors; Vitamin E

The baseline, intra-, and interindividual variability as well as storage stability of carotenoids, tocopherols, and retinoids in human buccal mucosal cells were determined because this information is lacking. All the buccal mucosal cell samples were collected after an overnight fast. In the variability study, 154 subjects (median age 57.5 y) provided three samples each at 7-10-d intervals over a 1-mo period. In the stability study, 13 young volunteers provided four samples each before and during the 11 d of oral administration of beta-carotene, alpha-tocopherol, and vegetable juice; the cells were pooled and stored as a pellet at -80 degrees C. Eleven micronutrients were analyzed simultaneously with HPLC. The results indicated that 1) lycopene and beta-carotene were the two major carotenoids, retinol was not detected in most cell samples; 2) the intra-individual variability was small, but the interindividual variability was very large; 3) two measurements of micronutrient concentration in fasting buccal mucosal cells should be adequate to establish a representative baseline for each micronutrient; and 4) the micronutrients under the storage conditions were stable for > or = 8 mo.

Topics: Administration, Oral; Adult; Aged; beta Carotene; Carotenoids; Female; Humans; Keratosis; Leukoplakia; Male; Middle Aged; Mouth Mucosa; Precancerous Conditions; Reference Values; Retinoids; Uterine Cervical Dysplasia; Vegetables; Vitamin E

Previous studies have shown that beta-carotene and alpha-tocopherol can act synergistically to inhibit the growth of experimentally induced oral cancer. The initial studies on the synergistic anticancer activity of antioxidants have been extended to include reduced glutathione and ascorbic acid. Sixty male hamsters (4-5 wks old) were divided into six equal groups. Groups 1-6 were treated with 7,12-dimethylbenz[a]anthracene (DMBA) (0.5% solution). Group 2 received a mixture containing equal amounts of beta-carotene, dl-alpha-tocopherol (vitamin E), glutathione, and l-ascorbic acid (vitamin C) (12.5 micrograms) delivered orally by pipette. Groups 3-6 were treated with beta-carotene alone (50 micrograms), vitamin E alone (50 micrograms), glutathione (50 micrograms) alone, and vitamin C alone (50 micrograms). Animals were euthanized at 12 and 14 weeks. Tumors were counted and measured, and tumor burden was calculated for each experimental group. The mixture of antioxidants significantly reduced tumor burden, whereas the beta-carotene, vitamin E, and reduced glutathione treatments also reduced tumor burden. beta-Carotene and glutathione provided greater levels of chemoprevention than vitamin E as single agents. In contrast, vitamin C treatment produced no antitumor effect but increased tumor burden by Week 14. This mixture of antioxidants produced a significant synergistic chemoprevention of oral cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Animals; Ascorbic Acid; beta Carotene; Carotenoids; Cricetinae; Drug Combinations; Drug Synergism; Glutathione; Leukoplakia; Male; Mesocricetus; Mouth Neoplasms; Vitamin E