isotretinoin and Precancerous-Conditions

The systematic review and meta-analysis of published randomised controlled trials (RCTs) was conducted to review the effectiveness of current chemopreventive agents in the treatment of oral leukoplakia lesions (OPLs) and prevention of their progression to oral cancer. Material was identified through a retrospective literature search of the electronic PubMed database, Embase and Cochrane Library between 2008 and 2016.Eight RCTs were included for systematic review. The pooled estimate showed a 14% greater chance of responding for those randomised to interventions compared with placebo (Risk Ratio [RR] 1.14, 95% confidence interval [CI] 0.72 to 1.81). The CI from individual studies overlapped. The results suggested that there were no significant differences in comparing clinical responses between chemopreventive agents with placebo in treatment of OPLs. It is time to investigate new agents for oral cancer chemoprevention.

Topics: Antineoplastic Agents; beta Carotene; Chemoprevention; Erlotinib Hydrochloride; Humans; Isotretinoin; Leukoplakia, Oral; Mouth Neoplasms; Precancerous Conditions; Provitamins; Tea; Treatment Outcome; Vitamin A; Vitamins

Chemoprevention is one of the cancer prevention methods, applied for the oral squamous cell carcinoma and its main precursor lesions--leukoplakia and erythroplakia. Presently, the most extensive clinically studied group used in such cases are retinoids: vitamin A (retinol), 13-cis-retinic acid (isotretinoin), N-(4-hydroxyphenyl)retinamide (fenretinide) and precursor of vitamin A--beta-carotene. However, despite good short-time effectiveness, retinoids do not prevent recurrences of the lesions and insignificantly increase cancer-free survival. Moreover, they are also characterized by relatively high toxicity. Vitamin E, Bowman-Birkprotease inhibitor, Spirulina fusiformis and green tee extracts as well as traditional Chinese herbs known as ZengShengPing were also found as effective agents. Lack of activity was reported for cyclooxygenase inhibitors--ketorolac and celecoxib. More promising data was collected from animal experimental studies with chemically induced oral squamous cell carcinoma. Chemopreventive activity was revealed for various agents including plant-derived compounds like resveratrol, green and black tee polyphenols, as well as protocatechuic, ellagic and caffeic acids.

Topics: Animals; Antineoplastic Agents; beta Carotene; Carcinoma, Squamous Cell; Chemoprevention; Drugs, Chinese Herbal; Fenretinide; Humans; Isotretinoin; Mouth Neoplasms; Neoplasm Recurrence, Local; Phytotherapy; Precancerous Conditions; Vitamin A

Treatment of lung cancer remains frustrating. Most patients with lung cancer are not candidates for curative therapy, and new therapies have not made a substantial impact on survival. Consequently, some clinical investigators have focused their efforts on developing prevention strategies. Chemoprevention, the administration of agents to block or reverse carcinogenesis, is being investigated in ongoing trials. Studies of chemoprevention in lung cancer have included trials to reverse premalignant lesions such as sputum atypia or squamous metaplasia of the bronchial epithelium. Clinical trials of lung cancer prevention have often studied groups of participants with tobacco or asbestos exposure. Other clinical trials are being conducted among patients who have been treated for an early-stage lung cancer. As the result of diffuse epithelial injury, these patients are at very high risk for developing second primary tumors, predominantly in the lungs and upper aerodigestive tract. It is our hope that these studies may establish a new strategy for preventing lung cancer.

Topics: Anticarcinogenic Agents; beta Carotene; Carcinoma, Non-Small-Cell Lung; Carotenoids; Clinical Trials as Topic; Humans; Isotretinoin; Lung Neoplasms; Neoplasms, Second Primary; Precancerous Conditions; Randomized Controlled Trials as Topic

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Animals; Female; Humans; Infant, Newborn; Isotretinoin; Kinetics; Precancerous Conditions; Pregnancy; Skin Neoplasms; Tretinoin

Topics: Adult; Benzoates; Bowen's Disease; Carcinoma, Basal Cell; Child; Etretinate; Female; Humans; Isotretinoin; Male; Precancerous Conditions; Psoriasis; Retinoids; Skin Diseases; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

To determine the utility of isotretinoin oral rinses as a method of chemoprevention for recurrent oral cavity squamous cell carcinoma (SCC), carcinoma in situ, and dysplasia.. Retrospective cohort study.. One hundred forty-three patients were initially enrolled in the study; however, 18 were excluded due to inability to tolerate therapy. The included patients were classified into four groups. Group 1 included patients with multiple early stage oral cavity lesions following initial resection. Group 2 included patients with SCC in situ after excision. Group 3 included patients with multifocal dysplasia following initial CO. Using a Bonferroni correction, the significance threshold was 0.0125. By that cutoff, isotretinoin rinses were found to be associated with lower recurrence in groups 1 and 3 (P = .00014, P = .00002, respectively) but not in groups 2 and 4 (P = .4, P = .3846, respectively).. Oral isotretinoin as chemoprophylaxis for patients treated for oral cavity squamous cell carcinoma, in situ disease, or dysplasia may be beneficial in decreasing recurrence rate.. 4. Laryngoscope, 127:1595-1599, 2017.

Topics: Carcinoma in Situ; Carcinoma, Squamous Cell; Cohort Studies; Combined Modality Therapy; Female; Humans; Isotretinoin; Laser Therapy; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Mouthwashes; Neoplasm Recurrence, Local; Neoplasm Staging; Precancerous Conditions; Retrospective Studies; Secondary Prevention

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

In a previous trial, we found that combined 13-cis-retinoic acid, IFN-alpha, and alpha-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that cyclin D1 (CD1) G/A870 single nucleotide polymorphism correlated with cancer risk. We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1, both genotype and protein expression, in association with cancer risk in this setting. Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined 13-cis-retinoic acid daily, alpha-IFN twice weekly, and alpha-tocopherol daily for 1 year; 14 nonprogressing patients then were randomized to maintenance fenretinide or placebo for 2 years. During induction, two patients had pathologic complete responses, six had partial responses (30% overall response rate), and five developed laryngeal cancer. There were no significant differences between maintenance fenretinide and placebo in response or cancer rates. Ten patients developed cancer overall. Twenty-four patients were evaluated for the CD1 G/A870 genotype, and 23 for pretreatment and posttreatment CD1 protein expression. Consistent with our earlier report, shorter cancer-free survival was associated with the CD1 AA/AG genotype (P = 0.05). Extending our earlier work, high CD1 expression was associated with worse cancer-free survival overall (P = 0.04) and within each CD1 genotype group. These findings support CD1 genotype and protein expression as important risk markers for laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription.

Topics: alpha-Tocopherol; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cyclin D1; Female; Fenretinide; Gene Expression; Genotype; Humans; Immunohistochemistry; Interferon-alpha; Isotretinoin; Laryngeal Diseases; Laryngeal Neoplasms; Male; Polymorphism, Single Nucleotide; Precancerous Conditions

Topics: Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Immunohistochemistry; Interferon-alpha; Isotretinoin; Mutation; Precancerous Conditions; Prospective Studies; Treatment Outcome; Tumor Suppressor Protein p53; Vitamin E

In a double-blind study 10 patients with oral leukoplakia were treated daily (three topical applications) with 0.1% isotretinoin gel or a placebo for 4 months. Nine patients completed the treatment, while one patient was lost to follow-up. Subsequently, the patients who had received the placebo used the active medication for an additional 4 months. All patients treated with the active medication showed a significant improvement of the oral lesions while, in the patients receiving only the placebo, the size of the lesions remained the same. Also the group of patients who received the active medication after the placebo showed an improvement in the size and clinical appearance of the lesions. A complete response was defined as the complete disappearance of the lesion as assessed by visual inspection, while a partial response was defined as a 50% or more reduction in the size of the lesions. In total we had a complete response and eight partial responses. No side-effects from the use of the gel were ever observed. The percentage of bcl-2-positive cells was evaluated in the basal layer from a minimum of 1000 cells in each case and the bcl-2 immunostaining was scored using three groups: - (< or = 10% cells); + (< or = 50% cells); +2 (> or = 50% cells). The presence of apoptotic bodies was evaluated in a random fashion in the parabasal layer in 20 HPF. Immunohistochemical analysis for bcl-2 protein showed that before treatment a weak positivity of the basal layers, with a focal positivity of some parabasal cells, was present: five out of nine specimens were positive. Only a few apoptotic bodies were observed. After treatment in almost all specimens it was possible to observe a complete bcl-2 negativity with a positivity in only one specimen out of nine. An increase in apoptotic bodies was observed. Statistical analysis showed that the difference between the bcl-2 positivity in the two groups was not statistically significant (P = 0.134) while, on the contrary, the difference in the count of the apoptotic bodies between the same two groups was statistically significant (P = 0.0193). In conclusion, the data obtained from this pilot study show that good results can be obtained with the topical use of 13-cis-retinoic acid.

Topics: Administration, Topical; Adult; Aged; Apoptosis; Biomarkers; Double-Blind Method; Female; Gels; Humans; Isotretinoin; Leukoplakia, Oral; Male; Middle Aged; Pilot Projects; Precancerous Conditions; Proto-Oncogene Proteins c-bcl-2

Retinoids are under intensive study for the treatment and prevention of cancer. Substantial dose-related toxicities of retinoids are a major obstacle to this work. In a recent retrospective analysis of combined 13-cis-retinoic acid (13cRA) and alpha-tocopherol (AT) in myelodysplasia, 13cRA toxicity was reduced significantly and 13cRA activity was enhanced. These results suggested the need for prospective testing of this new combination. This trial tested the hypotheses that At can reduce toxicity of high-dose 13cRA and does not interfere with 13cRA absorption/activity as reflected by reduced 13cRA serum levels.. This was a phase I trial design in which patients received fixed-dose 13cRA (100 mg/m2/d) plus escalating-dose AT (beginning at 800 IU/d, increased 400 IU/d each month until 2000 IU/d). We collected toxicity data every four weeks from self-report forms, clinical examinations and laboratory studies. AT effects on 13cRA toxicity were determined by comparing maximum toxicity at lowest AT dose with that at highest AT dose. We also measured serum levels of both agents every four weeks.. Of the 45 patients registered, 36 had cancer (active or prior history), 9 had premalignant lesions. Thirty-nine patients could be evaluated for initial-course toxicity; 31 for final course toxicity. Median time on treatment (all patients) was four months (range, 1-9 months); a total of 223 month-long courses of treatment were given. Eighteen percent of patients (7/39) developed grade 3 or 4 toxicity in the initial course. The rates of increase and decrease in 13cRA toxicity associated with increasing AT doses were similar: 36% decreased (11/31), 32% increased (10/31) (P = 0.84). At did not reduce 13cRA serum levels. After initial increases of mean AT plasma levels (17.9 micrograms/ ml at baseline to 45.4 micrograms/ml after first four-week course), subsequent AT plasma increases (< 2-fold) did not keep pace with increased AT doses (2-3-fold). No major activity occurred in the 21 patients with active refractory cancer. The complete response rate in patients with premalignant head-and-neck or lung lesions was 77.8% (7/9), which included two patients previously refractory to 13cRA alone.. Although escalating doses of AT did not reduce 13cRA toxicity, the rate of initial-course (including 800 IU/d of AT) high-grade toxicity was substantially lower than that typical of high-dose 13cRA-alone and similar to that typical of low-dose 13cRA-alone. Indeed, a trial of 13cRA-alone followed by 13cRA plus AT may have detected a significant toxicity difference. We did not design such a trial out of ethical concern for known side effects of high-dose 13cRA. The increase in AT serum levels was not proportional with increasing doses of AT, which may explain the lack of a dose-response effect of AT on 13cRA toxicity. Previous trials have established that 13cRA has an approximate 10% complete response rate in oral premalignancy. Our small trial's 77.8% complete response rate in premalignant lesions suggests that AT may enhance 13cRA clinical activity. Future trials of 13cRA plus AT are needed to define this combinations toxicity profile, clinical activity and pharmacokinetics.

Topics: Adult; Aged; Alanine Transaminase; Alkaline Phosphatase; Anticarcinogenic Agents; Antineoplastic Agents; Biomarkers; Cheilitis; Chemical and Drug Induced Liver Injury; Conjunctivitis; Drug Eruptions; Female; Humans; Hypertriglyceridemia; Isotretinoin; Leukoplakia, Oral; Lung Diseases; Male; Middle Aged; Neoplasms; Pain; Precancerous Conditions; Treatment Outcome; Vitamin E

We studied p53 protein's pattern of expression, association with retinoid response or resistance, and modulation by retinoid intervention in oral premalignancy. These p53 analyses were included in a prospective trial of the retinoid isotretinoin (1.5 mg/kg/day for 3 months) in 40 patients (45 oral premalignant lesions). Seven nonsmoking subjects (eight oral biopsies) were included as a control. Protein levels of p53 were determined separately for the whole epithelium and the basal, parabasal, and superficial layers. A wide range of accumulated p53 protein levels occurred in 40 (89%) of 45 lesions in basal and parabasal but not superficial layers. No p53 protein was detected in any normal controls. Accumulation of p53 increased in direct association with histological grade (P = 0.0004). An inverse relationship occurred between the levels of accumulated p53 protein and response to isotretinoin (P = 0.006). High-dose isotretinoin did not modulate accumulated p53 protein expression.

Topics: Adult; Aged; Female; Humans; Isotretinoin; Leukoplakia; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Prospective Studies; Time Factors; Tumor Suppressor Protein p53

Biomarkers are being sought that could serve as surrogate end points for chemoprevention trials. Micronuclei, cytoplasmic fragments of DNA, have been proposed as a biomarker and studied in oral pre-malignancy. This study evaluated micronuclei frequency in a randomized chemoprevention trial of oral pre-malignancy. A recent clinical trial evaluated the responses of pre-malignant oral lesions to 3 months of therapy with isotretinoin followed by 9 months of either low-dose isotretinoin or beta-carotene. For 57 study participants, micronuclei were counted in mucosal scrapings of the lesion and in normal-appearing mucosa at baseline and following 3 months and 12 months of therapy. Micronuclei counts were higher in scrapings from the lesion than in the normal-appearing mucosa. Following 3 months of isotretinoin, the micronuclei counts in scrapings of the lesion were significantly reduced. With treatment, the mean micronuclei count declined at 3 months. In a randomized comparison, both isotretinoin and beta-carotene maintained the suppression of micronuclei. The change in micronuclei count was not associated with the clinical or histological response to treatment. Chemoprevention treatment with isotretinoin led to a reduction in frequency of micronuclei, a marker of recent DNA injury, which was then maintained by both isotretinoin and beta-carotene.

Topics: beta Carotene; Biomarkers, Tumor; Carotenoids; Cell Transformation, Neoplastic; Female; Humans; Isotretinoin; Leukoplakia, Oral; Male; Micronuclei, Chromosome-Defective; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Precancerous Conditions; Remission Induction; Statistics, Nonparametric

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Calcitriol; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Isotretinoin; Male; Middle Aged; Precancerous Conditions; Skin Neoplasms

Retinoids have proven chemopreventive efficacy in both preclinical and clinical studies. This trial was designed to confirm the finding of an earlier uncontrolled trial that the synthetic retinoid etretinate had major activity in reversing squamous metaplasia found in the bronchial epithelium of chronic smokers.. We prospectively evaluated 152 smokers with bronchoscopy and obtained biopsies from six sites. Subjects with dysplasia and/or a metaplasia index of greater than 15% were randomly assigned to receive either 1 mg/kg isotretinoin or placebo daily for 6 months. Of 86 subjects randomized (41 isotretinoin, 45 placebo), 69 were reevaluated at the completion of treatment.. In the group as a whole, the metaplasia index decreased over time from a mean +/- SE of 35.8% +/- 2.7% at baseline to 28.1% +/- 3.3% at the completion of treatment (P = .01) by repeated measures analysis of variance [ANOVA]); a reduction in the metaplasia index (> 8%) was noted in both isotretinoin and placebo groups (19 of 35 [54.3%] and 20 of 34 [58.8%], respectively). Complete reversal of squamous metaplasia was noted in nine subjects from each group. However, the magnitudes of the mean metaplasia index changes did not differ significantly in the two treatment groups. In both groups, smoking cessation resulted in significant declines in the extent of squamous metaplasia, whereas no significant change in metaplasia index was found among those who continued to smoke.. Squamous metaplasia was frequently observed in bronchial biopsy samples from chronic smokers. From this study, we conclude that isotretinoin has no effect on squamous metaplasia, a potential intermediate end point of bronchial carcinogenesis. Although determining the exact role of isotretinoin in lung cancer prevention requires further study, the finding that there was a significant decrease in squamous metaplasia in the placebo group emphasizes the critical importance of a placebo-controlled study design in chemoprevention trials using intermediate end points.

Topics: Adult; Aged; Bronchi; Epithelium; Female; Humans; Infant, Newborn; Isotretinoin; Lung Neoplasms; Male; Metaplasia; Middle Aged; Placebos; Precancerous Conditions; Regression Analysis; Smoking

Ten cats with a total of 15 cancerous or precancerous lesions were examined for clinical response to and histopathologic changes after treatment with 13-cis-retinoic acid. Before treatment was started, the lesions were graded according to clinical severity and biopsied for histopathologic examination. Serum samples were prepared for determining vitamin A concentrations. For comparison, serum vitamin A concentrations in 10 clinically healthy cats were determined. 13-cis-Retinoic acid (approx 3.0 mg/kg) was given to affected cats once a day for an average of 68 days. At the completion of the therapeutic trial, additional biopsy tissues were obtained for histopathologic examination, and serum was assayed for 13-cis-retinoic acid. Of the 15 lesions examined, only 1 showed partial clinical and microscopic improvement during the therapy period. The mean serum vitamin A concentration of the affected cats was not statistically different from that of the 10 healthy cats. The results of this trial indicated that 13-cis-retinoic acid used at this dosage, daily frequency, and duration did not have therapeutic efficacy for squamous cell carcinomas or preneoplastic lesions in the cat and that the mean serum vitamin A concentration did not differ between the affected cats and clinically healthy cats.

Topics: Animals; Carcinoma, Squamous Cell; Cat Diseases; Cats; Clinical Trials as Topic; Head and Neck Neoplasms; Isotretinoin; Precancerous Conditions; Tretinoin; Vitamin A

A 9-month-old girl presented with massive bilateral diffuse nephroblastomatosis. After response to actinomycin D and vincristine over a period of 1 year, the nephroblastomatosis continuously progressed under this treatment. As retinoic acid signaling is critical for normal renal development and nephroblastomatosis seems histologically as undifferentiated embryonal tissue, we added 13-cis retinoic acid to the chemotherapy regimen. Three months thereafter, kidney volumes declined significantly over a period of 1 year. Interestingly, nephroblastomatosis-associated acquired von Willebrand disease also resolved. Retinoic acid maybe a novel nontoxic treatment option for nephroblastomatosis requiring further systematic evaluation.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Dactinomycin; Dermatologic Agents; Drug Resistance, Neoplasm; Female; Humans; Infant; Isotretinoin; Kidney; Kidney Neoplasms; Magnetic Resonance Imaging; Precancerous Conditions; Vincristine

To determine the chemotherapeutic effect of retinoids on albino mouse skin.. Eighty albino mice were selected for this study and were divided into four groups (A-D, 20 mice in each group). 7,12-Dimethylbenz(a)anthracene (DMBA) and tetradecanoylphorbal-13-acetate (TPA) were given for 15 weeks to produce tumors. Retinoids were given topically and orally after the development of tumors for the following 15 weeks.. Of the 80 mice, 69 (86.25%) developed different types of lesion and 11 (13.75%) remained lesion free. Of the 69 mice that developed lesions, 50 (62.50%) developed benign lesions and 19 (23.75%) developed malignant lesions. In all groups of mice, treatment with retinoids was effective against all benign lesions and the early stages of carcinogenesis of the skin. The chemotherapeutic effect against malignant tumors was not satisfactory.. This study demonstrates that retinoids are effective as chemopreventive agents in premalignant lesions of the skin, but have a very weak chemotherapeutic role in malignant neoplasms. If retinoids are given at an early stage, they can cause regression of premalignant lesions of the skin. They are best administered both orally and parenterally. These agents should be recommended as they reduce the potential effects of carcinogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Diterpenes; Isotretinoin; Mice; Precancerous Conditions; Retinyl Esters; Skin Neoplasms; Tetradecanoylphorbol Acetate; Vitamin A

To evaluate the efficacy and secondarily the toxic effects of biochemopreventive therapy (high-dose isotretinoin [13-cis-retinoic acid], alpha-tocopherol, and interferon alfa) in the reversal of advanced premalignant lesions of the upper aerodigestive tract and to correlate the therapeutic events with modulation of biomarkers.. Prospective, nonrandomized chemoprevention trial.. Tertiary cancer care referral center and ambulatory care.. Thirty-six patients with advanced premalignant lesions of the upper aerodigestive tract, without cancer during the 2 years before the intervention, with evaluable lesions, and without retinoid therapy for 3 months before the trial.. Administration of oral isotretinoin (100 mg/m2 per day), oral alpha-tocopherol (1200 IU/d), and subcutaneous interferon alfa (3 megaunits per square meter twice weekly) for 12 months, with serial biopsies and clinical examination at 0, 6, 12, and 18 months from study start.. Clinical and histologic responses to the intervention.. Of the 36 patients, evaluation was possible in 30 for response at 6 months and in 21 at 12 months. At 6 months, there were 10 pathologic complete responses and 7 partial responses; at 12 months, 7 complete and 3 partial responses. A striking difference in response was observed in favor of laryngeal lesions (9/19 [47%] complete response rate at 6 months and 7/14 [50%] at 12 months vs 1/11 [9%] and 0/7 [0%], respectively, for oral lesions). Toxic effects were acceptable and did not exceed grade 3.. Biochemoprevention is a promising biologic approach for laryngeal dysplasia and needs to be investigated further.

Topics: Adult; Aged; Antineoplastic Agents; Chemoprevention; Female; Humans; Interferon-alpha; Isotretinoin; Laryngeal Neoplasms; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Prospective Studies; Treatment Outcome; Vitamin E

The goal of chemoprevention is to reduce the risk of cancer development by reversing or blocking the tumorigenic process through the use of pharmacologic or natural agents. To determine the potential role of genetic alterations in assessing cancer risk and in evaluating the efficacy of chemopreventive agents, we studied 22 patients with advanced premalignant lesions of the head and neck who were part of a prospective cancer prevention trial that is investigating a regimen of 13-cis-retinoic acid, interferon alfa, and alpha-tocopherol administered for 12 months or until disease progression.. We used polymerase chain reaction analysis of microsatellite DNA sequences in cells from precancerous lesions to determine the frequencies of genetic alterations--namely, loss of heterozygosity (LOH) and microsatellite instability--at chromosomal loci that are commonly deleted in head and neck cancer.. Prior to treatment, 17 (81%) of 21, eight (44%) of 18, and eight (42%) of 19 patients who were informative (i.e., heterozygous) at chromosomes 9p21, 3p14, and 17p13, respectively, exhibited LOH in at least one of their lesion biopsy specimens. Among nine patients who exhibited LOH at chromosome 9p21 in pretreatment biopsy specimens and who had completed at least 5 months of therapy, the genetic loss persisted in eight--including three of the four patients who exhibited complete histologic responses (i.e., no evidence of dysplasia in their biopsy specimens).. Our data suggest that clinical and histologic assessments of the response to chemopreventive agents may be insufficient to determine their efficacy and that critical genetic alterations could be used as independent biomarkers to augment the ability to evaluate the efficacy of such agents.

Topics: Antineoplastic Agents; Chromosomes, Human, Pair 9; DNA, Neoplasm; Female; Genotype; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Loss of Heterozygosity; Male; Microsatellite Repeats; Phenotype; Polymerase Chain Reaction; Precancerous Conditions; Prospective Studies; Vitamin E

Nuclear retinoic acid receptor beta (RAR-beta) expression decreases in human premalignant oral lesions (POLs). RAR-beta suppression could result from a decrease in the cellular level of retinoids because RAR-beta gene transcription is enhanced by retinoids. To explore this hypothesis, we compared the binding of a monoclonal antibody (mAb) against all-transretinoic acid (RA; anti-RA mAbs) to normal oral tissue and POLs. All 7 normal specimens stained positive with the antibody compared to only 20 of 43 POLs; similarly, 7 of 7 normal specimens contained RAR-beta mRNA compared to only 14 of 43 POLs. Twenty-four specimens were available before and after a 3-month treatment with 13-cis-RA in vivo. Anti-RA mAb binding to these specimens increased from 10 of 24 before to 22 of 24 after treatment, and the expression of RAR-beta mRNA increased from 7 of 24 before to 21 of 24 after treatment, respectively. There was a strong agreement between the binding of anti-RA mAbs and the expression of RAR-beta. Thus, we propose that the binding of anti-RA mAbs reflects the level of retinoids in the tissues and that this level is related strongly to RAR-beta expression.

Topics: Antibodies, Monoclonal; Humans; Isotretinoin; Mouth Mucosa; Mouth Neoplasms; Precancerous Conditions; Receptors, Retinoic Acid; RNA, Messenger; Tretinoin

Retinoids are effective in the treatment and prevention of certain human cancers. Most of their actions are thought to result from changes in gene expression mediated by nuclear retinoic acid receptors and retinoid X receptors. We conducted a study to determine whether the expression of these receptors was altered in premalignant oral lesions and, if so, whether their expression could be restored by treatment with isotretinoin.. We performed in situ hybridization of retinoic acid receptors and retinoid X receptors using antisense riboprobes in specimens of oral mucosa from 7 normal subjects and specimens of premalignant oral lesions from 52 patients before treatment with isotretinoin and from 39 of the 52 patients after three months of treatment.. All the normal specimens expressed retinoic acid receptor-beta messenger RNA (mRNA). In contrast, retinoic acid receptor-beta mRNA was detected in only 21 of the 52 premalignant oral lesions (P = 0.003). Thirty-five of the 39 specimens available for evaluation after treatment expressed retinoic acid receptor-beta mRNA (P < 0.001). All normal and premalignant specimens expressed similar levels of mRNA for retinoic acid receptor-alpha and retinoic acid receptor-gamma and the three types of retinoic X receptors, alpha, beta, and gamma. The levels of retinoic acid receptor-beta mRNA increased in the specimens from 18 of the 22 patients who had responses to isotretinoin and in 8 of the 17 specimens from the patients without responses (P = 0.04).. The expression of retinoic acid receptor-beta mRNA is selectively lost in premalignant oral lesions and can be restored by treatment with isotretinoin. Restoration of the expression of retinoic acid receptor-beta mRNA is associated with a clinical response. Retinoic acid receptor-beta may have a role in mediating the response to retinoids and may be a useful intermediate biologic marker in trials of these agents for the prevention of oral carcinogenesis.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Female; Humans; Isotretinoin; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Precancerous Conditions; Receptors, Retinoic Acid; RNA, Messenger; Up-Regulation

Aberrant crypts are aggregates of single to multiple colonic crypts evidencing hallmarks of dysplasia and may be the earliest detectable pathological lesions for colon cancer. The aberrant crypt assay has been developed in 2 protocols. In one, putative chemoprevention agents are tested for inhibitory effects when administered concomitantly with a carcinogen. In the other, the objective of this study, aberrant crypts were induced in F344 rats by parenteral injection of the colon carcinogen azoxymethane (AOM) and allowed to develop for 4 weeks, when an average of 90-100 aberrant crypt foci per colon were found in the methylene blue-stained colon. Then, during the second 4 weeks of the experiment, aberrant crypts were allowed to further develop to a frequency of > 150 foci per colon, a time when multi-crypt foci were observed. During this time we tested the inhibitory effects of 4 analgesic drugs and 2 differentiation agents for effects of aberrant crypt growth and development. We found the non-steroidal anti-inflammatory drugs piroxicam, aspirin and ibuprofen, but not acetaminophen, to be effective in suppressing aberrant crypt formation or the progression to foci of multiple aberrant crypts. Treatment with chemosuppressing agents 13-cis-retinoic acid (13-cRA) and 4-hydroxyphenretinamide (4-HPR), known differentiating agents, however, did suppress expansion of aberrant crypt foci, with 13-cRA being the much more potent agent.

Topics: Acetaminophen; Adenoma; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Azoxymethane; Colonic Neoplasms; Drug Screening Assays, Antitumor; Fenretinide; Ibuprofen; Isotretinoin; Male; Piroxicam; Precancerous Conditions; Rats; Rats, Inbred F344

Thirty patients, 13 female and 17 male, have been followed from 3 months to 22 years (mean, 81 months; median, 63 months) and special studies have been performed on a proportion of these in order to try to predict malignant evolution. Age at onset was from 20 to 70 years (mean, 43 years; median, 42 years). Duration of disease was from 1 to 30 years (mean, 119 months; median 161 months). Seven patients also had parapsoriasis en plaque or plaque-stage mycosis fungoides at the time of diagnosis and one patient had erythroderma. None of the 22 uncomplicated lymphomatoid papulosis patients developed malignant cutaneous lymphoma during the period of observation, while the remaining 8 patients who had concurrent parapsoriasis en plaque, mycosis fungoides, or erythroderma did not deteriorate further. Single-cell deoxyribonucleic acid (DNA) measurements on the dermal infiltrate were done in 13 patients and were abnormal in 7 patients. Two of these had greatly abnormal DNA histograms and at the same time an abnormal clinical presentation with multiple nodules and tumors. The remaining five patients had DNA histograms that indicated a potential for malignancy. Monoclonal antibody studies were performed on skin biopsy specimens of 10 patients. The dermal infiltrate was dominated by T-helper lymphocytes and some Hodgkin and Reed-Sternberg cells could be detected by the antibodies Ki-1, Ki-24, and Ki-27. Human T-lymphotropic virus type I (HTLV-I) antibodies were found in 3 of 18 patients examined. Treatment with psoralens plus ultraviolet A (PUVA) was effective (partial or complete remission) in six patients but they relapsed at cessation of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Viral; Deltaretrovirus; Deltaretrovirus Antibodies; DNA; Female; Follow-Up Studies; Humans; Isotretinoin; Male; Methotrexate; Middle Aged; Precancerous Conditions; PUVA Therapy; Skin Diseases; Skin Neoplasms; Tretinoin

Topics: Chemical Phenomena; Chemistry; Humans; Isotretinoin; Neoplasms; Precancerous Conditions; Retinaldehyde; Skin Diseases; Tretinoin; Vitamin A; Vitamin A Deficiency

The possible effect of oral 13 cis retinoic acid (13-cis-RA) on the carcinogenic process induced by 28 weekly s.c. injections of 1,2-dimethylhydrazine (DMH) in 34 Wistar rats was investigated. Using immunohistology, precancerous and cancerous stages were compared with the same stages induced by DMH without additional 13-cis-RA in 33 rats. M1 antigens, which characterize modifications in goblet-cell differentiation occurring early in rat colonic carcinogenesis, were used to investigate the possible effect of retinoids on differentiation during precancerous stages. From 3-20 weeks after the start of the experiment, no significant differences were observed in the timing of M1 antigens in the 2 groups of rats. It was also observed that 13-cis-RA had no effect on histological lesions associated with precancerous mucosa, nor on the occurrence of intestinal adenocarcinomas. Thus, under these conditions, oral administration of 13-cis-RA did not significantly inhibit precancerous or cancerous stages of intestinal carcinoma development.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Carcinogens; Colonic Neoplasms; Dimethylhydrazines; Female; Intestinal Neoplasms; Isotretinoin; Methylhydrazines; Neoplasm Metastasis; Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Strains; Tretinoin

We investigated the effect of the synthetic vitamin A derivative isotretinoin (13-cis-retinoic acid) on advanced cancers in 103 patients and on preneoplastic lesions in five patients. Six of 14 patients with squamous cell epithelial cancers had objective regressions of skin or subcutaneous metastases. Three of five patients with preneoplastic lesions had objective responses. The major dose-limiting toxic effects were reversible dermatitis, emotional lability, and headaches. We conclude that the growth of some squamous cell epithelial malignancies can be inhibited by isotretinoin and suggest that other retinoids should be evaluated as antitumor agents.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Eruptions; Drug Evaluation; Emotions; Headache; Humans; Isotretinoin; Neoplasms; Precancerous Conditions; Tretinoin

Male Syrian golden hamsters received 12 weekly intratracheal exposures to 0.5% N-methyl-N-nitrosourea with a special catheter. Following exposures, animals were randomized into 4 groups of 63 hamsters and placed on diets of lab meal or meal with 120 mg 13-cis-retinoid acid (CRA)/kg, 327 mg ethyl retinamide (ER)/kg, or 343 mg N-(2-hydroxyethyl)retinamide (HR)/kg for 6 months at which time all hamsters were killed. The observed incidences of tracheal epithelial neoplasms (No. of animals with tumors/total No. of animals) were 10/63 (lab meal), 22/61 (CRA), 24/63 (ER), and 17/62 (HR). The incidence of carcinomas (No. of animals with tumors/total No. of animals) were 4/63 (lab meal), 12/61 (CRA), 12/63 (ER), and 11/62 (HR). The weight loss and mortality relative to those in the group fed the lab meal were significantly in the group fed HR but not in the other retinoid-treated groups.

Topics: Amyloidosis; Animals; Carcinoma; Cricetinae; Isotretinoin; Male; Mesocricetus; Methylnitrosourea; Neoplasms, Experimental; Precancerous Conditions; Probability; Tracheal Neoplasms; Tretinoin