isotretinoin and Mouth-Neoplasms

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

An increasing public awareness of antioxidants may prompt a patient's request to be treated without surgery if a leukoplakic lesion is discovered. However, surgical excision remains the treatment of choice for oral leukoplakia. The use of antioxidant supplements has shown some promise, but the predictability of success remains uncertain and long-term results are unavailable. Before the decision to use any antioxidant is made, it is critical to obtain a histopathologic diagnosis of the lesion. When dealing with a lesion diagnosed as hyperkeratosis, it may be appropriate to choose an antioxidant that may take some time for clinical improvement to occur. However, as the grade of epithelial dysplasia becomes more severe, consideration must be given to the possibility of malignant transformation during antioxidant treatment. We do not recommend the use of antioxidant supplements in the treatment of any carcinoma. The therapeutic use of antioxidant supplements outside of clinical trials conducted at academic medical centers should be done with considerable caution by practitioners in private practice. It should be emphasized that in these clinical trial patients were seen at frequent intervals to monitor their progress and to intervene if there was a noticeable deterioration in the clinical appearance of the lesion. In spite of the uncertainty with respect to antioxidant treatment, there are circumstances in which it should be considered. Recurrence after surgical excision when there is little reason to believe that a second surgical excision would be any more successful is an ideal candidate. Also, patients with widespread leukoplakia that involves a large area of the oral mucosa might be suitable for treatment with antioxidants, as well as patients who have extensive medical problems that make them surgical risks. The choice of which antioxidant(s) to use is complex because thus far there is no combination that is superior to the others. Beta-carotene with ascorbic acid or alpha-tocopherol is attractive because of a lack of side effects, but the range in reported values for lesion improvement has been broad and the clinical improvement typically takes several months. Clinical response with 13-cRA is faster but requires baseline and periodic serologic testing, as well as close monitoring for side effects. In those circumstances in which time is an important consideration, 13-cRA might be useful because clinical improvement can be evaluated within a matter of w

Topics: Animals; Antioxidants; Carcinoma; Cell Transformation, Neoplastic; Chemotherapy, Adjuvant; Clinical Trials as Topic; Drug Combinations; Humans; Isotretinoin; Keratolytic Agents; Leukoplakia, Oral; Mouth Neoplasms; Recurrence

Topics: Biomarkers, Tumor; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Mouth Neoplasms; Neoplasms, Second Primary; Retinoids

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

Once considered a futuristic concept, chemoprevention for pre-malignant oral leukoplakia lesions is now a reality. Oral leukoplakia can proceed to invasive disease and expose the upper aerodigestive tract to carcinoma. Risk factors, diagnosis and research in chemoprevention are discussed.

Topics: Erythroplasia; Humans; Isotretinoin; Leukoplakia, Oral; Mouth Neoplasms

Topics: Anticarcinogenic Agents; Carotenoids; Humans; Isotretinoin; Leukoplakia, Oral; Mouth Neoplasms; Retinoids; Vitamin A

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

Patients with oral premalignant lesion (OPL) have a high risk of developing oral cancer. Although certain risk factors, such as smoking status and histology, are known, our ability to predict oral cancer risk remains poor. The study objective was to determine the value of gene expression profiling in predicting oral cancer development. Gene expression profile was measured in 86 of 162 OPL patients who were enrolled in a clinical chemoprevention trial that used the incidence of oral cancer development as a prespecified endpoint. The median follow-up time was 6.08 years and 35 of the 86 patients developed oral cancer over the course. Gene expression profiles were associated with oral cancer-free survival and used to develop multivariate predictive models for oral cancer prediction. We developed a 29-transcript predictive model which showed marked improvement in terms of prediction accuracy (with 8% predicting error rate) over the models using previously known clinicopathologic risk factors. On the basis of the gene expression profile data, we also identified 2,182 transcripts significantly associated with oral cancer risk-associated genes (P value < 0.01; univariate Cox proportional hazards model). Functional pathway analysis revealed proteasome machinery, MYC, and ribosomal components as the top gene sets associated with oral cancer risk. In multiple independent data sets, the expression profiles of the genes can differentiate head and neck cancer from normal mucosa. Our results show that gene expression profiles may improve the prediction of oral cancer risk in OPL patients and the significant genes identified may serve as potential targets for oral cancer chemoprevention.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Squamous Cell; Female; Gene Expression Profiling; Humans; Isotretinoin; Male; Middle Aged; Mouth Neoplasms; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Survival Rate; Teratogens; Treatment Outcome; Young Adult

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

Altered cyclin D1 expression in advanced preinvasive lesions of the upper aerodigestive tract (UADT) is associated with an increased risk of developing cancer and histologic progression during and after combination biochemopreventive therapy (13-cis-retinoic acid, alpha-interferon, and alpha-tocopherol). Both alleles of the adenine (A)/guanine (G) cyclin D1 polymorphism located at nucleotide 870 encode two alternatively spliced transcripts, but the A allele preferentially encodes a protein with an extended half-life. We investigated whether the cyclin D1 genotype at nucleotide 870 was associated with baseline levels of cyclin D1 protein, post-treatment modulation of cyclin D1 protein levels, histologic response to treatment, and the outcome for subjects with preinvasive UADT lesions after biochemopreventive therapy.. UADT tissue biopsy samples were obtained before and 6 and 12 months after biochemopreventive treatment from 31 individuals with advanced preinvasive UADT lesions. Tissues were examined for cyclin D1 genotype (by DNA single-strand conformation polymorphism analysis), for cyclin D1 protein expression (by immunohistochemistry), and for cyclin D1 gene copy number (by fluorescence in situ hybridization). Associations of cyclin D1 genotype with histologic response to therapy and time to progression to a higher degree of dysplasia or invasive cancer were investigated. All statistical tests were two-sided.. The A allele was associated with increased baseline cyclin D1 expression in the parabasal epithelial layer (16 of 18 AA/AG subjects versus four of nine GG subjects; P =.02), decreased histologic response to biochemopreventive treatment (six of 21 AA/AG subjects versus four of 10 GG subjects; P =.70), decreased favorable modulation of cyclin D1 expression by the treatment (seven of 18 AA/AG subjects versus eight of nine GG subjects; P =.02), and shorter progression-free survival (P =.05).. The cyclin D1 A allele was associated with a diminished modulation of normal physiologic and treatment-induced decreased expression of cyclin D1, a decreased likelihood of response to biochemopreventive intervention, and an increased rate of progression to cancer development, findings that require validation in a larger cohort.

Topics: alpha-Tocopherol; Antineoplastic Combined Chemotherapy Protocols; Cyclin D1; Disease Progression; Gene Expression Regulation, Neoplastic; Genotype; Humans; Immunohistochemistry; Immunologic Factors; In Situ Hybridization, Fluorescence; Interferon-alpha; Isotretinoin; Laryngeal Neoplasms; Mouth Neoplasms; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Prospective Studies; Treatment Outcome

Dysplastic oral leukoplakia (DOL) has been the index lesion in prevention trials for upper aerodigestive tract squamous cell carcinoma (SCC). Vitamin A derivatives, including 13-cis retinoic acid (13-CRA), have been used to treat DOL and to reduce the risk of subsequent SCC. Results from a trial of 13-CRA in patients with DOL are presented here. Transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor messenger RNA (mRNA) expression were studied to validate their use as surrogate endpoint biomarkers in prevention trials for SCC.. In a prospective, randomized, double-blind trial of 13-CRA in 28 patients with DOL, TGF-alpha and epidermal growth factor receptor mRNA expression were analyzed in sequential biopsy specimens of DOL and of adjacent normal-appearing mucosa, utilizing a quantitative, competitive, reverse transcriptase polymerase chain reaction and were compared using the Wilcoxon signed-rank test for paired comparisons.. In biopsy specimens of DOL, TGF-alpha mRNA expression at baseline, but not baseline expression of epidermal growth factor receptor mRNA, was significantly elevated when compared with its expression in specimens from adjacent normal-appearing mucosa (p = 0.003). In patients randomized to 13-CRA who had > or = 50% clearance of DOL during treatment, significant modulation of TGF-alpha mRNA overexpression was seen after 6 months of treatment (p = 0.016). TGF-alpha mRNA overexpression at baseline predicted a subsequent response to 13-CRA (p 0.066).. The full extent of the association between TGF-alpha overexpression and the development of SCC is unknown. Evidence is presented in this article that TGF-alpha overexpression mediates the relationship between 13-CRA and DOL, but there is no direct evidence that it mediates the relationship between 13-CRA and the prevention of SCC. Determination of the extent to which TGF-alpha overexpression mediates this relationship and complete validation of TGF-alpha's role as a surrogate endpoint biomarker await the results of animal and human trials that utilize reduction in the incidence of SCC as their endpoint.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Disease Progression; Double-Blind Method; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Humans; Isotretinoin; Leukoplakia, Oral; Male; Mouth Neoplasms; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor alpha

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

Among the tissue, cellular, and molecular changes which take place during the development of squamous cell carcinoma (SCC) of the upper aerodigestive tract, only a limited number can be used as surrogate endpoint biomarkers (SEBs) in cancer chemoprevention trials. Molecular SEBs will be genes or gene products which can be measured accurately and reliably, are altered in intraepithelial neoplasia (dysplasia), correlate strongly with the true outcome (invasive cancer), and are modulated by a chemoprevention agent(s). To identify and modulate molecular SEBs in intraepithelial neoplasia of the upper aerodigestive tract, we studied expression of the epidermal growth factor receptor (EGFR), transforming growth factor-alpha (TGF-alpha), and HER-2/neu genes in oral leukoplakia before, during, and after treatment with 13-cis-retinoic acid, a vitamin A derivative. Four of nine patients treated for 3 months with 1 mg/kg/day of 13-cis-retinoic acid had complete resolution of their leukoplakia. Biopsies were taken of leukoplakia and adjacent normal-appearing mucosa before, during, and after treatment. Immunohistochemistry was performed using the BioGenex Super Sensitive Biotin-Streptavidin horseradish peroxidase detection system. Pretreatment expression of EGFR, TGF-alpha, and HER-2/neu in leukoplakia was increased when compared to normal-appearing mucosa. TGF-alpha expression decreased during treatment in leukoplakia, but not in normal-appearing mucosa, suggesting that TGF-alpha may serve as an intermediate endpoint in cancer chemoprevention trials.

Topics: Anticarcinogenic Agents; Biomarkers, Tumor; Biopsy; ErbB Receptors; Follow-Up Studies; Gene Expression; Humans; Immunohistochemistry; Isotretinoin; Leukoplakia, Oral; Mouth Mucosa; Mouth Neoplasms; Receptor, ErbB-2; Time Factors; Transforming Growth Factor alpha; Treatment Outcome

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

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

High-dose isotretinoin therapy has been determined to be an effective treatment for leukoplakia. However, a high rate of relapses and toxic reactions led us to conduct a trial of a much lower dose of isotretinoin in the hope of maintaining a response and limiting toxicity.. In the first phase of the study, 70 patients with leukoplakia underwent induction therapy with a high dose of isotretinoin (1.5 mg per kilogram of body weight per day) for three months; in the second phase, patients with responses or stable lesions were randomly assigned to maintenance therapy with either beta carotene (30 mg per day) or a low dose of isotretinoin (0.5 mg per kilogram per day) for nine months.. In the first phase, the rate of response to high-dose induction therapy in the 66 patients who could be evaluated was 55 percent (36 patients). The lesions of seven patients progressed, and therefore they did not participate in the second phase of the trial. Of the 59 patients included in the second phase, 33 were assigned to beta carotene therapy and 26 to low-dose isotretinoin therapy; these two groups did not differ significantly in prognostic factors. Of the 53 patients who could be evaluated, 22 in the low-dose isotretinoin group and 13 in the beta carotene group responded to maintenance therapy or continued to have stable lesions (92 percent vs. 45 percent, P < 0.001). In situ carcinoma developed in one patient in each group, and invasive squamous-cell carcinoma in five patients in the beta carotene group. Toxicity was generally mild, though greater in the group given low-dose isotretinoin therapy.. When preceded by high-dose induction therapy, low-dose isotretinoin therapy was significantly more active against leukoplakia than beta carotene and was easily tolerated.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Female; Head and Neck Neoplasms; Humans; Immunologic Factors; Isotretinoin; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Remission Induction

Oral squamous cell carcinoma (OSCC) is responsible for about 90% of oral malignancies and its incidence is increasing. Despite various treatment protocols, survival rate of OSCC is low. Chemotherapy that is used for treating this carcinoma in advanced stages is systemic therapy that destroys carcinogenic cells, and controls tumor metastasis. Chemotherapy is very toxic and has limitations, especially for patients in advanced stages. Considering positive effects of retinoid and vitamin D3 derivatives in treating some carcinomas, we decided to evaluate the effect of combination of these drugs on OSCC. In this study the effects of combination of 5-fluorouracil, 13-cis retinoic acid and vitamin D3 on cultured cell of OSCC have been evaluated.. OSCC cells were cultured in culture media and different concentration of 5-fluorouracil, 13-cis retinoic acid and vitamin D3 were added to cultured cell as separately and in combinations. The effect of treatment on cell proliferation and induction of apoptosis were evaluated by MTT and TUNEL assays respectively.. Combination of 5-fluorouracil and 13- cis retinoic acid had the highest inhibitory effect on SCC cell proliferation. Combination of two drugs had more apoptotic effect than each of them separately, and combination of three drugs had more effect than combination of two drugs.. Because combination of drugs had more inhibitory effect on cell proliferation than one of them and combination of three drugs had the most apoptotic effect than one of these drugs separately, these drugs may have synergic effect on OSCC.. Combination of three drugs has more inhibitory effect on cell proliferation and apoptotic effect than one of these drugs.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Drug Combinations; Drug Synergism; Fluorouracil; Humans; In Situ Nick-End Labeling; Isotretinoin; Mouth Neoplasms; Tetrazolium Salts; Thiazoles

Previous studies showed that many chemotherapeutic agents can induce immuno-suppression at therapeutic drug concentrations whereas low drug doses induce immuno-augmentation.. The effect of low-dose cisplatin, interferon-alpha, and 13-cis retinoic acid on receptors involved in immune-mediated apoptosis (Fas/CD95), cell growth (epidermal growth factor receptor) and lymphocyte adhesion (intercellular adhesion molecule-1) was investigated in two oral cancer cell lines (UT-SCC-20A and UT-SCC-24A). Different methods for cell preparation were studied: mechanical and enzymatic detachment, and culture on chamber slides. Receptor expression was investigated using immunohistochemical staining. The amount of soluble and cell-bound Fas was determined with the ELISA technique, and the functional relevance of Fas expression, apoptosis induction, was analyzed.. Cisplatin enhanced cytoplasm and membrane staining for Fas in both cell lines. After cisplatin treatment, the amount of soluble Fas was increased in UT-SCC-20A cultures, but no effect was observed in the UT-SCC-24A cell line. Apoptosis, measured as enhanced caspase-3 activity, was induced by an agonistic Fas antibody (CH11) after cisplatin treatment in UT-SCC-24A cells.. Low-dose cisplatin treatment enhanced Fas expression in both cell lines and increased susceptibility to apoptosis in one of them.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cisplatin; ErbB Receptors; fas Receptor; Humans; Immunologic Factors; Intercellular Adhesion Molecule-1; Interferon-alpha; Isotretinoin; Mouth Neoplasms

Retinoids inhibit the proliferation of several types of tumour cells, and are used for patients with several malignant tumours. In this study, we examined the effect of retinoic acids (RAs) on the invasive potentials of the oral squamous cell carcinoma (SCC) cells, BHY and HNt. BHY cells expressed all of retinoid nuclear receptors (RARalpha, beta, gamma, and RXRalpha) and cytoplasmic retinoic acid binding proteins (CRABP1 and CRABP2). HNt cells lacked the expression of RARbeta, but expressed other nuclear receptors and CRABPs. All-trans retinoic acid (ATRA) and 13-cis retinoic acid (13-cisRA) (10(-6)and 10(-7)M) inhibited the growth of the cells, but low-dose ATRA and 13-cisRA (10(-8)M) marginally affected the growth of the cells. Surprisingly, low-dose RAs enhanced the activity of tissue-type plasminogen activator (tPA), and activated pro-matrix metalloproteinases (proMMP2 and proMMP9). Activation of proMMP2 and proMMP9 was inhibited by aprotinin, a serine-proteinase, tPA inhibitor. Furthermore, low-dose RAs enhanced the in vitro invasiveness of BHY cells. These results indicate that low-dose RAs enhances the in vitro invasiveness of oral SCC cells via an activation of proMMP2 and proMMP9 probably mediated by the induction of tPA.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Division; Collagenases; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Precursors; Gelatinases; Humans; Isotretinoin; Matrix Metalloproteinase 9; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Mouth Neoplasms; Neoplasm Invasiveness; Receptors, Retinoic Acid; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Plasminogen Activator; Tretinoin; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator

Our 10-year translational study of the oral premalignant lesion (OPL) model has advanced the basic understanding of carcinogenesis. Although retinoids have established activity in this model, a substantial percentage of our OPL patients progress to cancer, especially after treatment is stopped. On the basis of our 10-year OPL study, we have developed the first comprehensive tool for assessing cancer risk of OPL patients. This cancer risk assessment tool incorporates medical/demographic variables, epidemiological factors, and cellular and molecular biomarkers. Between 1988 and 1991, 70 advanced OPL patients were enrolled in a chemoprevention trial of induction with high dose isotretinoin (1.5 mg/kg/day for 3 months) followed by 9 months of maintenance treatment with either low dose isotretinoin (0.5 mg/kg/day) or beta-carotene (30 mg/d; total treatment duration, 1 year). We assessed the relationship between cancer risk factors and time to cancer development by means of exploratory data analysis, logrank test, Cox proportional hazard model, and recursive partitioning. With a median follow-up of 7 years, 22 of our 70 patients (31.4%) developed cancers in the upper aerodigestive tract following treatment. The overall cancer incidence was 5.7% per year. The most predictive factors of cancer risk are OPL histology, cancer history, and three of the five biomarkers we assessed (chromosomal polysomy, p53 protein expression, and loss of heterozygosity at chromosome 3p or 9p). In the multivariable Cox model, histology (P = 0.0003) and the combined biomarker score of chromosomal polysomy, p53, and loss of heterozygosity (P = 0.0008) are the strongest predictors for cancer development. Retinoic acid receptor beta and micronuclei were not associated with increased cancer risk. We have demonstrated a successful strategy of comprehensive cancer risk assessment in OPL patients. Combining conventional medical/demographic variables and a panel of three biomarkers can identify high risk patients in our sample. This result will need to be validated by future studies. With the identification of high risk individuals, more efficient chemoprevention trials and molecular targeting studies can be designed.

Topics: Alcohol Drinking; Chromosome Aberrations; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 9; Disease-Free Survival; Female; Follow-Up Studies; Humans; Isotretinoin; Leukoplakia, Oral; Loss of Heterozygosity; Male; Middle Aged; Mouth; Mouth Neoplasms; Multivariate Analysis; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Receptors, Retinoic Acid; Risk Factors; Smoking; Tumor Suppressor Protein p53

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

Preclinical and clinical trials demonstrated the antiproliferative and chemopreventive potential of 13-cis retinoic acid in combination with interferon-alpha. The present study was designed to determine the radiosensitizing potential of both drugs after single and combined treatment of human squamous-cell carcinoma cells of the oral cavity in vitro.. The study was performed using the human squamous-cell carcinoma cell line SCC4, which was originally established from a tumor of the oral cavity. Based on clonogenic assays, the inhibition of clonogenic activity and radiosensitizing potential of 13-cis retinoic acid and interferon-alpha after single or combined treatment without and with subsequent irradiation was determined.. 13-cis retinoic acid (10 microM) and interferon-alpha (50 IU/ml) showed significant inhibition of clonogenic activity after single treatment. A combined treatment protocol resulted at least in a highly significant additive inhibition of clonogenicity. Treatment with both drugs (5 microM 13-cis retinoic acid, 25 IU/ml IFN-alpha) prior and post irradiation of the cells resulted in a pronounced enhancement of radiation toxicity resulting in significantly decreased SF2- and alpha-values. Combined treatment with both drugs was significantly more effective than single drug treatment.. The data presented indicate that pre- and post-irradiation treatment with 13-cis retinoic acid and interferon-alpha significantly enhance the radiosensitivity of human squamous-cell carcinoma cells, SCC4, in vitro. Therefore, they support the initiation of clinical trials to test the radio-oncological value of such a treatment regime for squamous-cell carcinomas.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Survival; Chemotherapy, Adjuvant; Combined Modality Therapy; Culture Media; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Combinations; Humans; Interferon-alpha; Isotretinoin; Mouth Neoplasms; Radiation-Sensitizing Agents; Radiotherapy Dosage; Time Factors; Tumor Cells, Cultured; Tumor Stem Cell Assay

Retinoids are a group of vitamin A analogues that have shown promise as chemopreventive and therapeutic agents in many types of malignancy and have been entered in clinical trials with some successful results. To better understand the mechanism that mediates retinoid action and the anti-proliferative effects, we treated 7 human oral squamous-cell carcinoma (SCC) cell lines (FADU, HEp-2, CCL-17, SCC-9, SCC-15, SCC-25 and HN-212) with 10(-6) M of all-trans retinoic acid (ATRA), 9-cis and 13-cis retinoic acid (RA) in continuous for different periods of time. We assessed the extent of growth inhibition, the stability of the anti-proliferative effect and the mRNA expression levels (by RT-PCR) of RA receptors (RARs), retinoid X receptors alpha (RXR alpha) and cytosolic RA-binding proteins (CRBP I and CRABP II) in treated cells compared with controls. The data obtained showed that all 3 RAs were able to inhibit the cellular growth of the tested cell lines, although to a different extent. The cis compounds were able to inhibit the proliferation of all cell lines, whereas ATRA was ineffective in inhibiting the proliferation of the CCL-17 cell line, which was naturally resistant to ATRA concentrations in the range between 10(-5) and 10(-6) M. All inhibitory effects were completely reversible since all cell lines restored their normal growth proliferation within few days after drug removal. RT-PCR analysis of the receptor and cell binding protein status of control and treated cells showed a good correlation between growth inhibition and induction of, or increase in, the expression levels of RAR beta in RA-treated cells. No differences were observed in RAR alpha and RXR alpha mRNA expression levels between control and treated cells. CRBP I, CRABP II and RAR gamma mRNA levels increased in some treated cell lines but not in all.

Topics: Alitretinoin; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Cycle; Cell Division; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Growth Inhibitors; Humans; Isotretinoin; Mouth Neoplasms; Neoplasm Proteins; Polymerase Chain Reaction; Receptors, Retinoic Acid; Retinoid X Receptors; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Transcription Factors; Tretinoin; Tumor Cells, Cultured; Up-Regulation

Topics: Anticarcinogenic Agents; beta Carotene; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Follow-Up Studies; Head and Neck Neoplasms; Humans; Isotretinoin; Mouth Neoplasms; Time Factors; Treatment Outcome

Cyclooxygenase-2 expression is up-regulated in transformed cells and tumors. Because this enzyme catalyzes the synthesis of prostaglandins, strategies aimed at suppressing its expression may prove useful in preventing or treating cancer. We investigated the ability of retinoids to suppress phorbol ester-mediated induction of cyclooxygenase-2 in human oral epithelial cells. Treatment with phorbol myristate acetate (PMA) resulted in approximately a 3-fold increase in the production of prostaglandin E2 (PGE2). Retinoids [all-trans-retinoic acid (RA), 13-cis-RA, and retinyl acetate] markedly suppressed PMA-mediated increases in amounts of cyclooxygenase-2 (Cox-2) and the production of PGE2. Retinoids also suppressed the induction of Cox-2 mRNA by PMA. Nuclear run-offs revealed increased rates of Cox-2 transcription after treatment with PMA; this effect was inhibited by all-trans-RA. Transient transfection experiments showed that PMA caused about a 2-fold increase in Cox-2 promoter activity, an effect that was suppressed by all-trans-RA. Our data indicate that treatment of oral epithelial cells with PMA is associated with enhanced transcription of Cox-2 and increased production of PGE2. These effects of PMA were inhibited by retinoids.

Topics: Anticarcinogenic Agents; Biotransformation; Carcinoma, Squamous Cell; Cyclooxygenase 2; Dinoprostone; Diterpenes; Enzyme Induction; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Isotretinoin; Membrane Proteins; Mouth Neoplasms; Neoplasm Proteins; Peroxidases; Prostaglandin-Endoperoxide Synthases; Retinyl Esters; Tetradecanoylphorbol Acetate; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured; Vitamin A

The carotenoids beta-carotene and canthaxanthin and the retinoid 13-cis-retinoic acid (13-RA) have inhibited oral carcinogenesis in the hamster cheek pouch (16 wks, 3 times/wk at 1.4 mg/kg) induced by an 0.5% solution of 7, 12-dimethylbenz[a]anthracene (DMBA). However, 13-RA at a higher dose (> 2.0 mg/kg per treatment) increased squamous cell carcinoma growth (Eur J Cancer Clin Oncol 24, 839-850, 1988). 13-RA, beta-carotene, and canthaxanthin administered to 60 hamsters (16 wks, 3 times/wk, 10 mg/kg) altered neovascularization characterized by immunohistochemistry for transforming growth factor-alpha (TGF-alpha) and factor VIII. 13-RA + DMBA resulted in more smaller-sized tumors, with a reduced volume and tumor burden (tumor controls, 185.9; 13-RA + DMBA, 151.0). The carotenoids reduced the number and the sizes of the carcinomas formed (beta-carotene, 60 tumors, 142.3 x 10(3) mm3; canthaxanthin, 30 tumors, 116.1 x 10(3) mm3). Factor VIII and TGF-alpha were expressed in high intensity at cancer sites of the 13-RA + DMBA and DMBA groups with > 50 and > 10 cells, respectively, per x 400 field. In contrast, beta-carotene- and canthaxanthin + DMBA-treated pouches showed > 20 and 5 cells, respectively, per x 400 field for factor VIII and TGF-alpha. These results suggest that 13-RA treatment may increase vascular growth, but the carotenoids also produced enhanced levels of endothelial cell growth and TGF-alpha compared with the untreated mucosa. The carotenoids may enhance tumor growth under the appropriate carcinogenic environment.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Canthaxanthin; Carcinoma, Squamous Cell; Cheek; Cricetinae; Dose-Response Relationship, Drug; Factor VIII; Immunoenzyme Techniques; Isotretinoin; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neovascularization, Pathologic; Transforming Growth Factor alpha

Although retinoids have proven to be effective as chemopreventive agents in reversing premalignant oral lesions and preventing second primary tumors, their mechanisms of chemopreventive efficacy in clinical settings have not been established. To better define this mechanism, we studied p53 protein and retinoic acid receptor beta (RAR-beta) expression in 52 baseline biopsy samples taken from premalignant oral lesions. We then studied p53 expression in 39 matched samples and RAR-beta expression in 38 matched samples before and after treating them with isotretinoin. The study results were then compared with clinical responses. To detect p53 protein expression, 4-micrometer sections of formalin-fixed, paraffin-embedded tissue specimens were used for immunohistochemical analysis with a monoclonal anti-p53 antibody, and levels of p53 expression were recorded with a labeling index (LI). Expression of RAR-beta mRNA was determined using nonradioactive in situ hybridization, and the staining intensity of RAR-beta mRNA was semiquantitated using scores from 0 (no expression) to 3+ (highest expression). p53 protein was detected in 85% of all lesions. High p53 protein expression (LI >/= 0.2) was detected in 25% of the lesions at baseline and in 18% of the lesions after isotretinoin therapy. The clinical response was 65% for lesions having low p53 expression (LI < 0.2) and 27% for lesions having high p53 expression (P = 0.027). Expression of RAR-beta mRNA was detected in 40% of the patients at baseline and increased to 90% of the patients after isotretinoin therapy (P < 0. 001). Seventy-two percent of the patients having low p53 expression had no RAR-betamRNA expression at baseline, whereas 22% of the patients having high p53 expression had no RAR-beta expression, which suggests that patients having low p53 expression tended to lose RAR-beta mRNA expression in their tissues. Eighty-three percent of patients having low p53 expression had up-regulation of RAR-beta mRNA after isotretinoin therapy, compared with 22% of patients with high p53 expression (P = 0.003). We correlated baseline p53 protein expression with RAR-beta modulation and clinical responses to isotretinoin therapy. The patients with low p53 protein expression at baseline and up-regulation of RAR-beta after isotretinoin therapy achieved a 70% rate of major response. The patients with low p53 protein expression and either no change or down-regulation of RAR-beta or with high p53 expression and up-regulation o

Topics: Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; Chemoprevention; Female; Humans; Hyperplasia; In Situ Hybridization; Isotretinoin; Leukoplakia; Male; Middle Aged; Mouth Neoplasms; Receptors, Retinoic Acid; RNA, Messenger; Transcription, Genetic; Tumor Suppressor Protein p53

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

The effect of 13-cis-retinoic acid (cRA) and all-trans-retinoic acid (tRA) used alone or in combination with interferon alpha-2a (alpha-IFN 2a) was tested on three established human cell lines: KB (epidermoid carcinoma of the oral cavity), SCC-25 (tongue squamous cell carcinoma) and MCF-7 (mammary carcinoma). Both retinoids significantly decreased cell proliferation (growth curves) and colony forming efficiency (CFE) in all cell lines, in a dose-dependent way (at a concentration ranging from 10(-5) to 10(-9) M) and differing from line to line, following the pattern: MCF-7 > SCC-25 > KB. Retinoids at any concentration (already at 10(-7) M) combined with alpha-IFN 2a (ranging from 100 to 500 IU/ml) were more effective in inhibiting cell proliferation than each of the two compounds alone. This was particularly evident with SCC-25 cells. Concerning MCF-7 cells, on the contrary, the effects produced by the association suggested a possible additive more than synergistic amplification of growth inhibition.

Topics: Breast Neoplasms; Carcinoma, Squamous Cell; Cell Division; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Interferon-alpha; Isotretinoin; Mouth Neoplasms; Tretinoin; Tumor Cells, Cultured

Topics: beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Cell Transformation, Neoplastic; Head and Neck Neoplasms; Humans; Immunologic Factors; Isotretinoin; Leukoplakia, Oral; Mouth Neoplasms

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Differentiation; Drug Evaluation; Female; Humans; Immunoenzyme Techniques; Isotretinoin; Keratins; Male; Micronucleus Tests; Middle Aged; Mouth Neoplasms; Protein Precursors; Transglutaminases

The effect of algae extract on tumor regression was studied. Phycotene (extract of Spirulina and Dunaliella algae) 250 micrograms in 0.1 ml MEM (minimum essential medium) was injected locally into DMBA (7, 12 dimethylbenz(a)anthracene)-induced squamous cell carcinomas of hamster buccal pouch in 20 animals. DMBA-induced carcinomas in 20 hamsters were injected locally with beta carotene 250 micrograms in 0.1 ml MEM; DMBA-induced carcinomas in 20 animals were injected locally with canthaxanthin, 250 micrograms in 0.1 ml MEM, and DMBA-induced carcinomas in 20 animals were injected locally with 13-cis-retinoic acid, 250 micrograms in 0.1 ml MEM. Twenty animals with DMBA-induced carcinomas were sham-injected controls using 0.1 ml MEM. The various agents were injected into the tumor bearing right buccal pouches twice-weekly for four weeks. Total tumor regression was found in 30% of phycotene animals, 20% of beta carotene animals and 15% of canthaxanthin animals after four weeks. Partial tumor regression was found in the remaining 70% of phycotene animals, 80% of beta carotene animals and 85% of canthaxanthin animals. None of the 13-cis-retinoic acid animals had total tumor regression, but 70% showed partial regression. No tumor regression was found in the DMBA control group and the sham-injected group.

Topics: Animals; Canthaxanthin; Carcinoma, Squamous Cell; Carotenoids; Chlorophyta; Cricetinae; Cyanobacteria; Isotretinoin; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neoplasms, Multiple Primary; Plant Extracts; Remission Induction; Tretinoin; Vitamin E

In order to determine whether 13-cis-retinoic acid, an analog of vitamin A, has antitumor activity in an oral cancer model system, the following study was undertaken. Fifty-three adult hamsters were divided into four groups. Group 1 was tested with a 0.5 percent solution of 9,10-dimethyl-1,2-benzanthracene (DMBA) in heavy mineral oil, which was painted on the right buccal pouch three times per week for 12 weeks. Group 2 received DMBA plus 13-cis-retinoic acid (RA) incorporated into gelatinized beadlets and mixed with a powdered commercial diet (dosage, 300 mg per kilogram of diet). Group 3 received only RA; Group 4 received a placebo. The animals were killed at 6, 12, and 18 weeks and tissues were studied clinically and histologically in a routine manner. Results show that all groups receiving DMBA developed epidermoid carcinomas. However, there were several other changes. In the RA-treated animals, particularly those treated with DMBA, there was an ingrowth of surface epithelium with development of ductal structures in the buccal pouch. There were changes in surface epithelium, and there were dense aggregates of lymphoid tissue with development of exophytic nodules suggestive of lymphoma. Animals fed RA showed a relative weight loss. The findings suggest that there was a hypervitaminosis A state yielding prominent epithelial metaplastic changes but not affecting the progression or production of carcinoma.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Carcinoma, Squamous Cell; Cheek; Cricetinae; Female; Isotretinoin; Male; Mesocricetus; Mouth Neoplasms; Neoplasms, Experimental; Tretinoin

Sixty-four male and female Syrian hamsters, 3 months of age and weighing 90 to 120 grams, were divided into four equal experimental groups. In animals of Groups 1 and 2 the left buccal pouch was painted three times weekly with a 0.5% solution of DMBA in heavy mineral oil. Group 2 animals also received 10 mg. of 13-cis-retinoic acid in peanut oil administered orally twice a week by pipette. Carcinogen retinoid were administered on alternate days. Group 3 animals served as controls, receiving only 13-cis-retinoic acid. Group 4 animals served as untreated controls. Four animals in each group (two males and two females) were killed at 10, 12, 14, and 16 weeks. The Group 2 animals, which received 13-cis-retinoic acid, exhibited a significant delay in DMBA carcinogenesis of buccal pouch mucosa, as studied both grossly and histologically. Both groups eventually demonstrated well-differentiated epidermoid carcinomas, but the tumors were smaller in the DMBA-retinoid animals.

Topics: Animals; Carcinoma, Papillary; Carcinoma, Squamous Cell; Cheek; Cricetinae; Female; Isotretinoin; Keratosis; Leukoplakia, Oral; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neoplasms, Experimental; Tretinoin