tretinoin and Precancerous-Conditions

The Ah receptor (AhR) has been characterized as a ligand-activated transcription factor which belongs to the bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) family of chemosensors. Transgenic mouse models revealed adaptive and developmental functions of the AhR in the absence of exogenous ligands. Use of persistent agonists such as dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds demonstrated that the AhR mediates a plethora of species- and tissue-dependent toxicities, including chloracne, wasting, teratogenicity, immunotoxicity, liver tumor promotion and carcinogenicity. However, molecular mechanisms underlying most aspects of these toxic responses as well as biological functions of the AhR are currently unknown. Previous studies of liver tumor promotion in the two-stage hepatocarcinogenesis model indicated that TCDD mediates clonal expansion of 'initiated' preneoplastic hepatocytes, identified as enzyme-altered foci (EAF) by inhibiting apoptosis and bypassing AhR-mediated growth arrest. In contrast, the Ah receptor has been shown in cell models to stimulate growth arrest and apoptosis. Possible underlying mechanisms of these AhR responses are discussed, including enhanced metabolism of retinoic acid which attenuates TGFbeta-mediated apoptosis and interaction of the Ah receptor with the hypophosphorylated retinoblastoma tumor suppressor protein. The discrepancy between in vivo findings in EAF and AhR functions may be solved by hypothesizing that sustained activation of the Ah receptor generates a strong selective pressure in liver treated with genotoxic carcinogens leading to selection and expansion of clones evading growth arrest and apoptosis. Models are discussed which may facilitate verification of this hypothesis.

Topics: Animals; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cell Survival; DNA-Binding Proteins; E2F Transcription Factors; Humans; Liver Neoplasms; Polychlorinated Dibenzodioxins; Precancerous Conditions; Receptors, Aryl Hydrocarbon; Retinoblastoma Protein; Transcription Factors; Tretinoin

The retinoids, natural and synthetic derivatives of vitamin A, are active in cancer therapy and prevention. Their biological effects are mediated through ligand-dependent interactions with retinoid receptors that associate with specific co-regulators. A better understanding of retinoid chemopreventive mechanisms is needed. Our prior work revealed that all-trans-retinoic acid (RA) prevented tobacco-specific carcinogenic transformation of cultured human bronchial epithelial cells. RA signaled G1 arrest that permitted repair of genomic DNA damage caused by these carcinogens. RA triggered G1 arrest at least partly through proteasome-dependent degradation of cyclin D1. Proteasomal inhibitors blocked RA-mediated cyclin D1 degradation. To confirm that a specific proteolysis pathway was induced by RA-treatment, a degradation assay was established using in vitro translated cyclin D1 and cellular extracts from RA-treated or untreated human bronchial epithelial cells. Incubation of RA-treated but not the control cellular extracts with in vitro translated cyclin D1 led to cyclin degradation. This degradation depended on the PEST domain of cyclin D1, implicating ubiquitination in this retinoid degradation. Retinoid receptor selective agonists demonstrated that retinoic acid receptor (RAR)beta and retinoid X receptor (RXR) but not RARalpha- or RARgamma-dependent pathways signaled this cyclin degradation. Findings were extended to the NT2/D1 human embryonal carcinoma differentiation model where a similar pathway was activated by RA-treatment. To determine whether G1 cyclins were involved directly in bronchial preneoplasia, immunohistochemical expression profiles for cyclins D1 and E were examined. Aberrant expression of these cyclins was frequent in bronchial preneoplasia. Taken together, these findings indicate that ubiquitin-dependent proteolysis of G1 cyclins is a retinoid chemoprevention mechanism. Whether the retinoids represent the optimal agents to activate this pathway is the subject of ongoing work. These findings provide a rationale for combining the retinoids in chemoprevention trials with other agents that do not activate this proteolysis pathway. What is now known about the retinoids as cancer prevention agents will be reviewed. Emphasis is placed on retinoid effects on cell cycle progression at G1.

Topics: Animals; Anticarcinogenic Agents; Bronchi; Bronchial Diseases; Carcinoma, Embryonal; Cell Differentiation; Cell Transformation, Neoplastic; Cyclins; Cysteine Endopeptidases; Endopeptidases; Epithelial Cells; G1 Phase; Gene Expression Profiling; Gene Expression Regulation; Humans; Metaplasia; Mice; Models, Biological; Multienzyme Complexes; Neoplasms; Precancerous Conditions; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Protein Structure, Tertiary; Receptors, Retinoic Acid; Retinoids; Tretinoin; Tumor Cells, Cultured; Ubiquitin; Vitamin A Deficiency

Midkine is a heparin-binding growth factor, implicated in various biological phenomena such as neuronal survival and differentiation, tissue remodeling and carcinogenesis. Together with pleiotrophin, midkine constitutes a family that is distinct from other heparin-binding growth factors. In this review, I will briefly describe biochemical and biological characteristics of midkine and then focus on its biological significance in cancer. The most intriguing feature of midkine in cancer is its augmented expression in advanced tumors at very high frequency in non-tissue specific manner. In addition, its high expression is also detected in precancerous lesions. Midkine exerts carcinogenesis-related activities, including transforming, anti-apoptotic, angiogenic and fibrinolytic ones. These data provide a possibility of clinical application of midkine. Serum midkine level can be a useful tumor marker. Gene therapy using its promoter region and therapeutic strategy choosing midkine as a molecular target are worth challenging.

Topics: Amino Acid Sequence; Animals; Biomarkers, Tumor; Carrier Proteins; Cytokines; DNA-Binding Proteins; Genetic Therapy; Heparin; Humans; Midkine; Molecular Sequence Data; Neoplasms; Nerve Growth Factors; Precancerous Conditions; Promoter Regions, Genetic; Transcription Factors; Tretinoin; WT1 Proteins

Topics: Anticarcinogenic Agents; Combined Modality Therapy; Head and Neck Neoplasms; Humans; Incidence; Laryngeal Neoplasms; Larynx; Precancerous Conditions; Tretinoin; United States

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

Since topical retinoic acid was first used for acne in 1959, many additional uses have been described for lesions on the skin, oral mucosa, and ocular surface epithelia. The topical application of retinoic acid has been shown to be effective in the treatment of several disorders of keratinization, keloids and hypertrophic scars, and various infections and inflammatory, pigmentation, and malignant and premalignant disorders. This article briefly reviews the use of topical retinoic acid for selected cutaneous conditions.

Topics: Administration, Topical; Humans; Mouth Diseases; Pigmentation Disorders; Precancerous Conditions; Skin Diseases; Skin Neoplasms; Tretinoin

To investigate the efficacy of all-trans retinoic acid (ATRA) in human gastric dysplasia.. In this double-blind study, patients with precancerous gastric dysplasia with or without intestinal metaplasia (IM) received either conventional treatment consisting of omeprazole and sucralfate (control group) or conventional treatment plus ATRA. Gastric mucosal biopsies were performed before and after drug treatment and were analysed histologically; expression of retinoblastoma (Rb) protein and HER2 protein in gastric mucosa were measured using immunohistochemistry.. A total of 122 patients were included in the study, 63 in the ATRA group and 59 in the control group. In the ATRA group, dysplasia was attenuated in 43 out of 63 patients (68%) compared with 22 out of 59 patients (37%) in the control group; however, IM was not affected by treatment in either group. ATRA treatment was associated with significantly increased Rb expression and decreased HER2 expression in gastric mucosa.. The use of conventional therapy plus ATRA for gastric dysplasia was associated with improved efficacy compared with conventional therapy alone. It was also accompanied by increased Rb expression and decreased HER2 expression in gastric mucosa. The addition of ATRA to conventional therapy for gastritis may improve the prognosis of gastric dysplasia.

Topics: Adult; Aged; Double-Blind Method; Drug Therapy, Combination; Female; Gastric Mucosa; Humans; Intestines; Male; Metaplasia; Middle Aged; Omeprazole; Precancerous Conditions; Prognosis; Retinoblastoma Protein; Stomach; Stomach Neoplasms; Sucralfate; Treatment Outcome; Tretinoin

Keratinocyte carcinomas (KCs) are the most common malignancies of the skin. As lesions have a low mortality rate, understanding quality-of-life (QoL) factors is necessary in their management.. To assess QoL and associated patient characteristics in those with a history of keratinocyte carcinomas.. We conducted a cross-sectional study of veterans with a history of KCs enrolled in a randomized controlled trial for chemoprevention of keratinocyte carcinomas. Study dermatologists counted actinic keratoses (AKs) and assessed for skin photodamage. QoL was assessed using Skindex-29 and KC-specific questions. Demographics were self-reported.. Participants (n = 931) enrolled at 5 clinical sites had worse QoL on all subscales (emotions, functioning, and symptoms) compared to a reference group of patients without skin disease. Univariate analysis demonstrated worse QoL associated with higher AK count, past 5-fluorouracil (5-FU) use, and greater sun sensitivity. Multivariate analysis demonstrated that higher AK count and past 5-FU use were independently related to diminished QoL. Higher comorbidities showed modest associations on the symptoms and functioning subscales. Number of previous KCs was not independently associated with any QoL differences.. Study population may not be generalizable to the general population. Counting of AKs is of limited reliability. Previous 5-FU use is self reported.. A history of ever use of 5-FU and present AKs was strongly associated with worse QoL. We find it more useful to consider these patients as having the chronic condition "actinic neoplasia syndrome," whose burden may be best measured by factors other than their history of KCs.

Topics: Administration, Topical; Aged; Aged, 80 and over; Analysis of Variance; Carcinoma, Squamous Cell; Chemoprevention; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hospitals, Veterans; Humans; Immunohistochemistry; Keratosis, Actinic; Male; Middle Aged; Multivariate Analysis; Precancerous Conditions; Probability; Quality of Life; Risk Assessment; Severity of Illness Index; Skin Neoplasms; Treatment Outcome; Tretinoin

Loss of retinoic acid receptor beta (RAR-beta) expression in the bronchial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus alpha-tocopherol (AT), could reverse RAR-beta expression loss in former smokers after 3 months of treatment.. Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-beta expression. McNemar's test was used to test changes in RAR-beta expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided.. A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-beta was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR-beta expression (P =.03) and reduction of metaplasia (P =.01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-beta expression compared with placebo (P =.03).. 9-cis-RA treatment can restore RAR-beta expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.

Topics: Adult; Aged; Alitretinoin; Antineoplastic Agents; Biopsy; Bronchi; Bronchoscopy; Double-Blind Method; Female; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization; Male; Metaplasia; Middle Aged; Precancerous Conditions; Receptors, Retinoic Acid; Respiratory Mucosa; RNA, Messenger; Smoking; Tretinoin

To report long term therapeutic effect in patients with esophageal pre-cancerous lesions in high-risk area of esophageal cancer.. The therapeutic trial enrolled 2,531 cases of severe dysplasia and 3,393 cases of mild dysplasia. A 2-arm randomized, placebo-controlled design was used in which the participants received Zeng Sheng Ping (ZSP, an herbal composite), retinamide or placebo for cases with severe dysplasia and riboflavin or placebo for those with mild dysplasia.. Treatment with ZSP and retinamide decreased malignant transformation rate of severe dysplasia by 52.2% and 43.2%, respectively after 5 years of treatment. When the treatment had been discontinued for 4 years, the rate of malignat transformation was decreased by 42.1% and 38.2% respectively, which remained significantly higher than that of the placebo-treated control. Riboflavin treatment was continued for 9 years. At the end of 5-year medication, the malignant transformation rate decreased by 34.8%, which was not significantly different from that of the placebo control. When the treatment was continued up to 9 years, the rate was further decreased to 37.0%, which became statistically significant.. ZSP, retinamide and riboflavin treatment can effectively prevent esophageal dysplasia from transforming into carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drugs, Chinese Herbal; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Precancerous Conditions; Tretinoin

Dysplasia of the uterine cervix is a recognized precancerous condition. Because of the observed ability of retinoids to suppress various cell lines in vitro, a number of clinical studies have examined the effect these agents have on cervical dysplasia, with the object of developing a means of chemoprevention of cervical malignancies in women at risk. Three cervical cancer chemoprevention trials with Retinamide II (RII) have been conducted at the Cancer Institute, Chinese Academy of Medical Sciences, Beijing, China. A pilot study used RII to intervene in cases of precancerous cervical dysplasia. Twenty-seven women with mild, moderate, or severe cervical dysplasia, pathologically confirmed, were treated by RII suppositories, 10 mg QD, given intravaginally for 6 months (each course lasting 3 months). The results indicated that after the second course, the overall response rate was 96.29% and the complete response rate was 88.89%. In general, side effects were mild. A little cervical and vaginal irritation was well tolerated. In the second double-blind study, patients with precancerous cervical lesions were randomized into two groups, one treated with RII suppository intravaginally and the other with a placebo, once daily for 50 days in two courses. Precancerous lesions in 68.76% of patients in the treatment arm disappeared, with an overall effective rate of 74.29% after two courses of treatment with RII. Its curative effect was approximately that of laser beam radiation and electrocautery (P > 0.05), and differed significantly (P < 0.01) from that of traditional antiinflammatories. RII can be a major measure in prevention and treatment of cervical cancer in high-incidence areas in China. In the third trial, we are conducting a randomized double-blind study placebo controlled, in a high-incidence area of cervical cancer (Xiang-Yuan county, Shang Xi Province, China). At present, the patients are being followed up and the study will be completed after 2 years.

Topics: Antineoplastic Agents; China; Double-Blind Method; Female; Humans; Incidence; Pilot Projects; Placebos; Precancerous Conditions; Tretinoin; Uterine Cervical Neoplasms

Renal transplant recipients experience a greatly increased frequency of neoplastic skin lesions, including aggressive squamous cell carcinomas. Recent reports suggest that high doses of systemic retinoids may exert a chemotherapeutic and chemoprophylactic effect. Similarly, topical retinoid, especially tretinoin, has also been shown to be anti-tumoragenic in various settings. Because of the serious toxicity of high-dose systemic retinoid, a protocol was developed that combined topical tretinoin with low-dose etretinate (10 mg daily) for the treatment of frequently occurring dysplastic skin lesions in renal transplant recipients. Seven patients elected to receive combined tretinoin and etretinate therapy, and 4 were treated with tretinoin alone. Clinical evaluations were performed monthly. By 3 months of therapy, 9 of 11 patients exhibited at least a 25% decrease in the number of neoplastic growths. After 6 months, 6 of 8 evaluable patients, including 2 of 3 individuals receiving tretinoin alone, exhibited at least a 50% decrease. Three of 4 patients on the combined regimen and 2 of 3 receiving tretinoin alone for at least 9 months, exhibited a significant decrease in the rate of development of new squamous cell cancers. At the start of treatment, epidermal specimens were almost completely devoid of Langerhans cells (CD1+ cells). Their density increased greatly and in proportion to the duration of therapy. Long term topical tretinoin with or without low-dose oral etretinate seems to be an effective regimen to suppress the development of new tumors and to reduce the numbers of existing lesions in renal transplant recipients.

Topics: Administration, Topical; Adult; Biopsy; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Drug Therapy, Combination; Etretinate; Humans; Immunohistochemistry; Kidney Transplantation; Pilot Projects; Precancerous Conditions; Skin; Skin Neoplasms; Tretinoin

Patients with cervical precancerous lesions were double blindly divided into 2 groups and treated with either Retinamide II (RII) or Riboflavin (VB2) suppository. The suppository containing RII 20mg or VB2 5mg was given intravaginally daily for 100 days, divided into 2 courses. Clinical examination, papanicolaou cytology and tissue biopsy under colposcope were carried out before and after treatment. The results showed that the disappearance rates of precancerous lesions (DRPL) after the second course of treatment with RII or VB2 were 68.5% and 52.00%, and the overall response rates were 74.29% and 56.0%, respectively. 1 or 2 yrs after treatment, DRPL of the RII, Riboflavin and laser groups did not show significant difference (P > 0.05). The statistically significant differences were among the RII, Riboflavin, laser groups and antiphlogistic treatment group (P < 0.01). The results indicate that local application of RII and Riboflavin may serve as chemopreventive agents for cervical cancer.

Topics: Administration, Intravaginal; Double-Blind Method; Female; Follow-Up Studies; Humans; Precancerous Conditions; Riboflavin; Suppositories; Tretinoin; Uterine Cervical Neoplasms

Mucosal dysplasia in the head and neck region is recognized to be a precancerous lesion. Between January 1983 and December 1987, a pilot study was conducted at the Manitoba Cancer Treatment and Research Foundation to determine the effects of beta-carotene and cis-retinoic acid on mucosal dysplasias. Eighteen patients were treated with a "cross-over" regimen. The overall response to treatment was 61%, with 33.3% complete responses. Patients who smoked had a significantly better response than nonsmokers. The response rate for 9 of 11 smokers was 81.2%, and 2 of 7 nonsmokers or 28.6% responded to this protocol. The beneficial effect of these drugs should be established by prospective, randomized trial in high risk populations.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Carotenoids; Drug Evaluation; Erythroplasia; Female; Humans; Leukoplakia, Oral; Lichen Planus; Male; Middle Aged; Mouth Diseases; Mouth Mucosa; Pilot Projects; Precancerous Conditions; Prospective Studies; Smoking; Tretinoin; Vitamin A

Since 1983, we have been conducting inhibitory therapy for precancerous lesions of the esophagus in two regions of Henan Province considered high-risk areas of esophageal carcinoma. Our goal was to effect a 50% reduction in the canceration rate of marked esophageal dysplasia. By means of a cytological survey, 2531 cases of marked esophageal dysplasia and 3393 cases of mild esophageal dysplasia were selected. The former were randomly divided into 3 groups for antitumor-B (ATB, a mixture of Chinese herbs), retinamide (4-ethoxycarbophenylretinamide) and placebo treatment respectively, and the latter into 2 groups treated with riboflavin and placebo respectively. Treatment was continued for 3 or 5 years (administration rate greater than 90% in all groups) and esophageal cytology reexamined (reexamination rates were 94.1% and 92.5% respectively). Our results were as follows: 1) ATB 3- and 5-year subjects saw the canceration rate of marked esophageal dysplasia drop by 52.2% and 47.3% respectively as compared to control (P less than 0.01). 2) Retinamide lowered the canceration rate by 37.3% after a 3-year treatment period, with this reduction reaching 43.2% after an additional 2 years of treatment with increased dosages (P less than 0.05, P less than 0.01). 3) In the riboflavin group, the canceration rate of mild esophageal dysplasia was reduced by 22.2% and 34.8% after 3 and 5 years of treatment respectively, but these differences were not statistically significant. The above results verify the efficacy of medicamentous inhibitory therapy for esophageal precancerous lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Drugs, Chinese Herbal; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Precancerous Conditions; Riboflavin; Tretinoin

9633 subjects aged 40 to 65 were sampled from high-risk areas for esophageal cancer and examined by esophageal exfoliative cytology. 2531 and 3393 cases of markedly and mildly dysplastic patients were screened out respectively. Those with marked dysplasia were randomized into 3 groups and given respective medications: antitumor B (Chinese herbs), 4-ethoxycarbophenylretinamide (retinamide) and placebo. The subjects with mild dysplasia were randomly divided into 2 groups for riboflavin and placebo treatment. After medication for 3 or 5 years the subjects were reexamined by esophageal exfoliative cytology. The incidence of esophageal cancer in the antitumor B group after taking medication for 3 and 5 years was reduced by 52.2% and 47.3% respectively as compared with the placebo group. These differences were statistically significant (chi 2 = 8.9115, P less than 0.01; chi 2 = 10.9573, P less than 0.01). The incidence of esophageal cancer in the retinamide group after 3 years of medication was reduced by 37.3% as compared with control, while the incidence among patients treated for 5 years dropped by 43.2% relative to control. This difference was statistically significant (chi 2 = 9.2836, P less than 0.01). The incidence of esophageal cancer in the riboflavin group was reduced by 22.2% and 34.8% respectively. The above results indicate that secondary prevention of esophageal cancer is possible and that inhibitory therapy of precancerous lesions of the esophagus is effective in preventing esophageal cancer. This method needs further trial and study in high risk areas of esophageal cancer. The reliability of the experimental results is critically discussed.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Drugs, Chinese Herbal; Esophageal Neoplasms; Female; Follow-Up Studies; Humans; Male; Middle Aged; Precancerous Conditions; Riboflavin; Tablets; Tretinoin

Since 1984, mass screening for cancer has been carried out in the realgar and tin mines, high incidence areas of lung cancer. Certain epidemical characteristics were found in precancerous lesion of lung cancer. Chemopreventive treatment were carried out by giving R1 [N-(p-ethoxycarbophenyl) retinamide] & R2 [N-(p-carboxyphenyl) retinamide]-retinoids synthesized by the Institute of Materia Medica, Chinese Academy of Medical Sciences. A prospective randomized double-blind control trial on the subjects with moderate or severe atypical hyperplasia cells in the sputum was conducted. Thirty-seven patients were treated by R1 (50 mg/d, p. o; total dose: 18.25 g/yr/case). In view of the absorption of R2 being better than R1, R2 (20 mg/d, p. o; total dose: 3.6/g/6mos/case) was given to 52 patients instead of R1. Patients in the control group were treated by riboflavin (50 mg/d, p. o.). The results showed that general status of the patients was improved. IgA and IgM in the serum were increased and the arsenic skin lesions were relieved after the treatment with R1 and R2. As compared with the control group, the incidence of lung cancer was 1:4 and mean degree of hyperplasia in the sputum dropped. It is suggested that these drugs are safe and effective in the chemoprevention of lung cancer. It is worth for further study.

Topics: Antineoplastic Agents; Arsenic; Clinical Trials as Topic; Double-Blind Method; Humans; Lung Neoplasms; Mining; Occupational Diseases; Precancerous Conditions; Random Allocation; Retinoids; Tin; Tretinoin

In 1983, intervention of precancerous lesion of esophagus was undertaken in the high risk area of esophageal cancer, Heshun Village, Linxian County. It had been expected that cancerous degeneration rate of esophageal dysplasia should be reduced by 50% so as the prevention of esophageal cancer could become possible. 6758 subjects of the general population aging from 40 to 65 were examined by esophageal exfoliative cytology, 1729 had marked dysplasia and 2411 had mild dysplasia of esophageal epithelium. Those with marked dysplasia were randomized into 3 groups to take their respective medication: antitumor B (Chinese herbs); retinamide (4-Ethoxycarbophenylretinamide) and placebo. The subjects with mild dysplasia were divided randomly into 2 groups for treatment by riboflavin and placebo. 95% of the subjects had taken 90% or more of the total medication for 3 years, at the end of which they were reexamined by esophageal exfoliative cytology. The reexamination rate was 94.1%. The incidence of esophageal cancer in the antitumor B group (3.9%) was reduced by 53% as compared with that of the placebo group (8.3%). This difference had statistical significant (means 2 = 7.672, P less than 0.05). The incidence of esophageal cancer in retinamide and riboflavin groups were reduced by 33.7% and 19% as compared with those of the control groups. The regression rate of dysplasia in the treatment groups were increased than that of the control groups. The above results showed that our hypothesis about the secondary prevention of esophageal cancer is correct. The intervention of precancerous lesion of the esophagus is effective in the prevention of esophageal cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Drugs, Chinese Herbal; Esophageal Neoplasms; Female; Humans; Hyperplasia; Male; Middle Aged; Precancerous Conditions; Riboflavin; Tretinoin

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

Long noncoding RNAs (LncRNAs) play a pivotal role in gastric tumorigenesis, while exosomes facilitate the LncRNAs transferring to recipient cells. However, the roles of exosomal LncRNAs in gastric premalignant lesions (GPL) remain unclear.. We analyzed the expression of LncHOXA10 and its role in GPL progression. The protective effect of all-trans retinoic acid (ATRA) on GPL was explored in vitro and in vivo.. Here, we found that LncHOXA10 expression was obviously increased in serum exosomes and gastric tissues from individuals with GPL, and exosomal LncHOXA10 from patients with GPL markedly promoted the malignant progression of human gastric epithelial cell line GES-1. Furthermore, RNA-pulldown assay revealed that LncHOXA10 mainly interacted with pyruvate carboxylase (PC), an essential enzyme in various cellular metabolic pathways. In gastric tissues from patients with GPL and gastric cancer (GC), PC was also upregulated and positively correlated with LncHOXA10 expression, which predicted a poor prognosis as well. Moreover, PC silencing attenuated the malignant effects of exosomal LncHOXA10 on GES-1 cells. ATRA also ameliorated the deterioration of GPL and prevented the malignant progression of GPL by reducing exosomal LncHOXA10 and PC expression.. Collectively, the LncHOXA10-PC axis participated in the early stage of GC tumorigenesis, and ATRA might be useful to prevent GPL from developing into GC because it targets this axis.

Topics: Animals; Antineoplastic Agents; Carcinogenesis; Cell Line, Tumor; Exosomes; Female; Gene Expression Regulation, Neoplastic; Homeobox A10 Proteins; Humans; Male; Middle Aged; Precancerous Conditions; Pyruvate Carboxylase; Rats; Rats, Wistar; RNA, Long Noncoding; Stomach Neoplasms; Tretinoin

Retinoic acid (RA) is the most biologically active metabolite of vitamin A and is important for stomach physiological function. However, little is known about the metabolic status of RA in human gastric lesions. From 2015 to 2018, 1,392 local residents in Lujiang County were recruited into a cross-sectional survey program, which included a questionnaire interview and blood collection. We detected the mRNA and protein expression of RA metabolism-relevant factors in gastric tissues from 68 local patients with gastric lesions. The effects of all-trans retinoic acid (ATRA) supplementation were investigated in a gastric precancerous lesions (GPLs) rat model. In the cross-sectional survey, no significant differences in the level of RA precursor (

Topics: Animals; Cross-Sectional Studies; Humans; Precancerous Conditions; Rats; Retinoic Acid 4-Hydroxylase; RNA, Messenger; Stomach; Tretinoin

We aimed to detect the expression of specific LncRNAs in exosomes isolated from the serum of patients with precancerous lesions and to study the effect of these serum exosomes on the activity of GES-1 cells in patients with precancerous lesions, as well as the activity of all-trans retinoic acid on GES-1 cells with or without the exosomes. Exosomes were extracted from the serum of patients with precancerous lesions and normal controls. Based on our previous sequencing results, quantitative real time-PCR was used to detect differentially expressed LncRNAs. Exosomes from the serum of patients with precancerous lesions were cocultured with GES-1 cells, and 5 μM all-trans retinoic acid was added as an intervention. Changes in cell viability and expression of LncHOXA10 were observed. Compared with the blank group, the proliferation activity of GES-1 cells cocultured with exosomes derived from the serum of patients with precancerous lesions was increased (P < 0.01), the proportion of cells in S phase was increased (P < 0.05). After adding 5 μM all-trans retinoic acid, the viability of cells decreased significantly (P < 0.01), the proportion of cells in S phase decreased significantly (P < 0.05). The expression of LncHOXA10 was decreased (P < 0.05). All-trans retinoic acid can conduct its chemopreventive effects by inhibiting the expression of LncHOXA10, thereby reducing the activity of LncHOXA10 in GES-1 cells cocultured with serum exosomes from patients with precancerous lesions.

Topics: Cell Cycle; Cell Proliferation; Exosomes; Female; Humans; Male; Precancerous Conditions; RNA, Long Noncoding; S Phase; Tretinoin

To evaluate disease dynamics, treatment results, and frequency of malignant transformation. Ten-year single center retrospective study. The study included 171 patients, 28-99 years old. Follow-up was 1-16 years. 49.5% exhibited changes in clinical presentation, with 19% yearly increase of probability for type shift. Index of extent (number of oral locations) showed a mean 40% decrease and 94.1% reported improvement. There were significant differences between treated and untreated patients (P=0.012). Patients with or without systemic diseases had identical treatment requirements for oral lesions. The prevalence of SCC was 5.8%. Oral lichen planus constantly changes presentation and extent of involvement. The effect of systemic diseases was insignificant in the present study. There is a clear value for treatment to reduce the extent of lesions. The results indicate that all clinical forms of the disease need to be equally followed since the clinical presentation typically changes over time, while malignant transformation can occur in all forms.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Clobetasol; Dexamethasone; Female; Humans; Lichen Planus, Oral; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Prednisone; Prevalence; Retrospective Studies; Tacrolimus; Tretinoin; Triamcinolone

Retinoids are known to suppress carcinogenesis in various epithelial tissues. Among them, all-trans-retinoic acid (atRA) is recognized as one such active retinoid. However, despite the known anticarcinogenic activity of atRA, it exhibits its short plasma half-life during repeated oral administration due to the "acute retinoid resistance" in the liver. This has been the major limitation in clinical applications of atRA. Therefore, in order to render atRA more suitable for clinical uses, sustained delivery of atRA using biodegradable microspheres is suggested in this study. When 50 mg atRA/kg of atRA-loaded microspheres were subcutaneously administered to rats once, the atRA concentration in plasma was maintained around 6.5 ng/ml for 7 weeks, with only minor signs of toxicity. When the chemopreventive efficacy of atRA-loaded microspheres was evaluated using a model of 4-nitroquinoline 1-oxide-induced oral carcinogenesis in F344 rats, a single injection of atRA-loaded microspheres significantly suppressed oral carcinogenesis. Additional injections of atRA-loaded microspheres, however, did not indicate further suppression of carcinogenesis.

Topics: 4-Nitroquinoline-1-oxide; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Male; Microspheres; Mouth Neoplasms; Neoplasms, Experimental; Palatal Neoplasms; Polyesters; Polyethylene Glycols; Precancerous Conditions; Rats; Rats, Inbred F344; Solubility; Tongue Neoplasms; Tretinoin

Hepatocellular carcinoma (HCC) is common worldwide and growing in importance in the West. HCC often occurs against a background of liver disease, tends to present at an advanced stage, and has a poor prognosis, suggesting that it is an ideal target for chemoprevention. We sought to identify in an animal model chemopreventive agents for HCC that might be tested in human subjects. To this end, we induced liver tumors by injecting ethyl-nitrosourea in 6-week-old male B6C3F1 mice. Two chemopreventive agents were administered over a period of 60 weeks: tamoxifen (420 mg/kg feed) and a retinoid, 13-cis-retinoic acid (200 mg/kg feed). Animals were killed at 60 weeks and their livers examined for HCC and premalignant lesions. All liver lesions (altered foci, adenomata, HCC) occurred significantly less frequently in the tamoxifen-treated group than the group given only ethylnitrosourea (HCC developed in 2 of 47 (4%) vs 11 of 44 (25%); P < .001). On the other hand, retinoic acid appeared to increase the number of liver tumors, and in 2 animals angiosarcoma developed. Tamoxifen significantly decreased the incidence of chemical hepatocarcinogenesis in this model, suggesting an important role for estrogens in the pathogenesis of HCC and suggesting that it should be tested in human beings as a chemopreventive agent against HCC.

Topics: Adenoma, Liver Cell; Animals; Anticarcinogenic Agents; Carcinoma, Hepatocellular; Chemoprevention; Disease Models, Animal; Ethylnitrosourea; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred Strains; Precancerous Conditions; Tamoxifen; Tretinoin

Chemopreventive activities of all-trans retinoic acid (AtRA), 9-cis retinoic acid (9cRA), retinol (ROL) and beta-carotene (betaC) were evaluated during hepatocarcinogenesis. Rats received 1 mg/100 g body wt AtRA (AtRA group), 9cRA (9cRA group), ROL (ROL group), 7 mg/100 g body wt betaC (betaC group) or corn oil (CO group, controls). Hepatocyte nodule incidence was reduced (P < 0.05) in betaC group (46%), but not (P > 0.05) in AtRA (92%), 9cRA (92%) and ROL (82%) groups, compared with the CO group (100%). Multiplicity of these preneoplastic lesions (PNL) was different (P < 0.05) between CO group (44 +/- 9) and 9cRA (11 +/- 4), ROL (7 +/- 3) and betaC (4 +/- 2) groups, except for AtRA group (27 +/- 9; P > 0.05). Number/cm(2) liver section, mean area (mm(2)) and percent liver section area occupied by total (persistent + remodeling) placental glutathione S-transferase (GST-P) positive PNL was reduced (P < 0.05) in AtRA (107 +/- 13; 0.12 +/- 0.06; 13.9 +/- 3.9), 9cRA (71 +/- 12; 0.12 +/- 0.06; 6.8 +/- 2.2), ROL (96 +/- 13; 0.11 +/- 0.22; 6.8 +/- 2.0) and betaC (106 +/- 13; 0.08 +/- 0.03; 10.8 +/- 2.5) groups compared with CO group (166 +/- 14; 0.18 +/- 0.09; 28.6 +/- 5.2). Percent of remodeling GST-P positive PNL was increased (P < 0.05) in 9cRA (92 +/- 1), ROL (96 +/- 1) and betaC (93 +/- 1) groups, but not (P > 0.05) in AtRA group (90 +/- 2), compared with the CO group (86 +/- 1). Compared with the CO group, all groups present in PNL reduced (P < 0.05) cell proliferation and no differences (P > 0.05) in apoptosis. DNA damage [comet length (mum)] was reduced (P < 0.05) in ROL (87.9 +/- 2.6) and betaC (89.2 +/- 4.0) groups, but not in AtRA (94.8 +/- 4.1) and 9cRA (94.2 +/- 1.5) groups, compared with the CO group (100.4 +/- 3.9). AtRA, 9cRA, ROL and betaC presented chemopreventive activities against hepatocarcinogenesis. These involve inhibition of cell proliferation, but not induction of apoptosis. Increased remodeling of GST-P positive PNL relates to 9cRA, ROL and betaC actions, while inhibition of DNA damage relates to ROL and betaC actions.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; beta Carotene; Body Weight; Cell Proliferation; Chemoprevention; Comet Assay; DNA Damage; Glutathione Transferase; Hepatocytes; Incidence; Liver Neoplasms, Experimental; Male; Organ Size; Precancerous Conditions; Rats; Rats, Wistar; Tretinoin; Vitamin A

Retinoic acid receptor-beta(2) (RAR-beta(2)) expression is suppressed in oral premalignant lesions and head and neck squamous cell carcinomas (HNSCCs). This study was conducted to determine whether RAR-beta(2) gene expression in such lesions can be silenced by promoter methylation.. RAR-beta(2) methylation was analyzed in DNA samples from 22 pairs of primary HNSCC and adjacent normal epithelium, 124 samples of oral leukoplakia, and 18 HNSCC cell lines using methylation-specific PCR. RAR-beta(2) promoter was methylated in 67, 56, and 53% of HNSCC tumors, HNSCC cell lines, and microdissected oral leukoplakia specimens, respectively. RAR-beta(2) hypermethylation was confirmed by sodium bisulfite-PCR combined with restriction enzyme digestion analysis and by random cloning and sequencing of bisulfite-treated DNA isolates.. Significantly higher RAR-beta(2) hypermethylation levels were found in tumor tissue compared with adjacent normal tissue (P = 0.002). RAR-beta(2) methylation in the cell lines was correlated with loss of RAR-beta(2) expression (P = 0.013) and inversely related to the presence of mutated p53 (P = 0.025). The demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) restored RAR-beta(2) inducibility by all-trans-retinoic acid (ATRA) in some of the cell lines, which posses a methylated RAR-beta(2) promoter. In some cell lines, this effect was associated with increased growth inhibition after combined treatment with 5-aza-CdR and ATRA.. RAR-beta(2) silencing by methylation is an early event in head and neck carcinogenesis; 5-Aza-CdR can restore RAR-beta(2) inducibility by ATRA in most cell lines, and the combination of 5-aza-CdR and ATRA is more effective in growth inhibition than single agents.

Topics: Adult; Aged; Aged, 80 and over; Base Sequence; Carcinoma, Squamous Cell; Cell Division; Cell Line, Tumor; Cloning, Molecular; DNA Methylation; DNA Primers; DNA, Neoplasm; Female; Gene Silencing; Head and Neck Neoplasms; Humans; Leukoplakia, Oral; Male; Middle Aged; Molecular Sequence Data; Mouth Neoplasms; Polymerase Chain Reaction; Precancerous Conditions; Promoter Regions, Genetic; Receptors, Retinoic Acid; Tretinoin

Retinoids regulate gene transcription through activating retinoic acid receptors (RARs)/retinoic X receptors (RXRs). Of the three RAR receptors (alpha, beta, and gamma), RARbeta has been considered a tumor suppressor gene. Here, we identified a novel RARbeta isoform-RARbeta5 in breast epithelial cells, which could play a negative role in RARbeta signaling. Similar to RARbeta2, the first exon (59 bp) of RARbeta5 is RARbeta5 isoform specific, whereas the other exons are common to all of the RARbeta isoforms. The first exon of RARbeta5 does not contain any translation start codon, and therefore its protein translation begins at an internal methionine codon of RARbeta2, lacking the A, B, and part of C domain of RARbeta2. RARbeta5 protein was preferentially expressed in estrogen receptor-negative breast cancer cells and normal breast epithelial cells that are relatively resistant to retinoids, whereas estrogen receptor-positive cells that did not express detectable RARbeta5 protein were sensitive to retinoid treatment, suggesting that this isoform may affect the cellular response to retinoids. RARbeta5 isoform is unique among all of the RARs, because a corresponding isoform was not detectable for either RARalpha or RARgamma. RARbeta5 mRNA was variably expressed in normal and cancerous breast epithelial cells. Its transcription was under the control of a distinct promoter P3, which can be activated by all-trans-retinoic acid (atRA) and other RAR/RXR selective retinoids in MCF-7 and T47D breast cancer cells. We mapped the RARbeta5 promoter and found a region -302/-99 to be the target region of atRA. In conclusion, we identified and initially characterized RARbeta5 in normal, premalignant, and malignant breast epithelial cells. RARbeta5 may serve as a potential target of retinoids in prevention and therapy studies.

Topics: Amino Acid Sequence; Base Sequence; Breast; Breast Neoplasms; Cell Line, Tumor; Cloning, Molecular; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Molecular Sequence Data; Precancerous Conditions; Promoter Regions, Genetic; Protein Isoforms; Receptors, Retinoic Acid; RNA, Messenger; Transcription, Genetic; Transfection; Tretinoin

To investigate the treatment efficient of viaminati on the laryngeal keratosis.. All 16 cases of laryngeal keratosis took viaminati.. 15 cases were recovered. 1 case was developed cancer.. Viaminati is effective in treating laryngeal keratosis and has not obvious side-effect.

Topics: Adult; Female; Humans; Keratolytic Agents; Keratosis; Laryngeal Diseases; Laryngeal Neoplasms; Male; Middle Aged; Precancerous Conditions; Tretinoin

Chemoprevention of breast cancer is an active area of investigation. Recent in vivo and in vitro studies have shown that thiazolidinediones (e.g., troglitazone) and retinoids are able to inhibit the growth of breast cancer cells. Troglitazone mediates its action via peroxisome proliferator-activated receptor gamma (PPARgamma). We evaluated the ability of troglitazone, alone or in combination with retinoids, to prevent the induction of preneoplastic lesions by 7,12-dimethylbenz[a]anthracene (DMBA) in a mouse mammary gland organ culture model.. Mammary glands of BALB/c mice were treated with DMBA (2 microg/mL) to induce preneoplastic lesions in organ culture. Effects of troglitazone, all-trans-retinoic acid (retinoic acid; ligand for retinoic acid receptor [RAR] alpha), and LG10068 (ligand for retinoid X receptors [RXRs]), singly or in combination, on the development of lesions were evaluated. Expression of retinoid receptors (RARalpha and RXRalpha) and PPARgamma was determined by western blot analysis. Statistical significance was determined by generalized chi-squared analysis using the GENCAT software program and Bonferroni correction. All P values are two-sided.. Troglitazone (at 10(-5) M) or retinoic acid (at 10(-6) M) markedly inhibited the development of mammary lesions (both P values <.05); however, together they did not enhance the effectiveness of the other. In contrast, LG10068 (at 10(-7) M or 10(-8) M) alone had very little ability to inhibit development of these lesions, but a combination of LG10068 (at 10(-8) M) and troglitazone (at 10(-5) M or 10(-6) M) almost completely inhibited (by 85% and 100%, respectively; both P values <. 05) the development of mammary lesions. The expression of PPARgamma and RXRalpha remained unchanged with the various treatments, whereas the expression of RARalpha was substantially reduced after treatment with the combination of retinoic acid and troglitazone.. To our knowledge, this is the first report showing the possibility of a PPARgamma ligand having chemopreventive activity. Furthermore, an RXR-selective retinoid, LG10068, appears to enhance this activity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Carcinogens; Chromans; Estradiol; Female; Ligands; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Organ Culture Techniques; Precancerous Conditions; Progesterone; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Retinoid X Receptors; Retinoids; Thiazoles; Thiazolidinediones; Transcription Factors; Tretinoin; Troglitazone

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

Topics: Animals; beta Carotene; Cell Division; Cocarcinogenesis; Diterpenes; Down-Regulation; Environmental Exposure; Ferrets; Gene Expression Regulation; Genes, fos; Genes, jun; Humans; Lung; Lung Neoplasms; Male; Metaplasia; Nicotiana; Plants, Toxic; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Receptors, Retinoic Acid; Retinyl Esters; Signal Transduction; Smoke; Transcription Factor AP-1; Tretinoin; Vitamin A

Using an in vitro lung carcinogenesis model consisting of normal, premalignant, and malignant human bronchial epithelial (HBE) cells, we analyzed the growth inhibitory effects of 26 novel synthetic retinoic acid receptor (RAR)- and retinoid X receptor (RXR)-selective retinoids. RAR-selective retinoids such as CD271, CD437, CD2325, and SR11364 showed potent activity in inhibiting the growth of either normal or premalignant and malignant HBE cells (IC50s mostly <1 microM) and were much more potent than RXR-selective retinoids. Nonetheless, the combination of RAR- and RXR-selective retinoids exhibited additive effects in HBE cells. As the HBE cells became progressively more malignant, they exhibited decreased or lost sensitivity to many retinoids. The activity of the RAR-selective retinoids, with the exception of the most potent retinoid, CD437, could be suppressed by an RAR panantagonist. These results suggest that: (a) RAR/RXR heterodimers play an important role in mediating the growth inhibitory effects of most retinoids in HBE cells; (b) CD437 may act through an RAR-independent pathway; (c) some of the RAR-selective retinoids may have the potential to be used in the clinic as chemopreventive and chemotherapeutic agents for lung cancer; and (d) early stages of lung carcinogenesis may be responsive targets for chemoprevention by retinoids, as opposed to later stages.

Topics: Antineoplastic Agents; Bronchi; Bronchial Neoplasms; Cell Division; Chemoprevention; Drug Resistance, Neoplasm; Epithelial Cells; Humans; Lung Neoplasms; Precancerous Conditions; Receptors, Retinoic Acid; Retinoids; Tretinoin

We have previously reported that the retinoids, 4-(hydroxyphenyl)retinamide (4-HPR) and 9-cis-retinoic acid (RA) prevented azoxymethane (AOM)-induced colon tumors and along with 2-(carboxyphenyl)retinamide (2-CPR) prevented aberrant crypt foci (ACF). In this study, we evaluated the effect of 2-CPR on AOM-induced colon tumors and the effect of the three retinoids on apoptosis and cell proliferation. Male F344 rats were administrated 15 mg/kg AOM at weeks 7 and 8 of age. 2-CPR (315 mg/kg) was administered in the diet starting either 1 week before or at week 12 after the first dose of AOM. The rats continued to receive the 2-CPR until killed at week 46. Unlike the demonstrated prevention of colon cancer by the other two retinoids, both dosing schedules of 2-CPR resulted in an approximate doubling of the yield of colon tumors. In adenomas, 2-CPR, 4-HPR and 9-cis-RA were equally effective in reducing mitotic activity, while only 4-HPR and 9-cis-RA but not 2-CPR enhanced apoptosis. When administered for only the 6 days prior to killing 4-HPR but not 2-CPR decreased the Mitotic Index and increased the Apoptotic Index in adenomas. In non-involved crypts, chronic exposure to 4-HPR and 9-cis-RA in contrast to 2-CPR reduced the Mitotic Index and enhanced the Apoptotic Index. In concurrence with our previous study, both 2-CPR and 4-HPR were very potent in preventing ACF when administered in the diet starting 1 week before the first dose of AOM and continuing for the 5 weeks of the study. Hence, unlike the other two retinoids, 2-CPR, although very potent in preventing ACF, enhanced rather than prevented AOM-induced colon cancer. Furthermore, our results suggest that the effect of 2-CPR on tumor yield is different from 4-HPR and 9-cis-RA because, unlike them, it does not enhance apoptosis.

Topics: Adenocarcinoma; Adenoma; Animals; Anticarcinogenic Agents; Apoptosis; Azoxymethane; Body Weight; Carcinogens; Colon; Colonic Neoplasms; Drug Screening Assays, Antitumor; Fenretinide; Male; Precancerous Conditions; Rats; Rats, Inbred F344; Tretinoin

Topics: Child; Humans; Laser Therapy; Male; Porokeratosis; Precancerous Conditions; Skin; Skin Diseases; Skin Neoplasms; Tretinoin

Retinoic acid (RA) was topically applied to the skin of Sencar mice during the promotion phase of specific tumor induction protocols that produce papillomas at low (12-O-tetradecanoylphorbol-13-acetate promoted, TPA) or high (mezerein-promoted) risk for premalignant progression and malignant conversion. RA consistently reduced the yield of papillomas and carcinomas in both protocols, but the frequency of malignant conversion in papillomas that emerged during RA treatment was not reduced. When TPA was reapplied after cessation of RA treatment, the number of papillomas increased 2-fold, suggesting that RA had not eliminated initiated cells. In vitro, RA prevented the emergence of transformed keratinocytes in an assay that mimics malignant conversion, suggesting that RA can suppress conversion if applied during the stage of premalignant progression. Examination of tumor markers at weeks 14 and 22 of the tumor-induction experiments in vivo indicated that papillomas evolving during RA treatment exhibited a phenotype of high progression risk, even in the TPA-promoted groups. In the majority of these tumors, the alpha6beta4 integrin and retinoid X receptor alpha transcripts were detected suprabasally, indicating an advanced state of premalignant progression. RA-treated tumors also expressed higher levels of transcripts for transforming growth factor (TGF)-beta1 and localized TGF-beta1 peptide in the basal portions of the tumor fronds. Because up-regulated expression of TGF-beta1 suppresses papilloma formation, these studies suggest a mechanism whereby RA can prevent papilloma eruption via a TGF-beta intermediate, but papillomas resistant to RA may have altered TGF-beta signaling and progress to carcinomas at an increased frequency.

Topics: Administration, Topical; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Biomarkers, Tumor; Carcinogens; Carcinoma, Basal Cell; Cell Transformation, Neoplastic; Disease Progression; Diterpenes; Female; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Inbred SENCAR; Papilloma; Phenotype; Precancerous Conditions; Receptors, Retinoic Acid; Retinoid X Receptors; Risk Factors; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Transcription Factors; Transforming Growth Factor beta; Tretinoin

Intratubular malignant germ cells (ITMGC), as assessed by clinicopathologic or cytogenetic studies, are regarded as a preinvasive lesion of all human testicular germ cell tumors with the exception of yolk sac tumors (in infants) and spermatocytic seminomas. To characterize specific surface molecules of ITMGC, we raised three mouse monoclonal antibodies (mAb) against NCR-G3 (G3), a multipotent, human embryonal carcinoma (EC) cell line, and screened cryostat sections of human testicular tissue containing ITMGC. These three mAb (HB5, IgG1; HF2, IgG1; HE11, IgG1) reacted to the surface of ITMGC, seminomas, and EC in vivo as well as to human EC cell lines in vitro. Expression of HB5 and HF2 antigens was down-regulated during cellular differentiation of G3 cells by retinoic acid or N,N'-hexamethylene-bis-acetamide treatment, whereas that of HE11 antigen was up-regulated with cellular differentiation by retinoic acid. Furthermore, these three mAb reacted to stage-specific prespermatogonia in the human fetus but not in human adults. HB5, HF2, and HE11 antigens were shown to be glycoproteins with molecular weights of approximately 80, 80, and 70 kd, respectively, and could be immunoprecipitated after deglycosylation treatment. Peptide mapping with Staphylococcus aureus V8 protease suggested that the HB5 and HF2 antigens were identical. We concluded that HB5/HF2 and HE11 antigens are oncodevelopmental antigens in testicular germ cell tumors and human spermatogenesis that may play a significant role in tumorigenesis and the development of human germ cells.

Topics: Adult; Aging; Animals; Antibodies, Monoclonal; Antibody Specificity; Antigens, Neoplasm; Antigens, Surface; Carcinoma, Embryonal; Cell Differentiation; Embryonic and Fetal Development; Female; Fetus; Germinoma; Gestational Age; Humans; Infant; Infant, Newborn; Male; Mice; Mice, Inbred BALB C; Organ Specificity; Precancerous Conditions; Reference Values; Spermatogonia; Testicular Neoplasms; Testis; Tretinoin; Tumor Cells, Cultured

Retinoids are proposed chemopreventive agents that inhibit cell proliferation and induce differentiation. Their ability to prevent azoxymethane (AOM)-induced aberrant crypt foci (ACF) and tumors and to modulate cell proliferation was investigated in the colon of male F344 rats. Thirteen retinoids were evaluated for prevention of ACF and two of them, 9-cis-retinoic acid (RA) and 4-(hydroxyphenyl)retinamide (4-HPR), were also evaluated for prevention of colon cancer. The retinoids were administered continuously in the diet starting 1 week prior to the first of two weekly 15 mg/kg i.p. injections of AOM and for a total of either 5 or 36 weeks in order to evaluate their effect on colonic ACF and tumors. At a concentration of 1 mmol/kg diet, 2-(carboxyphenyl)retinamide caused the greatest reduction (57.7%) in the yield of ACF. 9-cis-RA was toxic at 1 mmol/kg so that it was evaluated at 0.1 mmol/kg, resulting in a 41.6% reduction in ACF. The ability of the retinoids to reduce the proliferating cell nuclear antigen (PCNA) labeling index in ACF and in non-involved crypts correlated with their ability to prevent ACF. Both 9-cis-RA (0.1 and 0.2 mmol/kg diet) and 4-HPR (1 and 2 mmol/kg diet) were highly effective in decreasing the yield of AOM-induced colon tumors. In summary, retinoids were demonstrated to reduce cell proliferation and to prevent ACF and tumors in the colon, suggesting promise as preventive agents for colon cancer.

Topics: Alitretinoin; Animals; Anticarcinogenic Agents; Azoxymethane; Cell Division; Colonic Neoplasms; Fenretinide; Male; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Rats; Rats, Inbred F344; Tretinoin

The effects of N-(4-hydroxyphenyl)retinamide (4-HPR) and all-trans-retinoic acid (tRA) on the exogenous and endogenous models of rat liver carcinogenesis respectively using diethylnitrosamine (DEN) and a choline-deficient, L-amino acid-defined (CDAA) diet were studied. For the exogenous study, male Fischer 344 rats, 6 weeks old, were given a single i.p. dose of 200 mg/kg body wt of DEN, partially hepatectomized at week 3, administered 4-HPR at doses of 0, 0.04, 0.08 and 0.16% or tRA at 0, 0.004, 0.008 and 0.015% in diet from week 2 for 6 weeks, and killed at the end of week 8. For the endogenous study, rats were fed the CDAA diet containing 4-HPR or tRA for 12 weeks and killed at the end of week 12. 4-HPR decreased the numbers and sizes of the glutathione S-transferase placental form-positive foci, assayed as putative preneoplastic lesions, the levels of 8-hydroxyguanine (8-OHG), a parameter of oxidative DNA damage, and the bromodeoxyuridine labeling indices (BrdU L.I.) by all three doses in the DEN-initiated case and, more prominently, in the CDAA diet-associated case. In contrast, while tRA failed to exert inhibitory effects apparently on foci development, 8-OHG formation or BrdU labeling in the DEN-initiated case, it reduced the numbers and sizes of the foci, the 8-OHG levels and the BrdU L.I. by all three doses in the CDAA diet-associated case. Furthermore, both 4-HPR and tRA inhibited the CDAA diet-associated induction of hepatocyte necrosis and connective tissue increase but not intrahepatocellular fat accumulation. These results indicate that 4-HPR exerts chemopreventive effects against the exogenous and endogenous rat liver carcinogenesis, while tRA can inhibit only the latter.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anticarcinogenic Agents; Bromodeoxyuridine; Choline Deficiency; Deoxyguanosine; Fenretinide; Glutathione Transferase; Liver; Liver Neoplasms, Experimental; Male; Placenta; Precancerous Conditions; Rats; Rats, Inbred F344; Tretinoin

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 have demonstrated activity in the prevention of second primary tumors in patients with non-small cell lung cancer (NSCLC). They also contribute to the normal growth and differentiation of human bronchial epithelial (HBE) cells. Because retinoids mediate their actions through retinoid nuclear receptors (RARs and RXRs), aberrant signaling through retinoid receptors could contribute to lung carcinogenesis. Using a lung carcinogenesis model consisting of normal, premalignant, and malignant HBE cells, we examined all-trans retinoic acid (t-RA)-induced changes in cellular growth. These studies revealed that t-RA treatment inhibited the growth of normal HBE cells, but premalignant and malignant HBE cells were relatively resistant to t-RA. Coincident with the development of retinoid refractoriness, basal expression of the retinoic acid nuclear receptor beta (RAR-beta) increased. Analysis of receptor function by gel shift and transient transfection assays of normal, premalignant, and malignant HBE cells demonstrated that receptor-DNA binding and transcriptional activation properties were intact in the t-RA-refractory malignant HBE cells. To compare these findings to NSCLCs in patients, we investigated retinoid receptor expression in NSCLC biopsies. A subset of the tumors expressed RAR-beta, reflecting the RAR-beta expression observed in the malignant HBE cells in culture. These findings demonstrate that retinoid receptor function was intact in the t-RA-refractory malignant HBE cell line, suggesting that the defect in retinoid signaling in this lung carcinogenesis model is not intrinsic to the retinoid receptors.

Topics: Animals; Base Sequence; Bronchi; Carcinoma, Non-Small-Cell Lung; Cell Count; Cell Division; Cycloheximide; Dactinomycin; Epithelium; Humans; Keratolytic Agents; Lung Neoplasms; Mice; Molecular Sequence Data; Precancerous Conditions; Protein Synthesis Inhibitors; Rats; Receptors, Retinoic Acid; Tretinoin; Tumor Cells, Cultured

We describe an animal model to induce the histogenesis of squamous metaplasia of the cervical columnar epithelium, a condition usually preceding cervical neoplasia. This model is based on dietary retinoid depletion in female mice. Control sibling mice fed the same diet but with all-trans-retinoic acid (at 3 micrograms/g diet) showed the normal endocervical epithelial and glandular columnar morphology, typical of a simple epithelium without subcolumnar reserve cells. The stratified squamous ectocervical epithelium of these mice fed all-trans retinoic acid showed intense immunohistochemical staining in basal and suprabasal cells with mono-specific antibodies against keratins K5, K14, K6, K13, and, suprabasally, with antibodies specific for K1 and K10. At the squamocolumnar junction, the adjacent columnar epithelium (termed "suprajunctional") did not show staining for K5, K14, K6, K13, K1, and K10 but specifically stained for keratin K8, typical of simple epithelia and absent from the adjacent ectocervical squamous stratified lining (termed "subjunctional"), in striking contrast. Sections of the squamocolumnar junction from mice kept on the vitamin A-deficient diet for 10 weeks showed suprajunctional isolated patches of reserve cells, proximal and distal to the junction. These cells were detected prior to any symptoms of vitamin A deficiency, such as loss of body weight or respiratory discomfort. The subcolumnar reserve cells induced by vitamin A deficiency displayed positive staining for K5 and K14. As deficiency became severe, the reserve cells occupied the entirety of the suprajunctional basement membrane. This epithelium eventually became stratified and squamous metaplastic, the squamocolumnar junction was no longer discernible, and the entire endocervical epithelium and the endometrial glands lost K8 positivity, while acquiring K5, K14, K6, K13, K1, and K10 keratins typical of the ectocervix under normal conditions of vitamin A nutriture. Vitamin A deficiency also altered keratin expression and localization in squamous subjunctional epithelium. In situ hybridization studies for K1 and K5 mRNA showed their major site of expression at the basal (K5) and immediately suprabasal (K1) cell layers. The localization of both K5 and K1 proteins in these same cell layers, and above, is consistent with transcriptional regulation of these keratins. Early vitamin A deficiency caused the appearance of single subcolumnar reserve cells expressing K5 mRNA. After these ce

Topics: Animals; Carcinoma, Squamous Cell; Cervix Uteri; Diet; Disease Models, Animal; Epithelium; Female; Immunohistochemistry; In Situ Hybridization; Keratins; Metaplasia; Mice; Mice, Inbred BALB C; Mice, Nude; Phenotype; Precancerous Conditions; Retinoids; RNA, Messenger; Tretinoin; Uterine Cervical Neoplasms; Vitamin A Deficiency

The model of precancerous lesions of the bladder in rats was induced by N-butyl-(4-hydroxybutyl) nitrosamide (BBN). The animals were randomly divided into the following 3 groups: 1) given Antitumor-B (Chinese herbs); 2) given 4-ethoxycarbophenylretinamide (Retinamide); and 3) control. After treatment for 13 months the rats were killed for pathomorphological examination of the bladder. The results showed that the incidence of bladder cancer in group 1 and 2 was reduced by 90.7% (P < 0.01) and 75.0% (P < 0.01) respectively after treatment as compared with the control group. Our results provide a useful reference for clinical trial in the prevention of bladder cancer recurrence by using antitumor-B and Retinamide.

Topics: Animals; Antineoplastic Agents, Phytogenic; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Drugs, Chinese Herbal; Precancerous Conditions; Rats; Rats, Wistar; Tretinoin; Urinary Bladder Neoplasms

The main objectives were to determine the modulating effects of all-trans retinoic acid on the number, size and multiplicity of aberrant crypt foci as well as the in vivo expression of the genes c-myc and c-fos. These foci, which are hypothesized to be the pre-malignant lesions of colon cancer, were induced in Sprague-Dawley rats with a single injection of azoxymethane. Rats were fed either a control diet (AIN-76) or the control diet to which had been added 75 mg/kg or 150 mg/kg all-trans retinoic acid. Within 4 weeks, we observed that the diets containing all-trans retinoic acid reduced the total number and multiplicity of aberrant crypt foci in the colon. However, all-trans retinoic acid increased the size of the lesions that persisted, possibly due to a greater proportion of lesions with dilated crypts. In situ hybridization and immunohistochemistry were performed on the colons for the in vivo analysis of gene expression in these lesions. The expression of myc-specific mRNA and protein in aberrant crypt foci significantly decreased with both levels of all-trans retinoic acid. In contrast, fos-specific mRNA and protein in aberrant crypt foci significantly increased when 150 mg/kg all-trans retinoic acid was added to the diet. The most important findings of this investigation are that intervention with all-trans retinoic acid in the pre-malignant stage of colon carcinogenesis is effective in decreasing the number and growth of aberrant crypt foci and altering the expression of the c-myc and c-fos genes.

Topics: Animals; Azoxymethane; Body Weight; Colon; Colonic Neoplasms; Genes, fos; Genes, myc; Male; Precancerous Conditions; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-myc; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tretinoin

The purpose of this paper is to observe the blocking effect of topically subepithelial injected drug and Vit A acid painting on chemically induced oral precancerous lesion and to prove, on a certain extent, the hypothesis that subepithelial connective tissue could exert great influence on the differentiation of the epithelium. A total of 49 syrian hamster was used as experimental animal. Both buccal pouches of all animals were painted thrice weekly with 0.5% DMBA in acetone for 6 weeks. Then, they were divided into two groups: Control group and Experimental group. In the latter group, 70.8% precancerous lesions turned into normal epithelial tissue, whereas those untreated animals developed carcinoma by 62%.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Cheek; Cricetinae; Epithelium; Injections; Mesocricetus; Mouth Neoplasms; Precancerous Conditions; Thiazoles; Thiazolidines; Tretinoin

Repeated promotion of 7,12-dimethylbenz[alpha]anthracene-initiated cells in mouse skin with 12-O-tetradecanoylphorbol-13-acetate (TPA) induces them to grow as premalignant skin papillomas and some of these subsequently progress to carcinomas. In this study, we demonstrate that this TPA-induced progression of initiated cells to papillomas and carcinomas could be prevented by exposing them previously to weak promoting regimens or to agents that mimic TPA activity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benzoflavones; Benzyl Alcohols; Cell Transformation, Neoplastic; Cortisone; Dose-Response Relationship, Drug; Indoles; Mice; Mice, Inbred BALB C; Papilloma; Precancerous Conditions; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Vitamin E

Topics: Administration, Buccal; Animals; Cricetinae; Female; Male; Mesocricetus; Mouth Neoplasms; Precancerous Conditions; Tretinoin

The C3H strain of mouse has a high incidence of murine mammary tumor virus-induced mammary tumors, and tumorigenesis progresses via the intermediate formation of the preneoplastic, hyperplastic alveolar nodules (HANs). The C3H mouse also exhibits an elevation in 16 alpha-hydroxylation of estradiol which remains unaltered in relation to the age or presence of tumor, but which is detectable well before the emergence of overt mammary cancer. This metabolic pathway leads to the formation of 16 alpha-hydroxyestrone (16 alpha-OHE1), a putative promoter of mammary cancer. The present study examines the effect of two prototype chemopreventive agents, tamoxifen (TAM) and N-(4-hydroxyphenyl)retinamide (HPR), on 16 alpha-hydroxylation of estradiol and on the growth of HANs. Treatment with TAM, HPR, or a combination of TAM and HPR for 4 weeks in 6- to 8-week-old C3H mice resulted in a consistent elevation in the 16 alpha-hydroxylation pathway of estradiol metabolism relative to the placebo control group (20.50% +/- 2.35%, 21.46% +/- 1.49%, 18.00% +/- 1.75%, and 12.64% +/- 1.45% SD, respectively) and in a significant decrease in the mean frequency of HANs per mammary gland (1.4, 2.1, 0.0, and 5.8, respectively). Mice without any experimental manipulation exhibited an age-dependent progressive increase in HAN frequency from 1.5 per gland at 4 weeks of age to 12.1 per gland at 24 weeks of age. Administration of TAM, HPR, or a combination of TAM and HPR up to 22 weeks of age resulted in a continued suppression of HAN frequency, and the two agents in combination exerted an additive effect on the suppression of HAN development.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Drug Therapy, Combination; Estradiol; Female; Fenretinide; Hydroxylation; Hyperplasia; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Precancerous Conditions; Steroid 16-alpha-Hydroxylase; Tamoxifen; Tretinoin

Topics: Animals; Antineoplastic Agents; Cricetinae; Drugs, Chinese Herbal; Female; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Mucosa; Mouth Neoplasms; Neoplasm Transplantation; Precancerous Conditions; Thiazoles; Thiazolidines; Tretinoin

Although few actinic keratoses eventuate as squamous cell carcinomas, these precancerous lesions cannot be ignored. A medical regimen of topical tretinoin use and sun protection appears to be effective in treating and preventing these precancers, with the added cosmetic benefits of ameliorating the alterations which accompany sun damage on exposed skin.

Topics: Administration, Topical; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Neoplasms, Radiation-Induced; Precancerous Conditions; Skin Neoplasms; Sunlight; Tretinoin

Topics: Animals; Antineoplastic Agents; Nasal Cavity; Nasopharyngeal Neoplasms; Nitrosamines; Nose Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains; Tretinoin

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

Topical tretinoin has been used for a number of years to treat patients with acne vulgaris. This paper reviews some of the newer uses of tretinoin, including treatment of patients with photoaging of the skin, premalignant lesions, dry-eye disorders, and its use after dermabrasion.

Topics: Acne Vulgaris; Administration, Topical; Dermabrasion; Humans; Photosensitivity Disorders; Precancerous Conditions; Skin Neoplasms; Tretinoin; Wound Healing; Xerophthalmia

Twenty seven women with mild, moderate or severe cervical dysplasia proven by pathology were treated by retinamide RII suppository. Retinamide RII suppository, 10 mg QD, was given intravaginally for six months (three months as a course). Clinical examination, Papanicolaou cytology and tissue biopsy under colposcope were carried out before and after treatment. The results indicated that after the second course, 26 out of 27 patients responded; of them, precancerous lesions disappeared in 24 and even normal squamous epithelium was observed in 3. The overall response rate was 96.29% and the marked response rate was 88.89%. The general side effects were mild. There was little cervical and vaginal irritation which was well tolerated. The results of this clinical trial make available a practical base for chemoprevention of cervical cancer.

Topics: Antineoplastic Agents; Cervix Uteri; Female; Humans; Hyperplasia; Precancerous Conditions; Suppositories; Tretinoin; Uterine Cervical Neoplasms

Cholera toxin (CT) at concentrations of 0.1-100 ng/ml induced anchorage-independent growth and DNA synthesis of JB6 cells derived from mouse epidermis. This induction was reversible. CT caused marked increase in the level of intracellular cAMP. Forskolin also increased the cAMP level and induced anchorage-independent growth. However, 12-O-tetradecanoylphorbol-13-acetate (TPA) and 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] induced irreversibly anchorage-independent growth of JB6 cells but did not increase the cAMP level. TPA-resistant clone-30 cells were also resistant to CT in terms of anchorage-independent growth and cAMP induction. Retinoic acid inhibited the induction of anchorage-independent growth of JB6 cells by CT, TPA and 1 alpha,25(OH)2D3. These results suggest that anchorage-independent growth of JB6 cells is induced by cAMP-dependent and cAMP-independent pathways, both of which may include a retinoic acid-sensitive step.

Topics: Animals; Cell Adhesion; Cell Division; Cell Line; Cholera Toxin; DNA Replication; Kinetics; Mice; Precancerous Conditions; Skin Neoplasms; Tetradecanoylphorbol Acetate; Thymidine; Tretinoin

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

Topics: Animals; Cells, Cultured; Dimethyl Sulfoxide; Female; Fenretinide; Insulin; Mammary Glands, Animal; Mice; Mice, Inbred C57BL; Precancerous Conditions; Tretinoin

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

A study was conducted to investigate the in vitro binding affinity of new synthetic polyprenoids to cellular retinoid-binding proteins. Among 10 synthetic polyprenoic acid derivatives, 3,7,11,15-tetramethyl-2,4,6,10,14 hexadecapentaenoic acid (compound 1) was found to have the strongest binding affinity to cellular retinoic acid-binding protein (CRABP) from rat testis. As regards the chemical structure of the polyprenoic acids, it was found that suitable carbon chain length and double bond arrangement are both essential for binding affinity to CRABP. Moreover, compound I displayed a binding affinity to cellular retinoid receptors obtained from precancerous tissues such as mouse skin papillomas and rat liver hyperplastic nodules experimentally induced.

Topics: Animals; Binding, Competitive; Cell Fractionation; Chemical Phenomena; Chemistry; Diterpenes; Female; Hyperplasia; Liver; Male; Mice; Papilloma; Precancerous Conditions; Rats; Rats, Inbred Strains; Retinol-Binding Proteins; Terpenes; Testis; Tretinoin

The inhibitory effect of an aromatic retinoic acid analog, ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate, on bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was evaluated. Administration of 50 ppm of aromatic retinoid in the diet before BBN in the drinking water reduced the incidence of papillary or nodular hyperplasia as a preneoplastic lesion of the bladder epithelium (P < 0.05). When given before, during or after BBN, it also greatly reduced the incidence of papilloma (P < 0.001 before BBN, P < 0.01 during or after BBN treatment), and slightly inhibited the development of cancer. Administration of 100 ppm of aromatic retinoid before or during BBN administration also reduced the incidences of papillary or nodular hyperplasia (P < 0.01 before BBN, P < 0.05 during BBN treatment), and its administration before, during or after BBN treatment greatly reduced the incidences of papilloma (P < 0.001), and cancer (P < 0.01 before or after BBN, P < 0.001 during BBN treatment). Similar results were obtained by assessing the effect of the retinoid on the average numbers of various epithelial lesions per 10 cm length of basement membrane of the bladder in tissue slices. These results show that the aromatic retinoid inhibits both the initiation and promotion of bladder carcinogenesis induced in rats by BBN, and that its effect is dose-dependent.

Topics: Animals; Butylhydroxybutylnitrosamine; Cricetinae; Etretinate; Hyperplasia; Male; Mice; Nitrosamines; Papilloma; Precancerous Conditions; Rats; Tretinoin; Urinary Bladder; Urinary Bladder Neoplasms

Beneficial effects of oral retinoids in prophylaxis of epithelial neoplasias have been demonstrated by experimental works. In this study oral retinoid (RO 10-9359) was used in human dermatosis with high frequency of cutaneous malignancies: xeroderma pigmentosum with or without malignant neoplasias, Mibelli's porokeratosis with multifocal malignant degeneration, basal cell naevus syndrome with basal cell carcinomas, familial epithelioma of Ferguson-Smith and actinic keratosis. This work started in december 1977. Visible epitheliomas have been treated before trial. Initial dose of retinoid was 1 mg/kg daily, decreased depending on individual tolerance. Results were appreciated by comparising number of epitheliomas observed in years preceding retinoid therapy and number of them appearing during treatment; in two familial cases (basal cell naevus syndrom in twins and xeroderma pigmentosum in two brothers) comparison was made between treated and untreated patients. First results are very promising: an excellent response on solar keratosis is noted; epitheliomas occurrence seems actually to be prevented or delayed by oral retinoid therapy. Of course more numerous cases, a longer time, periods without treatment are necessary to confirm these interesting first results. On the other hand drug is not with this dose active on already constituted carcinomas.

Topics: Adolescent; Basal Cell Nevus Syndrome; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Etretinate; Female; Humans; Keratosis; Male; Precancerous Conditions; Skin Diseases; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

The anti-inflammatory effect of the new topical corticosteroid fluocortin butyl ester is approximately equal to that of hydrocortisone acetate but it has the advantage that systemic side-effects are lacking. Vitamin A acid and benzoyl peroxide have brought significant advances in the topical treatment of acne. For the treatment of chloasma and other hyperpigmentations the combination of vitamin A acid and hydroquinone with a corticoid is considerably more effective than any of the single components alone. Povidone-iodine with its extraordinarily low sensitization rate has proved useful for external antimicrobial treatment. Extensive or multiple precancerous lesions are effectively treated with 5-fluorouracil. New hair growth can be induced in alopecia areata by the local application of DNCB.

Topics: Acne Vulgaris; Administration, Topical; Alopecia; Benzoyl Peroxide; Dinitrochlorobenzene; Fluocortolone; Fluorouracil; Humans; Hydroquinones; Pigmentation Disorders; Precancerous Conditions; Skin Diseases; Tretinoin

Leukoplakia is neither a clinical, aetiological nor histopathological entity. Therefore treatment is difficult particularly in multifocal and advanced lesions. Since 1970, we have tested the therapeutic effect of different derivatives of all-trans-retinoic acid. The study includes 75 cases with homogeneous leukoplakia without or with minimal epithelial dysplasia. Over 60% of the cases treated showed positive early results. In follow-ups from 1 to 6 years about 45% of cases showed complete or partial remission. The rest showed relapses or even progression. In cases with recurrence without changes in the morphological characteristics, positive effects were achieved with 1 to 4 repeated courses of therapy. All derivatives of retinoic acid tested so far have shown undesirable side effects with systematic manifestations or local symptoms: interruption of treatment (4) or reduction of dosage (9) were unavoidable for that reason. Regarding the side effects, retinoic acid should only be given under clinical supervision. Of the derivates tested to date, aromatic retinoid seems to have the best curative potential in homogenic leukoplakia.

Topics: Humans; Leukoplakia, Oral; Mouth Neoplasms; Precancerous Conditions; Recurrence; Tretinoin; Vitamin A

Seventy-five specimens of human breast tissue were checked for the presence of cellular retinoic acid-binding protein (cRABP). Fifty-two percent of the primary carcinomas and 43% of the dysplastic breast lesions (stage MII) contained detectable amounts of crabp, whereas no cRABP was found in normal tissue. Sucrose gradient centrifugation and electrophoresis on agarose were used for analysis of the presence of cRABP. The cRABP of human origin (normal uterus and neoplastic mammary tissue) differed in its mobility in agarose electrophoresis from that of rat testis cRABP.

Topics: Animals; Breast Neoplasms; Carrier Proteins; Female; Humans; Male; Neoplasm Proteins; Precancerous Conditions; Rats; Testis; Tretinoin; Uterus; Vitamin A

15 patients with superficial basaliomas or premalignant epithelial neoplastic disorders (actinic keratosis, leukoplakia, Bowen's disease) were treated locally over three weeks with retinoic acid (RA) alone or in combination with 5-fluorouracil (5-FU). In 11 cases the lesions disappeared clinically, however, only 5 patients proved to be cured by histological examination. 4 of them were treated with RA combined with 5-FU. There was a decrease of the 3H-index after the first week and an increase after the third week of treatment. These findings suggest, that RA inhibits the proliferation of neoplastic keratinocytes and stimulates the proliferation of normal epidermal cells. Retinoic acid, therefore, has an inhibitory effect on epithelial neoplasias, particularly in combination with 5-FU. Since local therapy with RA and 5-FU is not sufficient for routine clinical purposes in all cases, their use should be restricted to selected patients.

Topics: Aged; Carcinoma, Basal Cell; Drug Therapy, Combination; Female; Fluorouracil; Humans; Keratosis; Leukoplakia; Light; Lip Neoplasms; Male; Middle Aged; Mouth Neoplasms; Neoplasms, Radiation-Induced; Precancerous Conditions; Scalp; Skin Neoplasms; Thorax; Tretinoin; Vitamin A

The antihyperplastic activity of beta-retinoic acid (RA) and nine synthetic analogues (retinoids) was examined in organ cultures of mouse prostate made hyperplastic by treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After 8 or 10 days, when most explants developed hyperplasia, the carcinogen was withdrawn and explants were incubated in control medium and medium containing different concentrations of a retinoid. The antimitotic activity of retinoids was compared with that of RA. Different retinoids produced variable degrees of mitotic inhibition in the hyperplastic prostate epithelium. The methylketo cyclopentenyl and 1-methoxyethyl cyclopentenyl analogues of RA were at least 50-fold more active than RA in reversing MNNG-induced hyperplasia. The trimethylmethoxyphenyl analogue of RA and retinyl methyl ether were significantly more active than RA. Three analogues, N-acetyiretinylamine, retinal acetyl hydrazone, and retinal oxime, were as active as RA. The chlorotrimethylphenyl analogue showed less activity than RA, and alpha-retinyl acetate was completely devoid of mitotic inhibitory activity.

Topics: Cell Division; Epithelium; Hyperplasia; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Organ Culture Techniques; Precancerous Conditions; Prostate; Prostatic Neoplasms; Structure-Activity Relationship; Tretinoin; Vitamin A

Topics: Animals; Carcinoma, Basal Cell; Humans; Neoplasms, Experimental; Papilloma; Precancerous Conditions; Skin Diseases; Skin Neoplasms; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Animals; Epithelium; Female; Humans; Lung Neoplasms; Mammary Neoplasms, Experimental; Neoplasms; Neoplasms, Experimental; Nutritional Requirements; Precancerous Conditions; Skin Neoplasms; Structure-Activity Relationship; Tretinoin; Urinary Bladder Neoplasms; Vitamin A; Vitamin A Deficiency

An objective system for histopathological and statistical evaluation of rat bladder lesions induced by the carcinogen, N-methyl-N-nitrosourea, is described. This system has been used to measure the inhibitory effects of 13-cis-retinoic acid on the development of bladder cancer in female Wistar/Lewis rats. 13-cis-Retinoic acid caused significant inhibition of development of both preneoplastic and neoplastic lesions in bladder epithelium.

Topics: Animals; Epithelium; Female; Methylnitrosourea; Neoplasms, Experimental; Precancerous Conditions; Rats; Statistics as Topic; Tretinoin; Urinary Bladder Neoplasms; Vitamin A