isotretinoin and Cocarcinogenesis

In 2001, we reported that mortality may have been higher with isotretinoin (30 mg/d for 3 years) than with placebo in the subgroup of current smokers among the 1,166 patients with definitively resected early-stage non-small cell lung cancer who participated in the randomized, controlled Lung Intergroup Trial. We report the overall and cause (cancer, cardiovascular disease, or other)-specific mortality associated with long-term isotretinoin after an extended median follow-up of 6.2 years that included the capture of cause-of-death data from 428 deceased patients. Overall mortality was 36.7% in each of the two trial arms, about two thirds related to cancer and one third to other or unknown causes. Overall and cancer deaths increased in current smokers in the isotretinoin arm during the treatment and the extended follow-up period. No mortality end point increased among never smokers and former smokers taking isotretinoin, and cancer deaths decreased marginally in this combined subgroup. Isotretinoin also increased deaths from cardiovascular disease in current smokers. The present analysis supports the safety of protracted isotretinoin use in the combined group of never smokers and former smokers, which has important public health implications, for example, for treating acne in young people. The increased mortality in current smokers in this study is further evidence of the multifaceted danger of active smoking. The overall indications of this study have public health implications for treating acne in young people and other uses of retinoids in smokers.

Topics: Acne Vulgaris; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cardiovascular Diseases; Cause of Death; Cocarcinogenesis; Combined Modality Therapy; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infections; Isotretinoin; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pneumonectomy; Proportional Hazards Models; Smoking

Studies were made on the inhibitory effects of CaCl2 and 13-cis-retinoic acid on induction of replicative DNA synthesis (RDS) in the pyloric mucosa of male F344 rats by the glandular stomach tumor promoter, NaCl. RDS in the pyloric mucosa showed a maximum of about a ten-fold increase 17 hr after administration of 3.3 M NaCl and returned to the control level 48 hr after the administration of NaCl. Administration of 400 mM CaCl2 1 hr before NaCl resulted in 60-80% inhibition of the increase in RDS 4-48 hr after NaCl administration. Administration of 20 to 400 mM CaCl2 1 to 2 hr before NaCl caused dose-dependent inhibition of the increase in RDS 17 hr after NaCl administration, with 400 mM CaCl2 causing 80-100% inhibition. Administration of 400 mM CaCl2 1 hr before NaCl also decreased the histological damage of the surface epithelial cells induced by NaCl. Administration of 13-cis-retinoic acid at doses of 10 micrograms-10 mg/kg body weight did not inhibit the increase in RDS in the pyloric mucosa that was induced by NaCl. These results suggest that CaCl2, but not 13-cis-retinoic acid, inhibits tumor promotion in the pyloric mucosa of rat stomach.

Topics: Animals; Calcium Chloride; Carcinogens; Cocarcinogenesis; DNA Replication; Gastric Mucosa; Isotretinoin; Male; Pylorus; Rats; Rats, Inbred F344; Sodium Chloride

The aim of the study was to analyze the incidence of spontaneous thymic lymphomas in AKR mice kept on a diet with normal and excess retinoid content. The mice whose diet was supplemented with 13-cis-retinoic acid (250 mg per kg chow) developed less lymphomas than those kept on a standard diet (15 mg per kg chow). The effect of cyclophosphamide on the early stage of lymphomogenesis was tested using a single dose (100 mg per kg body weight), injected intraperitoneally to AKR mice. Increased incidence of lymphoma following cyclophosphamide administration was observed as result of a) low sensitivity of prelymphoma and lymphoma cells and/or b) immunosuppressive effect of cyclophosphamide.

Topics: Animals; Cocarcinogenesis; Cyclophosphamide; Diet; Female; Injections, Intraperitoneal; Isotretinoin; Lymphoma; Male; Mice; Thymus Neoplasms; Tretinoin

Groups of Charles River Sprague-Dawley male rats were given intragastric intubations of methylbenzylnitrosamine after receiving one of the following diets for 4 weeks: control, zinc-deficient, or zinc-deficient diet plus 4% ethanol in the drinking water. One zinc-deficient group was zinc repleted after the dosing period; the other group, zinc-deficient plus 4% ethanol, received 13-cis-retinoic acid (13-cis-RA) after the dosing period. Zinc deficiency significantly enhanced esophageal tumor incidence; the addition of ethanol further enhanced tumor incidence. Zinc repletion reduced tumor incidence, whereas the addition of 13-cis-RA enhanced tumor incidence.

Topics: Animals; Body Weight; Cocarcinogenesis; Copper; Diet; Dimethylnitrosamine; Esophageal Neoplasms; Ethanol; Isotretinoin; Male; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Tretinoin; Zinc

Topics: Acne Vulgaris; Animals; Cocarcinogenesis; Etretinate; Humans; Immunity; Isomerism; Isotretinoin; Keratosis; Polyamines; Psoriasis; Skin; Skin Diseases; Teratogens; Tretinoin; Triglycerides; Vitamin A