phenanthrenes and Sarcoma

Chinese-herb nephropathy (CHN) is a rapidly progressive renal fibrosis associated with the intake of a Chinese herb (Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acids (AA). This study attempted to reproduce the main features of human CHN (renal failure, tubular atrophy, and interstitial fibrosis) in a rat model similar to that of cyclosporin-induced nephropathy. Salt-depleted male Wistar rats received daily subcutaneous injections of either 1 mg/kg body wt AA (low-dose AA group), 10 mg/kg body wt AA (high-dose AA group), or vehicle (control group) for 35 d. On days 10 and 35, assessment of renal function, measurements of urinary excretion of glucose, protein, and leucine aminopeptidase, and histologic analyses were performed (six rats euthanized/group). High-dose AA induced glucosuria, proteinuria, and elevated serum creatinine levels and reduced leucine aminopeptidase enzymuria on days 10 and 35, whereas low-dose AA had no significant effect. Tubular necrosis associated with lymphocytic infiltrates (day 10) and tubular atrophy surrounded by interstitial fibrosis (day 35) were the histologic findings for the high-dose AA-treated rats. In both AA groups, urothelial dysplasia was also observed, as well as fibrohistiocytic sarcoma at the injection site. A short-term model of AA-induced renal fibrosis was established in salt-depleted Wistar rats. These results support the role of AA in human CHN and provide a useful model for examination of the pathophysiologic pathways of renal fibrosis.

Topics: Animals; Aristolochic Acids; Body Weight; Carcinoma, Transitional Cell; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Fibrosis; Injections, Subcutaneous; Kidney; Kidney Failure, Chronic; Kidney Tubules; Male; Pelvic Neoplasms; Phenanthrenes; Rats; Rats, Wistar; Reference Values; Sarcoma; Sodium Chloride; Survival Analysis

Patients with objectively measurable soft tissue sarcoma, bone sarcoma, or mesothelioma who had failed at least one prior chemotherapy regimen received either bleomycin (20 U/M2 i.v. day 1 each week), chlorozotocin (150 mg/M2 i.v. q6 weeks), MGBG (500 mg/M2 i.v. each week, escalated in 50 mg/M2 weekly increments to a maximum dose of 700 mg/M2), or bruceantin (5.5 mg/M2 days 1, 8, 15, and 22, with cycles repeated every 6 weeks). One hundred eighty patients were evaluable: 53 on bleomycin, 51 on chlorozotocin, 38 on MGBG, and 38 on bruceantin. Two partial responses resulted from bleomycin, and one each from chlorozotocin and MGBG. Both responders on bleomycin had mesothelioma. Seventy-four percent of the patients were of ECOG performance status 0 or 1, and over half on each arm had moderate or worse toxicity. At these doses and schedules, none of the four drugs tested was active against previously treated sarcomas. Bleomycin, however, should be considered for further evaluation in mesothelioma patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Bleomycin; Bone Neoplasms; Drug Evaluation; Female; Glaucarubin; Humans; Male; Mesothelioma; Middle Aged; Mitoguazone; Phenanthrenes; Quassins; Sarcoma; Soft Tissue Neoplasms; Streptozocin

Topics: Animals; Antineoplastic Agents; Benz(a)Anthracenes; Benzopyrenes; Carcinogenesis; Carcinogens; Glycols; Hydrocarbons; Methylcholanthrene; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Phenanthrenes; Research; Sarcoma; Sarcoma, Experimental

Topics: Antiviral Agents; Bacteriophages; Orthomyxoviridae; Phenanthrenes; Phenanthridines; Pseudomonas aeruginosa; Sarcoma; Sarcoma, Experimental