CCNU-adriamycin association induces earlier and more severe nephropathy in rats.
Adriamycin (ADR) has a broad spectrum of antitumoral activity but is ineffective against human brain tumors. However, such tumors can be sensitive to a combination of adriamycin and lipophilic antineoplastic agents such as the nitrosoureas. CCNU, a nitrosourea, induces cholestasis in the rat and ADR is predominantly excreted via the biliary route. We decided to investigate the effect of CCNU on the nephrotic syndrome induced by ADR. Female Wistar rats were injected with a single dose of 10 mg/kg ADR and 24 h later were force fed 20 mg/kg CCNU in a single dose. Animals were sacrificed 4, 8, 15, 21, 28 or 60 days after the injection of ADR. A high rate of fatality (60%) occurred after the 21st day of treatment. Biological changes (alkaline phosphatase, SGPT, bilirubin) and ultrastructural studies showed that CCNU and CCNU + ADR induced the same degree of cholestasis. With the administered dose, CCNU is not nephrotoxic, ADR induces a nephrotic syndrome and ADR + CCNU appeared more nephrotoxic. With ADR, visceral epithelial foot process fusion was seen on day 15 and tubulo-interstitial lesions and glomerulosclerosis on day 60. With ADR + CCNU fusion of the foot process was seen on day 4, glomerular vacuolation on day 8, tubulo-interstitial alterations on day 15 and glomerulosclerosis on day 60. For both ADR and ADR + CCNU wrinkling and thickening of the basement membrane of proximal tubular cells were seen on day 60. Lipid mesangial overload was seen with ADR and was more intense with ADR + CCNU on day 60. CCNU hepatoxicity modifies the excretion of ADR and the predominantly renal excretion of ADR seems to induce earlier renal alterations in ADR + CCNU-treated rats. This study supports the concept that lipid mesangial overload may play an important role in chronic progressive glomerulosclerosis and thus the ADR + CCNU combination appears to be an interesting model in which to study these relationships.
Raguenez-Viotte
G
G
INSERM U 295 U.E.R., Médecine-Pharmacie, Université de Rouen, St.-Etienne du Rouvray, France.
Lahoue
M
M
Ducastelle
T
T
Morin
J P
JP
Fillastre
J P
JP
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood / Q000652:urine; D004317:Doxorubicin / Q000633:toxicity*; D004357:Drug Synergism; D005260:Female; D007668:Kidney / Q000473:pathology / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008130:Lomustine / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D014280:Triglycerides / Q000097:blood
D001798:Blood Proteins; D014280:Triglycerides; D008130:Lomustine; D004317:Doxorubicin; D002784:Cholesterol; D003404:Creatinine