Renal tissue injury and proliferative response after successive treatments with anticancer platinum derivatives and tobramycin.
The administration of anticancer platinum derivatives such as cisplatin, or aminoglycoside antibiotics is frequently associated with tubular necrosis which can eventually lead to acute renal failure. Previously, we have shown that renal tissue injury induced by these drugs elicits a process of tissue repair involving the stimulation of cell proliferation. The present study was undertaken to examine the morphological alterations and the proliferative response resulting from tobramycin administration to animals previously challenged with the platinum derivatives cisplatin and carboplatin. Female Sprague-Dawley rats were treated i.p. with cisplatin (8 mg/kg delivered in four daily injections) or carboplatin (40 mg/kg given in one injection) and sacrificed 21 or 60 days after drug administration. Tobramycin was administered i.p. twice a day at a daily dose of 10 mg/kg over the ten days preceding sacrifice. At 1 h before sacrifice, each animal received i.p. 200 microCi of [3H] thymidine for the measurement of DNA synthesis and cell proliferation (determined by histoautoradiography). Successive treatments with cisplatin and tobramycin appeared to produce an increase in the severity of histopathological alterations such as tubular necrosis and cystic degeneration. Moreover, cisplatin pretreatment dramatically increased the severity of tobramycin-induced lysosomal phospholipidosis. Histopathological alterations were followed by an important proliferative response partly associated with tubular regeneration but also due to fibroblastic proliferation which led to peritubular fibrosis. Surprisingly, the additive effect of cisplatin and tobramycin on renal injury became particularly striking with increasing time intervals between treatments. In contrast, successive treatments with carboplatin and tobramycin did not cause significative changes of the degree of renal injury, compared with either drug given alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Nonclercq
D
D
Laboratoire d'Histologie, Faculté de Médecine, Université de Mons-Hainaut, Belgium.
Toubeau
G
G
Tulkens
P
P
Heuson-Stiennon
J A
JA
Laurent
G
G
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016190:Carboplatin / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014031:Tobramycin / Q000633:toxicity*
D010743:Phospholipids; D004247:DNA; D016190:Carboplatin; D002945:Cisplatin; D014031:Tobramycin