COMPARISON OF THE CHRONIC TOXICITY OF PIROXANTRONE, LOSOXANTRONE AND DOXORUBICIN IN SPONTANEOUSLY HYPERTENSIVE RATS

Comparisons were made of the toxic effects produced in the heart, kidn ey and small intestine of spontaneously hypertensive rats (SHR) by the administration of 12 consecutive weekly doses of doxorubicin (I mg/kg ), and high, intermediate and low doses of piroxantrone (3, 1.5 and 0. 75 mg/kg) and losoxantrone (1, 0.5 and 0.25 mg/kg). Animals receiving saline were used as controls. The toxicities of the three drugs were e valuated by clinical chemistry and hematological determinations, light microscopy and transmission electron microscopy. The severity of the histologic alterations in heart, kidney and small intestine was assess ed semiquantitatively. Biochemical and molecular modeling studies were made to evaluate the formation of complexes of Fe(III) with piroxantr one and losoxantrone. The cardiac (myofibrillar loss and dilatation of the sarcoplasmic reticulum) and renal (glomerular vacuolization, tubu lar damage and laboratory evidence of a nephrotic syndrome) lesions in duced by all three agents had similar features. However, the cardiac l esions induced by losoxantrone and doxorubicin were significantly more severe (Billingham scores) than those produced by piroxantrone. The r enal lesions induced by piroxantrone and losoxantrone were less severe than those produced by doxorubicin. Similarly losoxantrone and piroxa ntrone-induced intestinal alterations (denudation of epithelial layer and inflammatory cellular infiltration) were less severe than those oc curring after treatment with doxorubicin. Both losoxantrone and piroxa ntrone were shown to form Fe(III): drug complexes that may cause oxida tive damage to various tissues. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.