Lack of cardiotoxicity of a new antineoplastic agent, a synthetic derivative of indenoisochinoline: comparison with daunorubicin in rabbits

Abstract

The effect of repeated i.v. administration (once weekly, 12 administrations) of a new antineoplastic agent, Oracin (6-[2-(2-hydroxyethyl)aminoethyl]-5, 11-dioxo-5,6-dihydro-11 H-indeno [1,2-c]-isochinoline hydrochloride, 10 mg/kg) and daunorubicin (3 mg/kg) were investigated in rabbits in vivo. The criterion of occurrence of cardiotoxicity was compared with a control group of animals. Noninvasive polygraphic records were used to evaluate the function of the heart. The morphological changes of the heart were evaluated after the death of animals. There were no significant changes found in the ratio of the pre-ejection period/left ventricular ejection time (PEP: LVET ratio) after administration of Oracin (values between 0.3080 and 0.3310) or in the control group (values between 0.3425 and 0.3885). The administration of daunorubicin induced a significant, progressive increase in the PEP: LVET ratio (0.3775-0.9473), which was significantly different both from the Oracin-treated and the control group of animals. Histological examination of the hearts from the control group revealed normal structure of the myocardium including minute changes (dispersed cardiomyocytes with intensively eosinophilic cytoplasm, and several single cells with degenerated myofibrils) similar to the normal changes in muscle tissue. A very similar scenario was found in the Oracin group with the exception of one case where a slightly higher number of degenerated and necrotic cells was occurring. Administration of daunorubicin resulted in severe dispersed damage of the myocardium (myocytolysis with subsequent interstitial fibrosis), the changes being markedly different from those of the Oracin treatment and the control group. On the basis of our results it is possible to conclude that the administration of Oracin (10 mg/kg i.v.) did not induce signs of cardiotoxicity in rabbits in vivo.

Cardiac troponin T as a marker of myocardial damage caused by antineoplastic drugs in rabbits

“…The dose of Oracin was chosen on the basis of the results of a preceding study of toxicity (the LD 50 after i.v. administration in rats was 62 mg/kg in male and 74 mg/kg in female animals; GersÏ l et al 1996). No signi®cant increase in cTnT levels was found, and the measurement of systolic time intervals and histological examinations of the heart also suggest that the eects of repeated administration of Oracin (at a weekly dose of 10 mg/kg) on myocardium can be regarded as very separate and very dierent from the cardiotoxic eects of daunorubicin.…”

“…The long-term intravenous administration of daunorubicin in rabbits is considered to be a satisfactory animal model for anthracycline-induced cardiomyopathy (GersÏ l and Hrdina 1994;GersÏ l et al 1996). In our study, this model was used to compare the eects of a new antitumour agent Oracin {6-[2-(2-hydroxyethyl) aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno [1,2-c]-isoquinoline hydrochloride; molecular formula: C 20 H 19 N 2 O 3 áHCl; molecular mass of the free base: 370.9 Da} with daunorubicin (molecular formula of daunorubicin hydrochloride: C 27 H 29 NO 10 áHCl; molecular mass: 563.99 Da) from the view point of their possible cardiotoxicity.…”

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…Pharmacokinetic studies show that oracin carbonyl undergoes reduction to form dihydrooracin, which abolishes the therapeutic efficacy of this drug. The absence of cardiotoxicity is one of the key advantages of using this drug (Gersl et al, 1996). In human liver microsomes 11β-hydroxysteroid dehydrogenase type 1 (an SDR member) have been found to participate in oracin reduction, whereas in the cytosol three members of AKR1C family do this.…”

Possibilities to increase the effectiveness of doxorubicin in cancer cells killing

“…ORC, a potential anticancer agent, is rapidly absorbed from the gastrointestinal tract and possesses a good bioavailability. Its acute, subchronic, and chronic toxicity is low, and antioxidant effects are not expected (Adamcova et al, 1999;Gersl et al, 1996;Schimmel et al, 2004). In breast cells, CBR1 is the principal enzyme in reducing ORC and has significantly higher affinity to ORC than to DOX (Gavelova et al, 2008).…”