Dose-response relationship of dexrazoxane for prevention of doxorubicin-induced cardiotoxicity in mice, rats, and dogs.

Dexrazoxane [(DZR), ADR 529, ICRF-187] ameliorates doxorubicin (DOX)-induced cardiotoxicity in animals, and is recommended as a cardioprotectant in patients receiving cumulative doses of DOX above 300 mg/m2. A DZR:DOX dose ratio of 10:1 is recommended based on studies in patients receiving 50 mg/m2. Since DOX may be used at much higher doses in certain clinical settings, we evaluated the ability of DZR to protect against cardiomyopathy in animals given bolus doses of DOX at varying dose levels. The severity and extent of the cardiomyopathy were evaluated histologically and expressed as the mean total score (MTS). Mice were given 10 doses of DOX (2 or 4 mg/kg) over a 7-week period. Without DZR, the MTS 4 weeks after the last treatment was 3.7 with 4 mg/kg DOX and 1.3 with 2 mg/kg DOX. DZR at 5:1, 10:1, and 20:1 dose ratios caused a dose-dependent decrease in the MTS but was less efficacious with the higher, more cardiotoxic dose of DOX. Rats were given DOX at 0.2, 0.4, and 0.8 mg/kg with a 20:1 ratio of DZR weekly for 13 weeks. Cardiomyopathy was most severe with the highest dose of DOX in the absence of DZR, especially in males, and progressed during the 6 weeks following the last treatment. DZR reduced the MTS in both sexes but in the males given the highest dose of DOX, there was still a significant amount of cardiac damage compared to vehicle-treated controls. Dogs were given 0.1, 0.3, and 0.8 mg/kg DOX with 20:1 DZR for 13 weeks. DZR reduced the MTS significantly (P < 0.05) in males and females but cardiac lesions were still present in each of the DZR-treated dogs. The results indicate that although DZR is highly effective in attenuating the cardiomyopathy caused by DOX, dose ratios of DZR:DOX capable of providing total or nearly complete cardioprotection at low doses of DOX are less efficacious at higher doses of DOX. One possible explanation for this effect is the marked pharmacokinetic difference between DZR and DOX, with DZR undergoing a much more rapid rate of elimination from the body compared to DOX. These findings point to the need for further studies to optimize the dose scheduling of DZR before using it clinically with bolus doses of DOX above those currently recommended.

Long-lasting effect of dexrazoxane against anthracycline cardiotoxicity in rats.

The long-lasting protective effect of dexrazoxane (ADR-529) against doxorubicin- and epirubicin-induced cardiotoxicity was evaluated in the multiple-dose 35-wk rat model. Groups of 36 male Sprague-Dawley rats were given ADR-529 30 min before administration of cardiotoxic doses of doxorubicin (1 mg/kg/wk) or epirubicin (1.13 mg/kg/wk). The compounds were intravenously injected once weekly for 7 consecutive wk at ADR-529; anthracycline ratios ranging from 5:1 to 20:1. These ratios covered the entire chemotherapeutic range in humans and allowed studying the chronic progressive cardiomyopathy in our rat model. Animals were observed for up to 35 wk to follow the time course of the well-characterized cardiomyopathy, which was evaluated through the well-established qualitative/quantitative morphological grading. It was clearly demonstrated in this rat model that ADR-529, at the ratios administered, provided ample cardioprotection for a duration of 35 wk, which corresponds to 25 yr of equivalent human time.

Evaluation of 4'-iodo-4'-deoxydoxorubicin-induced cardiotoxicity in two experimental rat models.

In the present study, 1 single-dose and 1 multiple-dose models were applied in studying 4'-iodo-4'-deoxydoxorubicin (I-DX) cardiotoxicity. Anthracycline cardiotoxicity has been reproduced in several animals including mice, rats, hamsters, rabbits, dogs, and monkeys. Of these species the rat can be considered the most suitable species for the study of anthracycline-induced cardiomyopathy. The cardiotoxicity induced by I-DX in male Sprague-Dawley rats was compared to that of doxorubicin (DX), used as standard positive control. Groups of 36-42 rats were observed for up to 35 wk to follow the progression of the lesions. Cardiomyopathy was evaluated through well-established qualitative/quantitative morphological grading. The new DX derivative proved to be clearly less cardiotoxic than DX with both treatment schedules. Although both models can be considered useful for evaluating and comparing the cardiotoxicity of new anthracycline derivatives and mimicking the transvenous endomyocardial biopsies in humans, the chronic test seems to be more suitable for compounds like I-DX, which possess a low cardiotoxic potential and which could go undetected in the single-dose test.

Renal function of isolated perfused kidneys from hypertensive (MHS) and normotensive (MNS) rats of the Milan strain at different ages.

Young pre-hypertensive rats of the Milan strain (MHS) have a faster glomerular filtration rate (GFR) and a higher urine flow in vivo than matched normotensive controls (MNS). Kidneys from both MHS and MNS at different ages were perfused in vitro with cell-free artificial medium, in order to further clarify the nature of these differences, in the absence of extrarenal uncontrolled factors. Isolated kidneys from young MHS showed a faster GFR, a larger tubular Na+ reabsorption and urine flow as compared to matched MNS: such differences endured throughout the 2 h of perfusion. These results support an intrinsic kidney abnormality as causing the above described differences between young rats of the two strains. Isolated kidneys from adult MHS showed faster GFR, higher renal perfusion flow and urine flow, yet similar tubular Na+ reabsorption when compared to MNS. Moreover a faster decay in kidney function was observed in the experiments with MHS. The existence of an extrarenal factor(s) correcting the intrinsic MHS kidney abnormality in vivo is suggested, as no differences were reported in kidney function of intact adult animals.