Investigation of doxorubicin tissue toxicity: does amifostine provide chemoprotection? An experimental study.

This experimental animal study of 12-weeks' duration, involving Wistar rats, tested the possible chemoprotection of Doxorubicin (adriamycin), cardiomyopathy and other toxicities by Amifostine. One hundred and five animals were divided into 3 groups: Groups A, B and C, which had Doxorubicin, simultaneous Doxorubicin and Amifostine treatment and normal saline for control, respectively. Treatment was administered once weekly for 12 consecutive weeks. The doses of each drug were appropriately calculated on the basis of other experiments in the literature and given in analogous dosage to human kilograms of body weight. Euthanasias and autopsies of six animals at a time from each animal group were performed on weeks 3, 6, 8, 10 and 12. The blood, heart, lung, liver, aorta, thymus, spleen, kidneys, adrenals, testis and ovaries and muscle and lipoid tissue were examined macroscopically and microscopically. Biochemical liver and kidney examinations, full blood count and serum lipids were examined before and during the weeks of treatment and autopsies. Increased cholesterol and triglycerides from the 6th week towards the end of the experiment and a gradual increase in cardiomyopathy were found, particularly in Group A. The findings were similar in Group B, except for the timing (the increase of serum lipids and the serious cardiac lesions were delayed by two weeks). No abnormalities were detected in the controls, Group C. In conclusion, Amifostine does not seem to be cardioprotective when administered with Doxorubicin, since it only delays the onset of cardiac lesions. In in vitro testing, Amifostine was found to be a scavenger of the oxygen-free radicals which are produced by Doxorubicin.

The effect of doxorubicin and its analogue mitoxantrone on cardiac muscle and on serum lipids: an experimental study.

This experimental study compares the toxic effect of the two cytotoxic drugs, doxorubicin and mitoxantrone, on cardiac muscle and on serum lipids. The cardiotoxicity of doxorubicin due to the cumulative effect of repeated administration is known. A relative compound, mitoxantrone, is a member of the androstenedione class of synthetic antitumor agents and its chemical structure, based on a quinone ring, is similar to that of doxorubicin. Doxorubicin has wide application in cancer medicine but its dose-limited cardiac effect creates the need for a substitute compound. Mitoxantrone, also an effective agent, may be able to cover this need. Three groups of 35 Wistar rats were used during this experimental study of 12 weeks' duration. Drugs at a certain calculated dose were administered once weekly. Group A animals were treated with doxorubicin, Group B with mitoxantrone and Group C, the controls, with normal saline. Six animals per group were autopsied after euthanasia in the 3rd, 6th, 8th, 10th and 12th weeks. Cardiac muscle, liver and other organs, plus blood, were removed for macro- and microscopical, and biochemical tests. Our results showed that there was a cumulative toxic effect of doxorubicin (adriamycin) on cardiac muscle starting in the 6th week which gradually increased to Grade III lesions by the 10th and 12th weeks. In parallel, an increase in serum lipids, mainly cholesterol and triglycerides was observed. Mitoxantrone-treated animals showed moderate cardiotoxic lesions (but not cumulative) and no increase in serum lipids. In vitro testing of oxygen-free radical production showed high production by doxorubicin and very low production by mitoxantrone. Thus, mitoxantrone appears to be safer than doxorubicin.