Ultrastructural evidence of cardiac damage resulting from thoracic irradiation and anthracyclines in the rat.

The effects of radiation combined with Adriamycin (ADR) or Dihydroxyanthraquinone (DHAQ, NSC 279836) on the induction of cardiomyopathy in the rat were investigated using electron microscopy. Rats were treated with ADR or DHAQ at 2.5, 5.0, or 10 mg/kg ip; thoracic irradiation at 12, 15, 18, 21, or 24 Gy of 25 MV X rays; or a combination of either drug at 5.0 mg/kg plus 15 Gy X rays. Survival times were observed to be linear, inverse functions of the dose of drug or radiation received. Combinations of ADR plus radiation produced an increased lethality while the combination of DHAQ and radiation produced similar lethality as DHAQ alone. Even for treatments that resulted in animal lethality, there was little histological evidence of abnormality observed in heart tissues by light microscopy. On the other hand, electron microscopic examination of cardiac tissues demonstrated dramatic decreases in mitochondrial number and destruction of mitochondrial structure. The treatments could be arranged in order of increasing severity of the damage produced as follows: 5 mg/kg ADR, 15 Gy X ray, 5 mg/kg DHAQ, 5 mg/kg ADR + 15 Gy X ray, 24 Gy X ray, and 5 mg/kg DHAQ + 15 Gy X ray. In several cases, mitochondrial abnormalities were sufficient so as to allow cardiomyopathy to be cited as the cause of death. These results indicate that electron microscopy can be used to document cellular changes that may only be functionally expressed as long-term normal tissue damage or animal lethality. The finding that DHAQ can produce significant cardiotoxicity, and that this cardiotoxicity is enhanced by concomitant thoracic irradiation, suggest caution while this drug is being investigated for clinical use.