Abstract
Dihydroxyanthraquinone (DHAQ; NSC 279836) is a recently synthesized compound that is structurally similar to Adriamycin and produces greater antitumor effects in murine model systems. We compared DHAQ to Adriamycin in rats, with and without irradiation of the chest at various intervals after drug treatment. A single injection of Adriamycin (1 mg/kg i.p.) had little effect on animal survival, even if combined with radiation (12 Gy 25 MV X-rays), >90% being alive at 1 year. A single injection of DHAQ (3 mg/kg i.p.) was equally uneffective up to 200 days after treatment (survival, >90%). However, between 200 and 370 days after treatment, all animals died, producing a median survival time of 280 days. Further, when DHAQ was combined with radiation, there was an increase in animal deaths between Days 30 and 200. For animals irradiated on Days 0, 43, and 93 after DHAQ treatment, only 50, 75, and 80%, respectively, survived to Day 200. All animals that survived past Day 200 subsequently died by 1 year, displaying the same kinetics of lethality as those animals that had received DHAQ only. A repeat experiment using DHAQ at 1 mg/kg produced similar results. Based on these findings, we conclude that DHAQ produces a long-term (>200 days) toxicity in rats that is not detectable by short-duration toxicity screening. In addition, radiation enhances short-term (<200 days) lethality, with the degree of enhancement decreasing as the interval between drug and radiation is increased.
This investigation was supported in part by BRSG S07 RR05373 awarded by the Biomedical Research Support Grant Program, Division of Research Resources, NIH, and USPHS Grant CA 29017, awarded by the National Cancer Institute, Department of Health and Human Services.
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