Radical dimer rescue of toxicity and improved therapeutic index of adriamycin in tumor-bearing mice.
The product of adriamycin (ADR) reductive glycosidic cleavage is the pharmacologically inactive 7-deoxyadriamycin aglycone. Bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) (DHM3) is a radical dimer which reacts with ADR in vitro to produce this aglycone. We utilized DHM3 to prevent ADR toxicity in mice. CD2F1 male mice were given a single dose of ADR, 25 mg/kg i.p., which was acutely lethal as indicated by a median survival time of 7 days. DHM3 administered as a single i.p. dose of 50 mg/kg 15 or 30 min following ADR provided significant protection with median survival times greater than 9 wk. Mice bearing ascitic L1210 leukemic cells were given ADR, 0, 6.6, 15, or 25 mg/kg i.p. 1 day following inoculation of tumor. DHM3 administered as a single 50 mg/kg i.p. dose 20 min after ADR had no significant effect on ADR efficacy at the lower dose range (% treated versus control = 171 and 285 for 6.6 and 15.0 mg/kg, respectively). Less than 15% of the animals in these treatment groups were long-term survivors. However, following high doses of ADR (25 mg/kg), DHM3 protected mice from ADR lethality and over 70% of animals were long-term survivors. The determination of parent ADR and ADR aglycone content in several tissues indicated that the concentration of ADR was reduced in those animals that received DHM3 15 min after ADR. Correspondingly an increase in ADR aglycone concentration in each tissue resulted from DHM3 treatment. DHM3 represents a novel class of compounds that can ameliorate ADR toxicity and has potential use as a rescue agent.