Addition of morpholinomethyl substituents to
razoxane (ICRF-159) produced a compound (bis-4-morpholinomethyl-3,5-dioxopiperazinyl-1,2-
propane (
MM-159) considerably more water-soluble than
razoxane. The increased solubility allowed
MM-159 to be examined for protective activity against chronic
doxorubicin (DXR)
cardiotoxicity. Adult beagle dogs of either sex were given, i.v. at 3-week intervals, either DXR (1.75 mg/kg) alone or DXR 15 min after
MM-159 (25 mg/kg). Control animals received
MM-159 (25 mg/kg) or saline without DXR. The experiment was terminated 3 weeks after the ninth injection (total DXR dose, 15.75 mg/kg). Of the eight animals given DXR alone, five died after receiving seven to eight
injections (12.25-14 mg/kg DXR) and the remaining three were killed after eight
injections because they were in poor condition. Marked
ascites was noted in four of these eight dogs. When frequency and extent of myocardial lesions (vacuolation and myofibrillar loss) were assessed on a scale from 0 to 4+, severe lesions (3+) were present in all eight dogs given DXR alone, but no abnormalities (lesion score 0) were found in the hearts of three of eight dogs given
MM-159 and DXR and the five remaining animals in this group had minimal (1+; four dogs) or mild (2+; one dog) alterations. DXR reduced the erythrocyte count,
hemoglobin, and hematocrit when administered alone, but not in combination with
MM-159. Such protection against DXR hematologic effects was not noted previously when dogs were pretreated with
ICRF-187, the d-isomer of
razoxane, despite the fact that pretreatment with
ICRF-187 was as effective as
MM-159 in reducing chronic DXR
cardiotoxicity. It remains to be determined whether there are other differences in
biological activity between
MM-159 and
ICRF-187.