The effects of the linkage of
daunorubicin (DNR) and the synthetic biodegradable
polymer polyhydroxyethyl-
L-glutamine (
PHEG) on general toxicity, therapeutic efficacy, and acute organ toxicity were investigated. General toxicity was assessed by means of mortality, or
body weight changes of male CBA mice weighing 22-25 g after a single-dose i.p. administration of 5 or 2.5 mg/kg DNR, free or bound. Linked DNR at a larger lethal dose significantly increased mean survival time (18 versus 12 days). Surprisingly, free DNR at a smaller dose produced larger increases in
body weight as compared with linked DNR. The linkage of DNR and
PHEG did not markedly change the therapeutic activity in three murine hemoblastoses--
plasmacytoma MOPS 406,
leukemia P388 and hemoblastosis La. Acute (24 h) changes in cardio- and hepatotoxicity were studied on female Wistar rats weighing 208 +/- 5 g after a single dose of 5 mg/kg i.v. both free and linked DNR, as well as after an administration of the
PHEG polymer alone (200 mg/kg i.v.). Free DNR caused a three-fold increase in
creatine kinase (CK) activity, the identical dose of linked DNR caused only a 1.7-fold increase. Free DNR administration resulted in a decrease in heart rate, other tested drugs did not significantly change either blood pressure or heart rate. Free DNR did not change the kinetics of
bromsulphalein (BSP) except for a decrease in extraction effectivity. Both linked DNR and
polymer alone significantly changed some kinetic parameters of BSP. The results showed that the biodegradable
polymer PHEG cannot be clinically used due to its hepatotoxic action. On the other hand, a decrease in total toxicity and
cardiotoxicity resulting from the linkage of DNR and
PHEG, the therapeutic efficacy being preserved, stimulates the efforts to find a suitable
polymer carrier of
anthracyclines without more serious side-effects.