Changes in the toxicity and therapeutic efficacy of daunorubicin linked with a biodegradable carrier.
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.
Hrdina
R
R
Institute of Experimental Biopharmacy, Czechoslovak Academy of Sciences, Hradec Králove.
Bogusová
T A
TA
Kunová
A
A
Kvĕtina
J
J
D000818:Animals; D001372:Aza Compounds / Q000737:chemistry*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D003630:Daunorubicin / Q000627:therapeutic use / Q000633:toxicity*; D004337:Drug Carriers / Q000008:administration & dosage*; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007941:Leukemia P388 / Q000188:drug therapy* / Q000401:mortality; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009570:Nitriles / Q000737:chemistry*; D010455:Peptides; D010954:Plasmacytoma / Q000188:drug therapy* / Q000401:mortality; D011741:Pyrimidine Nucleosides / Q000737:chemistry*; D013448:Sulfobromophthalein / Q000493:pharmacokinetics
D001372:Aza Compounds; D004337:Drug Carriers; D009570:Nitriles; D010455:Peptides; D011741:Pyrimidine Nucleosides; D013448:Sulfobromophthalein; C027887:poly-N(5)-(2-hydroxyethyl)glutamine; D003402:Creatine Kinase; D003630:Daunorubicin