Pharmacological and toxicological aspects of 4-demethoxy-3 '-deamino-3 '-aziridinyl-4 '-methylsulphonyl-daunorubicin (PNU-159548): A novel antineoplastic agent
C. Geroni et al., Pharmacological and toxicological aspects of 4-demethoxy-3 '-deamino-3 '-aziridinyl-4 '-methylsulphonyl-daunorubicin (PNU-159548): A novel antineoplastic agent, CANCER RES, 61(5), 2001, pp. 1983-1990
4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-1
59548) belongs to a novel class of antitumor compounds (termed alkycyclines
) and is currently undergoing phase II clinical trial. In the present study
, we investigated the in vitro and in vivo antitumor activity. the pharmaco
kinetics, and the toxicological profile of this compound. PNU-159548 showed
good cytotoxic activity in murine and human cancer cells growing in vitro,
with an average concentration for 50% growth inhibition of 15.8 ng/ml. The
drug showed strong antitumor efficacy in vivo after i.v. and p.o. administ
ration against rapidly proliferating murine leukemias and slowly growing tr
ansplantable human xenografts. At nontoxic doses, PNU-159548 produced compl
ete regression and cures in ovarian, breast, and human small cell lung carc
inomas. Fourteen of 16 models studied, including colon, pancreatic, gastric
, and renal carcinomas, astrocytoma and melanoma, were found to be sensitiv
e to PNU-159548. In addition, PNU-159548 was effective against intracranial
ly implanted tumors. Toxicological studies revealed myelosuppression as the
main toxicity in both mice and dogs. The maximum tolerated doses, after a
single administration, were 2.5 mg/kg of body weight in mice, 1.6 mg/kg in
rats, and 0.3 mg/kg in dogs. In the cyclic studies, the maximum tolerated d
oses were 0.18 mg/kg/day (cumulative dose/cycle: 0.53 mg/kg) in rats and 0.
05 mg/kg/day (cumulative dose/cycle: 0.1.5 mg/kg) in dogs. PNU-159548 showe
d minimal cardiotoxicity, when compared with doxorubicin in the chronic rat
model at a dose level inducing similar myelotoxicity. Animal pharmacokinet
ics, carried out in mice, rats, and dogs, was characterized by high volumes
of distribution, plasma clearance of the same order of the hepatic blood f
low, and short terminal half-life. These findings support the conclusion th
at FNU-159548 is an excellent candidate for clinical trials in the treatmen
t of cancer.