Clinical pharmacology of a novel diarylsulfonylurea anticancer agent.
LY186641 (diarylsulfonylurea, [DSU]) is a novel anticancer agent because of its unique diarylsulfonylurea chemical structure, broad-spectrum antisolid-tumor activity in preclinical models, presumed novel mechanism of action and preclinical toxicities of methemoglobinemia (Met Hgb) and decreased red blood cell (RBC) survival. In this study, the in vitro drug sensitivity of human tumors as well as clinical pharmacology and toxicology of DSU in patients with cancer were examined. DSU was administered orally, daily for 7 days with a 3-week treatment cycle. Dose-limiting toxicities were Met Hgb and RBC hemolysis. The maximum-tolerated dose was found to be 1,200 mg/m2/d for 7 days. In pharmacokinetic studies, DSU was found to have a prolonged serum half-life (approximately 30 hours) and a large area under the plasma disappearance curve (8,883.3 micrograms.hr/mL at 1,200 mg/m2/d). A partial remission was observed in one patient with refractory ovarian cancer. In conclusion, DSU can be safely administered to cancer patients and does display antitumor activity. Potential means of obviating the toxicities of this compound are discussed.
Taylor
C W
CW
Department of Internal Medicine, University of Arizona College of Medicine, Tucson 85724.
Alberts
D S
DS
Ketcham
M A
MA
Satterlee
W G
WG
Holdsworth
M T
MT
Plezia
P M
PM
Peng
Y M
YM
McCloskey
T M
TM
Roe
D J
DJ
Hamilton
M
M
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013453:Sulfonylurea Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D013453:Sulfonylurea Compounds; C058179:sulofenur