Clinical pharmacology of a novel diarylsulfonylurea anticancer agent.

Abstract

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.

Hypoprothrombinemia from coadministration of sulofenur (LY 186641) and warfarin: Report of three cases

“…Phase I trials established an acceptable toxicity profile and a maximum tolerated dose for the drug [1,2] The three cases reported here represent the only three patients in whom Solufenur and warfarin were coadministered. In all three, a marked prolongation of PT occurred while the two drugs were given, which promptly corrected when the Sulofenur was discontinued.…”

Effects of Sulfonylureas on Tumor Growth: A Review of the Literature

“…First-generation DSUs, which are structurally similar to glibenclamide with an unknown anticancer mechanism, reached clinical application in some cases but with poor tolerability and disappointing results [50,54,55].…”

“…Since the end of the 1980s, the anticancer effects of DSUs-compounds structurally similar to oral antidiabetic glibenclamidehave been described in vitro and in vivo [50]. In particular, several authors reported antitumor activity of N-(4-methylphenylsulfonyl)-NЈ-(4-chlorophenyl)urea (LY181984) and N-(5-indanylsulfonyl)-NЈ-(4-chlorophenyl)urea (LY186641; sulofenur) in in vitro and in vivo models of solid tumors, with modest activity in hematologic cancer [50 -53].…”

“…The anticancer effects of sulofenur on solid tumors were also explored in phase I and II clinical trials [50,54,55]. On the basis of partial response observed in the phase I trial in a ovarian cancer patient [50], the phase II trial was designed to elucidate response rates and toxicity profile in stage III-IV previously treated ovarian cancer patients [54].…”

“…On the basis of partial response observed in the phase I trial in a ovarian cancer patient [50], the phase II trial was designed to elucidate response rates and toxicity profile in stage III-IV previously treated ovarian cancer patients [54]. Sulofenur at the daily dose of 800 mg/m 2 showed prolonged stable disease (median: 20 weeks) in 42% of the study population and partial response (6.5-18 weeks) in 15% of the patients.…”