benzofurans and sulofenur

Diarylsulfonylureas represent a class of antitumor agent with significant therapeutic efficacy against rodent and human models of cancer. Despite the exciting preclinical activity of sulofenur, the prototypic agent, clinical activity was poor. Here we review the activity of sulofenur and a second generation diarylsulfonylurea, LY295501 N-[5-(2, 3-dihydrobenzofuryl) sulfonyl]-N'-(3,4-dichlorophenyl)urea, against colon tumor xenografts, and some of the cellular pharmacology of this class of antitumor agents.

Topics: Adenocarcinoma; Adult; Animals; Antineoplastic Agents; Benzofurans; Child; Clinical Trials, Phase I as Topic; Colonic Neoplasms; Drug Resistance, Multiple; Humans; Phenylurea Compounds; Sulfonylurea Compounds; Transplantation, Heterologous

Treatment of NRK-52E (normal) and H/1.2-NRK-52E (Harvey-ras transfected NRK-52E) rat kidney epithelial-like cells with two Eli Lilly antitumor compounds, sulofenur and LY295501 (15.6 microM-1000 microM) resulted in concentration- and time-dependent cell killing. Cytosolic Ca2+ became elevated in both cell lines in the presence of extracellular Ca2+ but only minimally in its absence. Both drugs were more toxic to the tumorigenic cells than to the normal cells, but LY295501 was significantly more toxic to both cells. The similarity in toxic response by both cell lines suggests a similar mechanism of toxic action for both drugs. Since LY295501 is highly toxic to tumorigenic cells but has a manageable dose-limiting toxicity it shows excellent potential for use in chemotherapy.

Topics: Animals; Antineoplastic Agents; Benzofurans; Calcium; Cell Survival; Cell Transformation, Neoplastic; Cytosol; Genes, ras; Humans; Kidney; Membrane Potentials; Mice; Mice, Nude; Mitochondria; Neoplasms, Experimental; Phenylurea Compounds; Rats; Sulfonylurea Compounds; Tumor Cells, Cultured

Sulofenur and a second generation diarylsulfonylurea (DSU), N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea (LY295501), were evaluated against a panel of eight colon adenocarcinoma xenografts. Of these tumors, four were derived from adult patients and four from young patients (age range 11-26 years). Both drugs were administered twice daily by oral gavage, 5 days each week for two or three consecutive weeks. The maximum tolerated dose for sulofenur was 300 mg/kg/dose for three courses and 200 mg/kg/dose for LY295501. Against 'adult' derived tumors, sulofenur caused a high proportion of objective regressions of advanced xenografts in two of four lines, with significant inhibition of growth in three tumor lines. Colon adenocarcinomas from young patients were similarly sensitive to sulofenur with a high proportion of complete and partial responses in two of three lines. LY295501 demonstrated a very similar spectrum of activity against this panel of xenografts. Tumors intrinsically resistant to sulofenur were resistant to LY295501, although this agent was slightly more active than sulofenur against tumors from younger patients. In addition, xenografts were established from a cloned colon adenocarcinoma line (GC3/c1) and its derivative GC3/LYC5) selected in vitro for resistance to sulofenur. GC3/c1 xenografts were highly responsive to both sulofenur and LY295501, whereas GC3/LYC5 xenografts were completely resistant to both agents administered at the maximum tolerated dose and schedule. These results indicate that the second generation DSU, LY295501, demonstrates a similar spectrum of activity against colon tumors as does sulofenur, and that the mechanism of action and/or resistance to the two drugs is probably similar.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Benzofurans; Colonic Neoplasms; Female; Humans; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Phenylurea Compounds; Sulfonylurea Compounds; Transplantation, Heterologous