Efficacy of sulofenur and a second generation diarylsulfonylurea, N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea (LY295501), against colon adenocarcinoma xenografts.
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.
Houghton
P J
PJ
Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN 38101, USA.
Cheshire
P J
PJ
Myers
L
L
Lutz
L
L
Toth
J
J
Grindey
G B
GB
Houghton
J A
JA
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001572:Benzofurans / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D001572:Benzofurans; D010671:Phenylurea Compounds; D013453:Sulfonylurea Compounds; C094382:N-(5-(2,3-dihydrobenzofuryl)sulfonyl)-N'-(3,4-dichlorophenyl)urea; C058179:sulofenur