Discovery and preclinical antitumor efficacy evaluations of LY32262 and LY33169.
The discoveries of a new antitumor agent (LY32262) (N-[2,4-dichlorobenzoyl]phenylsulfonamide) and a close analog (LY33169) are described. For this discovery, a disk-diffusion-soft-agar-colony-formation-assay was used to screen a portion of the Eli Lilly inventory, with the evaluation of each agent against normal cells, leukemic cells and several solid tumors, including a multidrug-resistant solid tumor (with marked selective cytotoxicity for Colon-38 and Human-Colon-15/MDR compared to normal fibroblasts and L1210 leukemic cells characterizing the discovery). In mice, LY32262 and/or LY33169 had curative activity against Colon Adenocarcinoma-38, Human Colon-116, Human Prostate LNCaP, and Human Breast WSU-Br-1. In addition, many other tumors were highly sensitive: Panc-03 = 2.4 log kill (LK); Panc-02 = 2.9-4.1 LK; Squamous Lung LC-12 = 2.1 LK; Colon-26 = 2.2 LK; AML1498 = 2.7 LK; Human Sm Cell Lung DMS-273 = 6.3 LK; Human Squamous Lung 165 = 3.7 LK; Human Ovarian BG-1 = 3.7 LK; Human Colon CX-1 (H29) = 1.6 LK; Human Colon-15/MDR (a p-glycoprotein positive multidrug resistant tumor) = 2.3 LK; Human CNS-gliosarcoma-SF295 = 3.8 LK. Several tumors were only marginally responsive or totally unresponsive: Mammary Adenocarcinoma-16/C = 0.6 LK; Mammary Adenocarcinoma-17 = no kill; Colon Adenocarcinoma-11 = no kill; L1210 leukemia = 1.3 LK; Human Prostate PC-3 = 0.5 LK; Human Adenosquamous Lung H125 = no kill; and Human Breast Adenocarcinoma MX-1 = 0.9 LK. There was no absolute tissue of origin correlation with antitumor efficacy, although colon tumors were most responsive and mammary tumors least responsive. The cause of the "hit and miss" efficacy has not been determined.
Corbett
Thomas H
TH
Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. Corbettt@karmanos.org
White
Kathryn
K
Polin
Lisa
L
Kushner
Juiwanna
J
Paluch
Jennifer
J
Shih
Chuan
C
Grossman
Cora Sue
CS
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004355:Drug Stability; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D019999:Pharmaceutical Solutions; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001549:Benzamides; C483602:N-(2,4-dichlorobenzoyl)-4-chlorophenylsulfonamide; C483601:N-(2,4-dichlorobenzoyl)phenylsulfonamide; D019999:Pharmaceutical Solutions; D013449:Sulfonamides