Antitumor Activity of a Duocarmycin Analogue Rationalized to Be Metabolically Activated by Cytochrome P450 1A1 in Human Transitional Cell Carcinoma of the Bladder

• Published in: Molecular cancer therapeutics Vol. 12; no. 1; pp. 27 - 37
• Main Authors: Sutherland, Mark, Gill, Jason H., Loadman, Paul M., Laye, Jonathan P., Sheldrake, Helen M., Illingworth, Nicola A., Alandas, Mohammed N., Cooper, Patricia A., Searcey, Mark, Pors, Klaus, Shnyder, Steve D., Patterson, Laurence H.
• Format: Journal Article
• Language: English
• Published: United States 01.01.2013
• Subjects: Animals; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biotransformation; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - enzymology; Carcinoma, Transitional Cell - pathology; Cell Line, Tumor; Cell Survival - drug effects; CHO Cells; Cricetinae; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Female; Gene Expression; Humans; Indoles - metabolism; Indoles - pharmacokinetics; Indoles - pharmacology; Liver - metabolism; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Microsomes, Liver - metabolism; Pyrroles - metabolism; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; Tumor Burden - drug effects; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - enzymology; Urinary Bladder Neoplasms - pathology; Xenograft Model Antitumor Assays

We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cance...