Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A phase I and pharmacokinetic study of its prodrug, CB1954

Guy Chung-Faye, Daniel Palmer, David Anderson, J Clark, A Downes, Joanna Baddeley, Syed Hussain, Philip Murray, Peter Searle, PA Harris, David Ferry, David Kerr

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] is converted by the bacterial enzyme nitroimidazole reductase (NTR) into a potent cytotoxic bifunctional alkylating agent, which can be delivered to tumors in adenoviral vectors as virus-directed, enzyme prodrug therapy. This report summarizes a Phase I and pharmacokinetic study of the prodrug, CB1954. Thirty patients, ages 23-78 years (median 62 years), with predominantly gastrointestinal malignancies were treated. CB1954 was administered by i.v. injection every 3 weeks or i.p. followed by 3-weekly i.v. injections, toward a maximum of six cycles. The dose was escalated from 3 to 37.5 mg/m2. No significant toxicity was seen until 24 mg/m2 (recommended i.v. dose). Dose-limiting toxicities (DLT) were diarrhea and hepatic toxicity, seen at 37.5 mg/m2. DLT has not been observed at the current i.p. dose of 24 mg/m2. There was no alopecia, marrow suppression, or nephrotoxicity. Clearance data suggest hepatic metabolism, and
Original languageEnglish
Pages (from-to)2662-2668
Number of pages7
JournalClinical Cancer Research
Volume7
Publication statusPublished - 1 Jan 2001

Fingerprint

Dive into the research topics of 'Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A phase I and pharmacokinetic study of its prodrug, CB1954'. Together they form a unique fingerprint.

Cite this