title: Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: a phase I and pharmacokinetic study of its prodrug, CB1954.
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 <5% of CB1954 was renally excreted. There was a nonlinear relationship between i.v. dose and area under the curve (AUC). At the recommended i.v. dose of 24 mg/m2, the AUC was 5.8 microM/h. Intraperitoneal administration (24 mg/m2) achieved an AUC of 387 microM/h, giving a considerable regional advantage. In vitro, the AUC required to achieve the IC50 for CB1954, in NTR-expressing cancer cells, ranges from 10-50 microM/h. Thus, CB1954 is well tolerated at a dose of 24 mg/m2, and sufficient serum/peritoneal levels are achieved for an enzyme-prodrug approach to be feasible. We are now conducting a Phase I trial combining adenovirus-mediated NTR and i.v. CB1954 (24 mg/m2) in patients with primary and secondary liver tumors.
authors.affiliation: CRC Institute of Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TA, United Kingdom.
authors.forename: G
authors.initials: G
authors.lastname: Chung-Faye
authors.forename: D
authors.initials: D
authors.lastname: Palmer
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.forename: J
authors.initials: J
authors.lastname: Clark
authors.forename: M
authors.initials: M
authors.lastname: Downes
authors.forename: J
authors.initials: J
authors.lastname: Baddeley
authors.forename: S
authors.initials: S
authors.lastname: Hussain
authors.forename: P I
authors.initials: PI
authors.lastname: Murray
authors.forename: P
authors.initials: P
authors.lastname: Searle
authors.forename: L
authors.initials: L
authors.lastname: Seymour
authors.forename: P A
authors.initials: PA
authors.lastname: Harris
authors.forename: D
authors.initials: D
authors.lastname: Ferry
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced; D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001388:Aziridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009601:Nitroreductases / Q000235:genetics; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D011355:Prodrugs; C100099:tretazicar; D009601:Nitroreductases