Virus-directed, Enzyme Prodrug Therapy with Nitroimidazole Reductase: A Phase I and Pharmacokinetic Study of its Prodrug, CB1954
<p style="text-align:justify;">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 p...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
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American Association for Cancer Research
2001
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| _version_ | 1826264172885704704 |
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| author | Chung-Faye, G Palmer, D Anderson, D Clark, J Downes, M Baddeley, J Hussain, S Murray, P Searle, P Seymour, L Harris, P Ferry, D Kerr, D |
| author_facet | Chung-Faye, G Palmer, D Anderson, D Clark, J Downes, M Baddeley, J Hussain, S Murray, P Searle, P Seymour, L Harris, P Ferry, D Kerr, D |
| author_sort | Chung-Faye, G |
| collection | OXFORD |
| description | <p style="text-align:justify;">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 μm/h. Intraperitoneal administration (24 mg/m2) achieved an AUC of 387 μm/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 μm/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.</p> |
| first_indexed | 2024-03-06T20:03:29Z |
| format | Journal article |
| id | oxford-uuid:282218e0-6f3b-417b-9563-4bc8060724e7 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T20:03:29Z |
| publishDate | 2001 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | oxford-uuid:282218e0-6f3b-417b-9563-4bc8060724e72022-03-26T12:10:56ZVirus-directed, Enzyme Prodrug Therapy with Nitroimidazole Reductase: A Phase I and Pharmacokinetic Study of its Prodrug, CB1954Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:282218e0-6f3b-417b-9563-4bc8060724e7Symplectic Elements at OxfordAmerican Association for Cancer Research2001Chung-Faye, GPalmer, DAnderson, DClark, JDownes, MBaddeley, JHussain, SMurray, PSearle, PSeymour, LHarris, PFerry, DKerr, D<p style="text-align:justify;">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 μm/h. Intraperitoneal administration (24 mg/m2) achieved an AUC of 387 μm/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 μm/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.</p> |
| spellingShingle | Chung-Faye, G Palmer, D Anderson, D Clark, J Downes, M Baddeley, J Hussain, S Murray, P Searle, P Seymour, L Harris, P Ferry, D Kerr, D Virus-directed, Enzyme Prodrug Therapy with Nitroimidazole Reductase: A Phase I and Pharmacokinetic Study of its Prodrug, CB1954 |
| title | Virus-directed, Enzyme Prodrug Therapy with Nitroimidazole Reductase: A Phase I and Pharmacokinetic Study of its Prodrug, CB1954 |
| title_full | Virus-directed, Enzyme Prodrug Therapy with Nitroimidazole Reductase: A Phase I and Pharmacokinetic Study of its Prodrug, CB1954 |
| title_fullStr | Virus-directed, Enzyme Prodrug Therapy with Nitroimidazole Reductase: A Phase I and Pharmacokinetic Study of its Prodrug, CB1954 |
| title_full_unstemmed | Virus-directed, Enzyme Prodrug Therapy with Nitroimidazole Reductase: A Phase I and Pharmacokinetic Study of its Prodrug, CB1954 |
| title_short | Virus-directed, Enzyme Prodrug Therapy with Nitroimidazole Reductase: A Phase I and Pharmacokinetic Study of its Prodrug, CB1954 |
| title_sort | virus directed enzyme prodrug therapy with nitroimidazole reductase a phase i and pharmacokinetic study of its prodrug cb1954 |
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