CB 1954

Tretazicar (CB 1954), an antitumor prodrug, is highly selective against the Walker 256 rat tumour line. Tretazicar is enzymatically activated to generate a bifunctional agent, which can form DNA-DNA interstrand cross-links. Tretazicar in rat cells involves the reduction of its 4-nitro group to a 4-hydroxylamine by the enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1)[1][2].

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA Alkylator/Crosslinker

Tretazicar (CB 1954) (0.1-1000 μM; 3 days) has sensitivity for retrovirally transduced AB22 (AB22-nr) cells with an IC50 of 3 μM[3]. DNA cross-link formation in affected cells is a result of the bioactivation of the drug by the enzyme DT diaphorase (NAD(P)H dehydro-genase (quinone)) in the Walker cells which reduces the 4-nitro group of Tretazicar. The product of this reaction is a difunctional alkylating agent, 5-aziridin-1-yl-4-hydroxylamino-2-nitrobenzamide[4].

Tretazicar (CB 1954) (80 mg/kg; i.p. on days 2 and 9) results in a significant increase in survival[3]. Animal Model: Female BALB/c mice (AB22-nr, SKOV3 human ovarian tumour xenograft)[3] Dosage: 80 mg/kg Administration: i.p. on days 2 and 9 Result: The median survival of the AB22-nr was 49 days. Resulted in a significant increase in survival.

[1]. Knox RJ,et al. Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by human NAD(P)H quinone oxidoreductase 2: a novel co-substrate-mediated antitumor prodrug therapy. Cancer Res. 2000 Aug 1;60(15):4179-86.

[2]. Knox RJ, et al. CB 1954: from the Walker tumor to NQO2 and VDEPT. Curr Pharm Des. 2003;9(26):2091-104.

[3]. Green NK, et al. Immune enhancement of nitroreductase-induced cytotoxicity: studies using a bicistronicadenovirus vector. Int J Cancer. 2003 Mar 10;104(1):104-12.

[4]. Drabek D, et al. The expression of bacterial nitroreductase in transgenic mice results in specific cell killing by the prodrug CB1954. Gene Ther. 1997 Feb;4(2):93-100.

MOLECULAR FORMULA :

C9-H8-N4-O5

MOLECULAR WEIGHT :

252.21

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

29 mg/kg

TOXIC EFFECTS :

Gastrointestinal - gastritis Gastrointestinal - ulceration or bleeding from stomach Blood - hemorrhage

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

22 mg/kg

TOXIC EFFECTS :

Gastrointestinal - gastritis Gastrointestinal - ulceration or bleeding from stomach Blood - hemorrhage

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

22 mg/kg

TOXIC EFFECTS :

Gastrointestinal - gastritis Gastrointestinal - ulceration or bleeding from stomach Blood - hemorrhage

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraduodenal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

10 mg/kg

TOXIC EFFECTS :

Gastrointestinal - gastritis Gastrointestinal - ulceration or bleeding from stomach Blood - hemorrhage

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

176 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

MUTATION DATA

TYPE OF TEST :

DNA damage

TEST SYSTEM :

Rodent - hamster Lung

DOSE/DURATION :

10 umol/L

REFERENCE :

BCPCA6 Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- Volume(issue)/page/year: 37,4661,1988