Hepatic nitroreduction, toxicity and toxicokinetics of the anti-tumour prodrug CB 1954 in mouse and rat

Toxicology

Volumn 240, Issue 1-2, 2007, Pages 70-85

  Tang, Magdalene Huen Yin ^a   Helsby, Nuala A ^a,b   Goldthorpe, Michael A ^a   Thompson, Kirsty M ^a   Al Ali, Saad ^a   Tingle, Malcolm D ^a  

^a UNIVERSITY OF AUCKLAND   (New Zealand)

^b UNIVERSITY OF AUCKLAND   (New Zealand)

Author keywords

Animal model; CB 1954 (5 (aziridin 1 yl) 2,4 dinitrobenzamide); Hepatotoxicity; Nitroreduction; Toxicokinetics

Indexed keywords

5 (1 AZIRIDINYL) 2,4 DINITROBENZAMIDE; AMINOTRANSFERASE; ANTINEOPLASTIC AGENT; CYTOCHROME P450 REDUCTASE; GLUTATHIONE; PRODRUG; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE (PHOSPHATE) DEHYDROGENASE (QUINONE); THIOL;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG ACTIVATION; DRUG METABOLISM; GASTROINTESTINAL SYMPTOM; IMMUNOHISTOCHEMISTRY; LIVER CELL DAMAGE; LIVER LEVEL; LIVER TOXICITY; MAXIMUM TOLERATED DOSE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; REDUCTION; SPRAGUE DAWLEY RAT; STRAIN DIFFERENCE; TOXICOKINETICS;

ANIMALS; ANTINEOPLASTIC AGENTS; AZIRIDINES; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; GLUTATHIONE; HEPATITIS, TOXIC; HUMANS; MALE; MICE; MICE, INBRED STRAINS; MICROSOMES, LIVER; NAD(P)H DEHYDROGENASE (QUINONE); NADPH-FERRIHEMOPROTEIN REDUCTASE; PRODRUGS; RATS; RATS, SPRAGUE-DAWLEY; SPECIES SPECIFICITY;

ANIMALIA; MUS; RATTUS;

EID: 34548851418     PISSN: 0300483X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tox.2007.07.018     Document Type: Article

References (68)

1. Al-Ali S.Y., Hassan I.M., and Sadek S. Ultrastructural changes in rat livers perfused in vitro and in vivo with a high dose of methotrexate. Histol. Histopathol. 20 (2005) 1131-1145
2. Amacher D.E. Reactive intermediates and the pathogenesis of adverse drug reactions: the toxicology perspective. Curr. Drug. Metab. 7 (2006) 219-229
3. Anlezark G.M., Melton R.G., Sherwood R.F., Coles B., Friedlos F., and Knox R.J. The bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954). I. Purification and properties of a nitroreductase enzyme from Escherichia coli-a potential enzyme for antibody-directed enzyme prodrug therapy (ADEPT). Biochem. Pharmacol. 44 (1992) 2289-2295
4. Anlezark G.M., Melton R.G., Sherwood R.F., Wilson W.R., Denny W.A., Palmer B.D., Knox R.J., Friedlos F., and Williams A. Bioactivation of dinitrobenzamide mustards by an E. coli B nitroreductase. Biochem. Pharmacol. 50 (1995) 609-618
5. Ask K., Decologne N., Asare N., Holme J.A., Artur Y., Pelczar H., and Camus P. Distribution of nitroreductive activity toward nilutamide in rat. Toxicol. Appl. Pharmacol. 201 (2004) 1-9
6. Aydin G., Ozcelik N., Cicek E., and Soyoz M. Histopathologic changes in liver and renal tissues induced by Ochratoxin A and melatonin in rats. Hum. Exp. Toxicol. 22 (2003) 383-391
7. Baron J., Redick J.A., Greenspan P., and Taira Y. Immunohistochemical localization of NADPH-cytochrome c reductase in rat liver. Life Sci. 22 (1978) 1097-1102
8. Berson A., Wolf C., Berger V., Fau D., Chachaty C., Fromenty B., and Pessayre D. Generation of free radicals during the reductive metabolism of the nitroaromatic compound, nilutamide. J. Pharmacol. Exp. Ther. 257 (1991) 714-719
9. Björnsson E. Drug-induced liver injury: Hy's rule revisited. Clin. Pharmacol. Ther. 79 (2006) 521-528
10. Boelsterli U.A. Mechanisms of NSAID-induced hepatotoxicity: focus on nimesulide. Drug Saf. 25 (2002) 633-648
11. Boland M.P., Knox R.J., and Roberts J.J. The differences in kinetics of rat and human DT diaphorase result in a differential sensitivity of derived cell lines to CB 1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide). Biochem. Pharmacol. 41 (1991) 867-875
12. Bridgewater J.A., Springer C.J., Knox R.J., Minton N.P., Michael N.P., and Collins M.K. Expression of the bacterial nitroreductase enzyme in mammalian cells renders them selectively sensitive to killing by the prodrug CB 1954. Eur. J. Cancer 31A (1995) 2362-2370
13. Buchweitz J.P., Ganey P.E., Bursian S.J., and Roth R.A. Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy?. J. Pharmacol. Exp. Ther. 300 (2002) 460-467
14. Chen S., Knox R., Wu K., Deng P.S., Zhou D., Bianchet M.A., and Amzel L.M. Molecular basis of the catalytic differences among DT-diaphorase of human, rat and mouse. J. Biol. Chem. 272 (1997) 1437-1439
15. Chung-Faye G., Palmer D., Anderson D., Clark J., Downes M., Baddeley J., Hussain S., Murray P.I., Searle P., Seymour L., Harris P.A., Ferry D., and Kerr D.J. Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: a phase I and pharmacokinetic study of its prodrug, CB 1954. Clin. Cancer Res. 7 (2001) 2662-2668
16. Cobb L.M. Toxicity of the selective antitumor agent 5-aziridino-2,4-dinitrobenzamide in the rat. Toxicol. Appl. Pharmacol. 17 (1970) 231-238
17. Cotgreave I.A., and Moldeus P. Methodologies for the application of monobromobimane to the simultaneous analysis of soluble and protein thiol components of biological systems. J. Biochem. Biophys. Methods 13 (1986) 231-249
18. Donald S., Verschoyle R.D., Edwards R., Judah D.J., Davies R., Riley J., Dinsdale D., Lopez Lazaro L., Smith A.G., Gant T.W., Greaves P., and Gescher A.J. Hepatobiliary damage and changes in hepatic gene expression caused by the antitumor drug ecteinascidin-743 (ET-743) in the female rat. Cancer Res. 62 (2002) 4256-4262
19. Donald S., Verschoyle R.D., Greaves P., Colombo T., Zucchetti M., Falcioni C., Zaffaroni M., D'Incalci M., Manson M.M., Jimeno J., Steward W.P., and Gescher A.J. Dietary agent indole-3-carbinol protects female rats against the hepatotoxicity of the antitumor drug ET-743 (trabectidin) without compromising efficacy in a rat mammary carcinoma. Int. J. Cancer 111 (2004) 961-967
20. Fau D., Berson A., Eugene D., Fromenty B., Fisch C., and Pessayre D. Mechanism for the hepatotoxicity of the antiandrogen, nilutamide. Evidence suggesting that redox cycling of this nitroaromatic drug leads to oxidative stress in isolated hepatocytes. J. Pharmacol. Exp. Ther. 263 (1992) 69-77
21. Friedlos F., Denny W.A., Palmer B.D., and Springer C.J. Mustard prodrugs for activation by Escherichia coli nitroreductase in gene-directed enzyme prodrug therapy. J. Med. Chem. 40 (1997) 1270-1275
22. Graichen M.E., Neptun D.A., Dent J.G., Popp J.A., and Leonard T.B. Effects of methapyrilene on rat hepatic xenobiotic metabolizing enzymes and liver morphology. Fundam. Appl. Toxicol. 5 (1985) 165-174
23. Greaves P. Histopathology of preclinical toxicity studies: interpretation and relevance in drug safety evaluation. Elsevier Science B.V. (2000) pp. 432-544
24. Green N.K., Youngs D.J., Neoptolemos J.P., Friedlos F., Knox R.J., Springer C.J., Anlezark G.M., Michael N.P., Melton R.G., Ford M.J., Young L.S., Kerr D.J., and Searle P.F. Sensitization of colorectal and pancreatic cancer cell lines to the prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by retroviral transduction and expression of the E. coli nitroreductase gene. Cancer Gene Ther. 4 (1997) 229-238
25. Helsby N.A., Wheeler S.J., Pruijn F.B., Palmer B.D., Yang S., Denny W.A., and Wilson W.R. Effect of nitroreduction on the alkylating reactivity and cytotoxicity of the 2,4-dinitrobenzamide-5-aziridine CB 1954 and the corresponding nitrogen mustard SN 23862: distinct mechanisms of bioreductive activation. Chem. Res. Toxicol. 16 (2003) 469-478
26. Helsby N.A., Atwell G.J., Yang S., Palmer B.D., Anderson R.F., Pullen S.M., Ferry D.M., Hogg A., Wilson W.R., and Denny W.A. Aziridinyldinitrobenzamides: synthesis and structure-activity relationships for activation by E. coli nitroreductase. J. Med. Chem. 47 (2004) 3295-3307
27. Helsby N.A., Ferry D.M., Patterson A.V., Pullen S.M., and Wilson W.R. 2-Amino metabolites are key mediators of CB 1954 and SN 23862 bystander effects in nitroreductase GDEPT. Br. J. Cancer 90 (2004) 1084-1092
28. Henderson R.F. Species differences in the metabolism of benzene. Environ. Health Perspect. 104 Suppl. 6 (1996) 1173-1175
29. Henderson R.F., Thornton-Manning J.R., Bechtold W.E., and Dahl A.R. Metabolism of 1,3-butadiene: species differences. Toxicology 113 (1996) 17-22
30. James N.D., Patel P., Mautner V., Young J.G., Hull D., Searle P., Leung H., Ellis J., Wallace M., and Young L.S. A clinical trial of virus-encoded enzyme prodrug therapy (VDEPT) using adenovirus encoded nitroreductase (ntr) and CB 1954 in patients with localized prostate cancer (PCa). J. Clin. Oncol. 22 (2004) 4572
31. Jarman M., Melzack D.H., and Ross W.C. The metabolism of the anti-tumour agent 5-(1-aziridinyl)-2,4-dinitrobenzamide (CB 1954). Biochem. Pharmacol. 25 (1976) 2475-2478
32. Jiang Y., Han J., Yu C., Vass S.O., Searle P.F., Browne P., Knox R.J., and Hu L. Design, synthesis, and biological evaluation of cyclic and acyclic nitrobenzylphosphoramide mustards for E. coli nitroreductase activation. J. Med. Chem. 49 (2006) 4333-4343
33. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat. Rev. Drug Discov. 4 (2005) 489-499
34. Kelland L.R. Of mice and men: values and liabilities of the athymic nude mouse model in anticancer drug development. Eur. J. Cancer 40 (2004) 827-836
35. Kestell P., Pruijn F.B., Siim B.G., Palmer B.D., and Wilson W.R. Pharmacokinetics and metabolism of the nitrogen mustard bioreductive drug 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (SN 23862) and the corresponding aziridine (CB 1954) in KHT tumour-bearing mice. Cancer Chemother. Pharmacol. 46 (2000) 365-374
36. Knox R.J., Boland M.P., Friedlos F., Coles B., Southan C., and Roberts J.J. The nitroreductase enzyme in Walker cells that activates 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) to 5-(aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide is a form of NAD(P)H dehydrogenase (quinone) (EC 1.6.99.2). Biochem. Pharmacol. 37 (1988) 4671-4677
37. Knox R.J., Friedlos F., Jarman M., and Roberts J.J. A new cytotoxic, DNA interstrand cross-linking agent, 5-(aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide, is formed from 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by a nitroreductase enzyme in Walker carcinoma cells. Biochem. Pharmacol. 37 (1988) 4661-4669
38. Knox R.J., Friedlos F., Marchbank T., and Roberts J.J. Bioactivation of CB 1954: reaction of the active 4-hydroxylamino derivative with thioesters to form the ultimate DNA-DNA interstrand cross-linking species. Biochem. Pharmacol. 42 (1991) 1691-1697
39. Kopf-Maier P., and Mboneko V.F. Anomalies in the hormonal status of athymic nude mice. J. Cancer Res. Clin. Oncol. 116 (1990) 229-231
40. Leonard T.B., Popp J.A., Graichen M.E., and Dent J.G. Alpha-naphthylisothiocyanate-induced alterations in hepatic drug metabolizing enzymes and liver morphology: implications concerning anticarcinogenesis. Carcinogenesis 2 (1981) 473-482
41. Leonard T.B., Neptun D.A., and Popp J.A. Serum gamma glutamyl transferase as a specific indicator of bile duct lesions in the rat liver. Am. J. Pathol. 116 (1984) 262-269
42. Litterst C.L., Sikic B.I., Mimnaugh E.G., Guarino A.M., and Gram T.E. In vitro drug metabolism in male and female athymic, nude mice. Life Sci. 22 (1978) 1723-1730
43. Lofgren S., Hagbjork A.L., Ekman S., Fransson-Steen R., and Terelius Y. Metabolism of human cytochrome P450 marker substrates in mouse: a strain and gender comparison. Xenobiotica 34 (2004) 811-834
44. McManus M.E., Hall P.D., Stupans I., Brennan J., Burgess W., Robson R., and Birkett D.J. Immunohistochemical localization and quantitation of NADPH-cytochrome P-450 reductase in human liver. Mol. Pharmacol. 32 (1987) 189-194
45. O'Leary K.A., Li H.C., Ram P.A., McQuiddy P., Waxman D.J., and Kasper C.B. Thyroid regulation of NADPH:cytochrome P450 oxidoreductase: identification of a thyroid-responsive element in the 5′-flank of the oxidoreductase gene. Mol. Pharmacol. 52 (1997) 46-53
46. Palmer B.D., Wilson W.R., Cliffe S., and Denny W.A. Hypoxia-selective antitumor agents 5. Synthesis of water-soluble nitroaniline mustards with selective cytotoxicity for hypoxic mammalian cells. J. Med. Chem. 35 (1992) 3214-3222
47. Palmer B.D., Wilson W.R., Atwell G.J., Schultz D., Xu X.Z., and Denny W.A. Hypoxia-selective antitumor agents. 9. Structure-activity relationships for hypoxia-selective cytotoxicity among analogues of 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide. J. Med. Chem. 37 (1994) 2175-2184
48. Palmer B.D., Wilson W.R., Anderson R.F., Boyd M., and Denny W.A. Hypoxia-selective antitumor agents. 14. Synthesis and hypoxic cell cytotoxicity of regioisomers of the hypoxia-selective cytotoxin 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide. J. Med. Chem. 39 (1996) 2518-2528
49. Palmer D.H., Mautner V., Hull D., Ellis J., Mountain A., Searle P., Young L.S., Gerritsen W., James N.D., and Kerr D.J. Virus-directed enzyme prodrug therapy (VDEPT): a clinical trial of adenovirus-delivered nitroreductase (NTR) in combination with CB 1954 in patients with primary or secondary liver cancer. J. Clin. Oncol. 23 (2005) 3157
50. Patel P., Mautner V., Searle P., Young J.G., Hull D., Ellis J., Wallace D.M.A., Leung H.Y., Young L.S., and James N.D. Suicide gene therapy using adenovirus encoded nitroreductase and CB 1954 in patients with locally relapsed prostate cancer. J. Clin. Oncol. 23 (2005) 3091
51. Patterson A.V., Ferry D.M., Edmunds S.J., Gu Y., Singleton R.S., Patel K., Pullen S.M., Hicks K.O., Syddall S.P., Atwell G.J., Yang S., Denny W.A., and Wilson W.R. Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104. Clin. Cancer Res. 13 (2007) 3922-3932
52. Roth R.A., Luyendyk J.P., Maddox J.F., and Ganey P.E. Inflammation and drug idiosyncrasy-is there a connection?. J. Pharmacol. Exp. Ther. 307 (2003) 1-8
53. Schober W., Luch A., Soballa V.J., Raab G., Stegeman J.J., Doehmer J., Jacob J., and Seidel A. On the species-specific biotransformation of dibenzo[a,l]pyrene. Chem. Biol. Interact. 161 (2006) 37-48
54. Searle P.F., Chen M.J., Hu L., Race P.R., Lovering A.L., Grove J.I., Guise C., Jaberipour M., James N.D., Mautner V., Young L.S., Kerr D.J., Mountain A., White S.A., and Hyde E.I. Nitroreductase: a prodrug-activating enzyme for cancer gene therapy. Clin. Exp. Pharmacol. Physiol. 31 (2004) 811-816
55. Siim B.G., Denny W.A., and Wilson W.R. Nitro reduction as an electronic switch for bioreductive drug activation. Oncol. Res. 9 (1997) 357-369
56. Squella J.A., Gonzalez P., Bollo S., and Nunez-Vergara L.J. Electrochemical generation and interaction study of the nitro radical anion from nimesulide. Pharm. Res. 16 (1999) 161-164
57. Tang M.H.Y., Helsby N.A., Wilson W.R., and Tingle M.D. Aerobic 2- and 4-nitroreduction of CB 1954 by human liver. Toxicology 216 (2005) 129-139
58. Tay V.K., Wang A.S., Leow K.Y., Ong M.M., Wong K.P., and Boelsterli U.A. Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro. Free Radic. Biol. Med. 39 (2005) 949-959
59. Wal J.M., Corpet D.E., Peleran J.C., and Bories G.F. Comparative metabolism of chloramphenicol in germfree and conventional rats. Antimicrob. Agents Chemother. 24 (1983) 89-94
60. Walgren J.L., Mitchell M.D., and Thompson D.C. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit. Rev. Toxicol. 35 (2005) 325-361
61. Walker S.A., Whitten L.B., Seals G.B., Lee W.E., Archibong A.E., and Ramesh A. Inter-species comparison of liver and small intestinal microsomal metabolism of fluoranthene. Food Chem. Toxicol. 44 (2006) 380-387
62. Walton M.I., Wolf C.R., and Workman P. Molecular enzymology of the reductive bioactivation of hypoxic cell cytotoxins. Int. J. Radiat. Oncol. Biol. Phys. 16 (1989) 983-986
63. Walton M.I., Sugget N., and Workman P. The role of human and rodent DT-diaphorase in the reductive metabolism of hypoxic cell cytotoxins. Int. J. Radiat. Oncol. Biol. Phys. 22 (1992) 643-647
64. Wilson W.R., Pullen S.M., Hogg A., Helsby N.A., Hicks K.O., and Denny W.A. Quantitation of bystander effects in nitroreductase suicide gene therapy using three-dimensional cell cultures. Cancer Res. 62 (2002) 1425-1432
65. Wilson W.R., Hicks K.O., Pullen S.M., Ferry D., Helsby N.A., and Patterson A.V. Bystander effects of bioreductive drugs: potential for exploiting pathological tumor hypoxia with dinitrobenzamide mustards. Radiat. Res. 167 (2007) 625-636
66. Workman P., Morgan J.E., Talbot K., Wright K.A., Donaldson J., and Twentyman P.R. CB 1954 revisited. II. Toxicity and anti-tumour activity. Cancer Chemother. Pharmacol. 16 (1986) 9-14
67. Workman P., White R.A., and Talbot K. CB 1954 revisited. I. Disposition kinetics and metabolism. Cancer Chemother. Pharmacol. 16 (1986) 1-8
68. Wu L., Gu J., Cui H., Zhang Q.Y., Behr M., Fang C., Weng Y., Kluetzman K., Swiatek P.J., Yang W., Kaminsky L., and Ding X. Transgenic mice with a hypomorphic NADPH-cytochrome P450 reductase gene: effects on development, reproduction, and microsomal cytochrome P450. J. Pharmacol. Exp. Ther. 312 (2005) 35-43