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Apaziquone

Apaziquone is an indolequinone bioreductive prodrug and analog of mitomycin C with potential antineoplastic and radiosensitization activities. Apaziquone is converted to active metabolites in hypoxic cells by intracellular reductases, which are present in greater amounts in hypoxic tumor cells. The active metabolites alkylate DNA, resulting in apoptotic cell death. This agent displays activity towards both hypoxic solid tumors, which exhibits higher expression of cytochrome P450 reductase, and well-oxygenated malignant cells that overexpress the bioreductive enzyme NQO1 (NAD(P)H: quinone oxidoreductase). Apaziquone may selectively sensitize hypoxic tumor cells to radiocytotoxicity. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:  Spectrum Pharmaceuticals, Inc.

Recent review on apaziquone: Apaziquone is a promising local agent for the treatment and prevention of recurrent urothelial carcinoma of the bladder. The limited number of Phase II studies has demonstrated potency and relatively low toxicity. In light of the dearth of randomized controlled trials, Phase III studies are urgently needed before any conclusive pronouncements on this agent can be made.(source: Expert Opin Investig Drugs. 2012 Feb;21(2):251-60.)

Phase II study of intravesical apaziquone for patients with non-muscle invasive bladder cancer.

OBJECTIVES:  To study the time-to-recurrence and duration of response in non-muscle invasive bladder cancer (NMIBC) patients, with a complete ablative response after intravesical apaziquone instillations.  CONCLUSIONS: The CR of the marker lesion in 67% of patients was followed by a recurrence-free rate of 56.5% at 1-year FU, and 49.5% at 2-year FU. These long-term results are good in comparison with the results of other ablative studies. [source: World J Urol. 2009 Jun;27(3):337-42.]

Phase I/II pilot study of intravesical apaziquone (EO9) for superficial bladder cancer.  PURPOSE: The quinone based bioreductive drug apaziquone (EO9) failed to demonstrate efficacy in previous phase II studies following intravenous administration. We determined the dose of apaziquone that can be safely administered intravesically and explored its activity for superficial bladder transitional cell carcinoma.  CONCLUSIONS: Intravesical administration of 4 mg/40 ml apaziquone was well tolerated and had ablative activity against superficial bladder cancer marker lesions. [source:  J Urol. 2006 Oct;176(4 Pt 1):1344-8.]

1: Yutkin V, Chin J. Apaziquone as an intravesical therapeutic agent for urothelial non-muscle-invasive bladder cancer. Expert Opin Investig Drugs. 2012 Feb;21(2):251-60. Epub 2011 Dec 21. PubMed PMID: 22188461.

2: Arentsen HC, Hendricksen K, Hulsbergen-van de Kaa CA, Reddy G, Oosterwijk E, Alfred Witjes J. The orthotopic Fischer/AY-27 rat bladder urothelial cell carcinoma model to test the efficacy of different apaziquone formulations. Urol Oncol. 2012 Jan;30(1):64-8. Epub 2009 Nov 27. PubMed PMID: 19945311.

3: Jain A, Phillips RM, Scally AJ, Lenaz G, Beer M, Puri R. Response of multiple recurrent TaT1 bladder cancer to intravesical apaziquone (EO9): comparative analysis of tumor recurrence rates. Urology. 2009 May;73(5):1083-6. Epub 2009 Feb 20. PubMed PMID: 19232688.

4: Hendricksen K, van der Heijden AG, Cornel EB, Vergunst H, de Reijke TM, van Boven E, Smits GA, Puri R, Gruijs S, Witjes JA. Two-year follow-up of the phase II marker lesion study of intravesical apaziquone for patients with non-muscle invasive bladder cancer. World J Urol. 2009 Jun;27(3):337-42. Epub 2009 Feb 13. PubMed PMID: 19214526; PubMed Central PMCID: PMC2694322.

5: Witjes JA, Kolli PS. Apaziquone for non-muscle invasive bladder cancer: a critical review. Expert Opin Investig Drugs. 2008 Jul;17(7):1085-96. Review. PubMed PMID: 18549344.

6: Hendricksen K, Gleason D, Young JM, Saltzstein D, Gershman A, Lerner S, Witjes JA. Safety and side effects of immediate instillation of apaziquone following transurethral resection in patients with nonmuscle invasive bladder cancer. J Urol. 2008 Jul;180(1):116-20. Epub 2008 May 15. PubMed PMID: 18485407.

7: Vainchtein LD, Rosing H, Mirejovsky D, Huynh V, Lenaz L, Schellens JH, Beijnen JH. Enhanced resolution triple-quadrupole mass spectrometry for ultra-sensitive and quantitative analysis of the investigational anticancer agent EO9 (apaziquone) and its metabolite EO5a in human and dog plasma to support (pre)-clinical studies of EOquin given intravesically. Rapid Commun Mass Spectrom. 2008;22(4):462-70. PubMed PMID: 18231986.

8: Vainchtein LD, Rosing H, Mirejovsky D, Huynh V, Lenaz L, Hillebrand MJ, Schellens JH, Beijnen JH. Quantitative analysis of EO9 (apaziquone) and its metabolite EO5a in human plasma by high-performance liquid chromatography under basic conditions coupled to electrospray tandem mass spectrometry. J Mass Spectrom. 2006 Oct;41(10):1268-76. PubMed PMID: 16981212.

9: van der Heijden AG, Moonen PM, Cornel EB, Vergunst H, de Reijke TM, van Boven E, Barten EJ, Puri R, van Kalken CK, Witjes JA. Phase II marker lesion study with intravesical instillation of apaziquone for superficial bladder cancer: toxicity and marker response. J Urol. 2006 Oct;176(4 Pt 1):1349-53; discussion 1353. PubMed PMID: 16952629.

10: Puri R, Palit V, Loadman PM, Flannigan M, Shah T, Choudry GA, Basu S, Double JA, Lenaz G, Chawla S, Beer M, Van Kalken C, de Boer R, Beijnen JH, Twelves CJ, Phillips RM. Phase I/II pilot study of intravesical apaziquone (EO9) for superficial bladder cancer. J Urol. 2006 Oct;176(4 Pt 1):1344-8. PubMed PMID: 16952628.

11: Vainchtein LD, Rosing H, Mirejovsky D, Lenaz L, Schellens JH, Beijnen JH. Stability experiments in human urine with EO9 (apaziquone): a novel anticancer agent for the intravesical treatment of bladder cancer. J Pharm Biomed Anal. 2007 Jan 4;43(1):285-92. Epub 2006 Aug 22. PubMed PMID: 16920321.