Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

Abstract

Introduction: Apaziquone (also known as EO9 and Qapzola TM ) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 min or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date. Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers. ARTICLE HISTORY

Hypoxia-targeted drug delivery

“…72,73,83 Three major pathways are believed to be involved: (i) ROS generation by redox cycling to induce DNA strand breaks followed by quinone moiety reduction promoted by a one-electron reductase, (ii) DNA alkylation by the electrophilic centres at C3 and C2 indole position upon quinone reduction by one-and two-electron reductase, and (iii) DNA alkylation by aziridine ring opening after protonation. 84 Under normoxic conditions, tumours expressing NQO1 displayed good response towards 3. However, under hypoxic condition, one-electron reductase (P450R) activity was predominant and resulted in enhanced sensitivity to 3 in tumours expressing low levels of NQO1.…”

Inactivation of apaziquone by haematuria: implications for the design of phase III clinical trials against non-muscle invasive bladder cancer

“…Apaziquone is a prodrug that requires enzymatic activation to generate cytotoxic intermediates with one and two electron oxidoreductases playing a prominent role in drug activation [ 2 ]. The identification of enzymes capable of metabolising apaziquone in human blood has not been elucidated in this study, but it is important to recognise that the RBC component of whole blood is not just concerned with the transport and release of oxygen but it has other metabolic functions that impact upon the pharmacokinetic and pharmacodynamic property of drugs including anti-cancer agents [ 20 , 21 ].…”

“…Apaziquone, originally known as EO9 (3-hydroxy-5-aziridinyl-1- methyl-2-(1H-indole-4,7-dione)prop-β-en-α-ol), has had a long and chequered history culminating in its clinical evaluation against non-muscle invasive bladder cancer [ 1 , 2 ]. Whilst its pharmacokinetic properties are undesirable for systemic administration, they are paradoxically advantageous in the treatment of non-muscle invasive bladder cancer (NMIBC) where intravesical administration ensures adequate delivery to the tumour site and any drug leaching out into the blood stream is rapidly removed leading to low risk of systemic side effects.…”

“…Whilst its pharmacokinetic properties are undesirable for systemic administration, they are paradoxically advantageous in the treatment of non-muscle invasive bladder cancer (NMIBC) where intravesical administration ensures adequate delivery to the tumour site and any drug leaching out into the blood stream is rapidly removed leading to low risk of systemic side effects. Apaziquone is a bioreductive prodrug that requires enzymatic activation to DNA damaging species [ 2 ] and following the demonstration that NMIBC possesses the appropriate enzymology to activate apaziquone [ 3 , 4 ], significant ablative activity against NMIBC marker lesions was reported in phase I and II clinical trials [ 5 , 6 ]. The level of activity observed in marker lesion studies was higher than that reported for other chemotherapy drugs and immune response modifiers [ 7 ] and 2-year response rates demonstrated that long-term responses were good in comparison to other ablative studies [ 8 , 9 ].…”

Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy

“…Hypoxia is a common feature of various solid tumors influencing many aspects of cancer biology, including increased resistance to therapy and disease progression through angiogenesis, glycolytic switch in metabolism, and amplified anti-apoptotic and metastatic potentials [8]. Therefore, the development of cancer-targeted therapies directed against hypoxia is of great importance, especially with hypoxia-activated prodrugs (HAP) [9], like AQ4N [10], apaziquone [11,12], SN30000 [13,14], evofosfamide (TH-302) [15][16][17][18][19][20], PR-104 [21,22] or TH-4000 [23] for example ( Figure 1). HAPs are designed to be bioactivated by one-electron oxygensensitive reductases, such as NADPH cytochrome P450 oxidoreductase (POR), to specifically release active cytotoxic species in hypoxic regions of the tumor microenvironment, using a "trigger" or "oxygen concentration sensor" [24][25][26][27][28].…”