A novel strategy for NQO1 (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) mediated therapy of bladder cancer based on the pharmacological properties of EO9

Abstract

The indolequinone EO9 demonstrated good preclinical activity but failed to show clinical efficacy against a range of tumours following intravenous drug administration. A significant factor in EO9's failure in the clinic has been attributed to its rapid pharmacokinetic elimination resulting in poor drug delivery to tumours. Intravesical administration of EO9 would circumvent the problem of drug delivery to tumours and the principal objective of this study is to determine whether or not bladder tumours have elevated levels of the enzyme NQO1 (NAD(P)H:quinone oxidoreductase) which plays a key role in activating EO9 under aerobic conditions. Elevated NQO1 levels in human bladder tumour tissue exist in a subset of patients as measured by both immunohistochemical and enzymatic assays. In a panel of human tumour cell lines, EO9 is selectively toxic towards NQO1 rich cell lines under aerobic conditions and potency can be enhanced by reducing extracellular pH. These studies suggest that a subset of bladder cancer patients exist whose tumours possess the appropriate biochemical machinery required to activate EO9. Administration of EO9 in an acidic vehicle could be employed to reduce possible systemic toxicity as any drug absorbed into the blood stream would become relatively inactive due to an increase in pH. © 2001 Cancer Research Campaign http://www.bjcancer.com

Immunohistochemical analysis of NAD(P)H:quinone oxidoreductase and NADPH cytochrome P450 reductase in human superficial bladder tumours: Relationship between tumour enzymology and clinical outcome following intravesical mitomycin C therapy

“…The results of the immunohistochemical studies clearly demonstrate that a broad spectrum of NQO1 expression exists with a significant number of patients' tumours containing high NQO1 levels (Table I). These results are entirely consistent with previous studies 24,25 and suggest that NQO1 is a good target for drug development in bladder cancer. A narrow range of P450R protein levels were observed with most tumours having moderate to high protein expression, a result which is again consistent with previous findings in bladder, lung and breast cancers.…”

“…Whilst a detailed discussion of the relative merits of immunohistochemistry and semiquantitative RT-PCR is beyond the scope of this article, issues such as the relationship between gene expression (or immunoreactive protein) and enzyme activity, spatial localisation of mRNA or protein in tumour as opposed to stromal cells and the semiquantitative nature of both assays are frequently raised points that affect both methodologies used to a greater or lesser extent. The antibodies used in our study have previously been shown to selectively stain for both NQO1 23,24 and P450R (data not shown) with good correlations between immunoblotting, protein staining and enzyme activity in cell cultures and tumours. The presence of intratumour heterogeneity with regard to NQO1 protein expression (Figs.…”

Molecular analysis of transitional cell carcinoma using cDNA microarray

“…We also identified N33, a tumor suppression gene (Levy et al, 1999), and several apoptosis-related genes (e.g. caspase-4 and quinone-1, the latter was previously shown to be overexpressed in human bladder cancer; Choudry et al, 2001). Overall, of the 23 known genes identified as significantly upregulated in TCC, eight were previously related to bladder carcinoma.…”

NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Pro187Ser Polymorphism and the Risk of Lung, Bladder, and Colorectal Cancers: a Meta-analysis

“…Major risk factors for bladder cancer are cigarette smoking and occupational exposures to chemicals, such as aromatic amines and polycyclic aromatic hydrocarbons (17). A recent study found that NQO1 expression is elevated in bladder tumor tissues in a subset of patients (50% had a greater than four times increase in NQO1 level), suggesting that NQO1 plays a role in bladder carcinogenesis (18).…”