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

The indolequinone EO9 demonstrated good preclinical activity but failed to show clinical efficacy against a range of tumours following intravenous dru g administration. A significant factor in EO9's failure in the clinic has b een attributed to its rapid pharmacokinetic elimination resulting in poor d rug delivery to tumours. Intravesical administration of EO9 would circumven t the problem of drug delivery to tumours and the principal objective of th is study is to determine whether or not bladder tumours have elevated level s of the enzyme NQO1 (NAD(P) H:qui none oxidoreductase) which plays a key r ole in activating EO9 under aerobic conditions. Elevated NQO1 levels in hum an bladder tumour tissue exist in a subset of patients as measured by both immunohistochemical and enzymatic assays. In a panel of human turnout 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 tumour s possess the appropriate biochemical machinery required to activate EO9. A dministration of EO9 in an acidic vehicle could be employed to reduce possi ble systemic toxicity as any drug absorbed into the blood stream would beco me relatively inactive due to an increase in pH. (C) 2001 Cancer Research C ampaign.