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 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.
Choudry
G A
GA
Cancer Research Unit, University of Bradford, Bradford, BD7 1DP, UK.
Stewart
P A
PA
Double
J A
JA
Krul
M R
MR
Naylor
B
B
Flannigan
G M
GM
Shah
T K
TK
Brown
J E
JE
Phillips
R M
RM
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001388:Aziridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D045563:Indolequinones; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011808:Quinone Reductases / Q000378:metabolism*; D013379:Substrate Specificity; D001743:Urinary Bladder / Q000201:enzymology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases; C060817:apaziquone