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

G A Choudry, P A Hamilton Stewart, J A Double, M R Krul, B Naylor, G M Flannigan, T K Shah, J E Brown, R M Phillips

Research output: Contribution to journalArticle

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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.

LanguageEnglish
Pages1137-1146
Number of pages10
JournalBritish Journal of Cancer
Volume85
Issue number8
Publication statusPublished - 16 Oct 2001
Externally publishedYes

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apaziquone
Urinary Bladder Neoplasms
NAD
Oxidoreductases
Pharmacology
Pharmaceutical Preparations
Therapeutics
Indolequinones
Neoplasms
Intravesical Administration
Poisons
Enzyme Assays
benzoquinone
Tumor Cell Line
Intravenous Administration

Cite this

Choudry, G A ; Hamilton Stewart, P A ; Double, J A ; Krul, M R ; Naylor, B ; Flannigan, G M ; Shah, T K ; Brown, J E ; Phillips, R M. / 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. In: British Journal of Cancer. 2001 ; Vol. 85, No. 8. pp. 1137-1146.
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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.",
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Choudry, GA, Hamilton Stewart, PA, Double, JA, Krul, MR, Naylor, B, Flannigan, GM, Shah, TK, Brown, JE & Phillips, RM 2001, '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', British Journal of Cancer, vol. 85, no. 8, pp. 1137-1146.

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. / Choudry, G A; Hamilton Stewart, P A; Double, J A; Krul, M R; Naylor, B; Flannigan, G M; Shah, T K; Brown, J E; Phillips, R M.

In: British Journal of Cancer, Vol. 85, No. 8, 16.10.2001, p. 1137-1146.

Research output: Contribution to journalArticle

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T1 - 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

AU - Choudry, G A

AU - Hamilton Stewart, P A

AU - Double, J A

AU - Krul, M R

AU - Naylor, B

AU - Flannigan, G M

AU - Shah, T K

AU - Brown, J E

AU - Phillips, R M

N1 - Copyright 2001 Cancer Research Campaign http://www.bjcancer.com.

PY - 2001/10/16

Y1 - 2001/10/16

N2 - 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.

AB - 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.

KW - Antineoplastic Agents/therapeutic use

KW - Aziridines/pharmacokinetics

KW - Humans

KW - Hydrogen-Ion Concentration

KW - Immunohistochemistry

KW - Indolequinones

KW - Indoles/pharmacokinetics

KW - Quinone Reductases/metabolism

KW - Substrate Specificity

KW - Urinary Bladder/enzymology

KW - Urinary Bladder Neoplasms/drug therapy

M3 - Article

VL - 85

SP - 1137

EP - 1146

JO - British Journal of Cancer

T2 - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

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ER -