Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N

Helen McCarthy, A Yakkundi, V McErlane, Ciara Hughes, G Keilty, Margaret Murray, LH Patterson, DG Hirst, SR McKeown, T Robson

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

The bioreductive drug, AQ4N, is metabolized under hypoxic conditions and has been shown to enhance the antitumor effects of radiation and chemotherapy drugs. We have investigated the role of cytochrome P450 3A4 (CYP3A4) in increasing the metabolism of AQ4N using a gene-directed enzyme prodrug therapy (GDEPT) strategy. RIF-1 murine tumor cells were transfected with a mammalian expression vector containing CYP3A4 cDNA. In vitro AQ4N metabolism, DNA damage, and clonogenic cell kill were assessed following exposure of transfected and parental control cells to AQ4N. The presence of exogenous CYP3A4 increased the metabolism of AQ4N and significantly enhanced the ability of the drug to cause DNA strand breaks and clonogenic cell death. Cotransfection of CYP reductase with CYP3A4 showed a small enhancement of the effect in the DNA damage assay only. A single injection of CYP3A4 into established RIF-1 murine tumors increased the metabolism of AQ4N, and when used in combination with radiation, three of nine tumors were locally controlled for >60 days. This is the first demonstration that CYPs alone can be used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N. AQ4N is the only CYP-activated bioreductive agent in clinical trials. Combination with a GDEPT strategy may offer a further opportunity for targeting radiation-resistant and chemo-resistant hypoxic tumor cells.
LanguageEnglish
Pages40-48
JournalCancer Gene Therapy
Volume10
Issue number1
Publication statusPublished - Jan 2003

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Enzyme Therapy
Cytochrome P-450 CYP3A
Prodrugs
Genes
DNA Damage
Neoplasms
Pharmaceutical Preparations
Radiation
DNA Breaks
AQ4N
Radiation Effects
Oxidoreductases
Cell Death
Complementary DNA
Clinical Trials
Drug Therapy
Injections

Keywords

  • GDEPT
  • cytochrome P450
  • AQ4N
  • radiation
  • bioreductive prodrug
  • CYP3A4

Cite this

McCarthy, H., Yakkundi, A., McErlane, V., Hughes, C., Keilty, G., Murray, M., ... Robson, T. (2003). Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N. Cancer Gene Therapy, 10(1), 40-48.
McCarthy, Helen ; Yakkundi, A ; McErlane, V ; Hughes, Ciara ; Keilty, G ; Murray, Margaret ; Patterson, LH ; Hirst, DG ; McKeown, SR ; Robson, T. / Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N. In: Cancer Gene Therapy. 2003 ; Vol. 10, No. 1. pp. 40-48.
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McCarthy, H, Yakkundi, A, McErlane, V, Hughes, C, Keilty, G, Murray, M, Patterson, LH, Hirst, DG, McKeown, SR & Robson, T 2003, 'Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N', Cancer Gene Therapy, vol. 10, no. 1, pp. 40-48.

Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N. / McCarthy, Helen; Yakkundi, A; McErlane, V; Hughes, Ciara; Keilty, G; Murray, Margaret; Patterson, LH; Hirst, DG; McKeown, SR; Robson, T.

In: Cancer Gene Therapy, Vol. 10, No. 1, 01.2003, p. 40-48.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N

AU - McCarthy, Helen

AU - Yakkundi, A

AU - McErlane, V

AU - Hughes, Ciara

AU - Keilty, G

AU - Murray, Margaret

AU - Patterson, LH

AU - Hirst, DG

AU - McKeown, SR

AU - Robson, T

PY - 2003/1

Y1 - 2003/1

N2 - The bioreductive drug, AQ4N, is metabolized under hypoxic conditions and has been shown to enhance the antitumor effects of radiation and chemotherapy drugs. We have investigated the role of cytochrome P450 3A4 (CYP3A4) in increasing the metabolism of AQ4N using a gene-directed enzyme prodrug therapy (GDEPT) strategy. RIF-1 murine tumor cells were transfected with a mammalian expression vector containing CYP3A4 cDNA. In vitro AQ4N metabolism, DNA damage, and clonogenic cell kill were assessed following exposure of transfected and parental control cells to AQ4N. The presence of exogenous CYP3A4 increased the metabolism of AQ4N and significantly enhanced the ability of the drug to cause DNA strand breaks and clonogenic cell death. Cotransfection of CYP reductase with CYP3A4 showed a small enhancement of the effect in the DNA damage assay only. A single injection of CYP3A4 into established RIF-1 murine tumors increased the metabolism of AQ4N, and when used in combination with radiation, three of nine tumors were locally controlled for >60 days. This is the first demonstration that CYPs alone can be used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N. AQ4N is the only CYP-activated bioreductive agent in clinical trials. Combination with a GDEPT strategy may offer a further opportunity for targeting radiation-resistant and chemo-resistant hypoxic tumor cells.

AB - The bioreductive drug, AQ4N, is metabolized under hypoxic conditions and has been shown to enhance the antitumor effects of radiation and chemotherapy drugs. We have investigated the role of cytochrome P450 3A4 (CYP3A4) in increasing the metabolism of AQ4N using a gene-directed enzyme prodrug therapy (GDEPT) strategy. RIF-1 murine tumor cells were transfected with a mammalian expression vector containing CYP3A4 cDNA. In vitro AQ4N metabolism, DNA damage, and clonogenic cell kill were assessed following exposure of transfected and parental control cells to AQ4N. The presence of exogenous CYP3A4 increased the metabolism of AQ4N and significantly enhanced the ability of the drug to cause DNA strand breaks and clonogenic cell death. Cotransfection of CYP reductase with CYP3A4 showed a small enhancement of the effect in the DNA damage assay only. A single injection of CYP3A4 into established RIF-1 murine tumors increased the metabolism of AQ4N, and when used in combination with radiation, three of nine tumors were locally controlled for >60 days. This is the first demonstration that CYPs alone can be used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N. AQ4N is the only CYP-activated bioreductive agent in clinical trials. Combination with a GDEPT strategy may offer a further opportunity for targeting radiation-resistant and chemo-resistant hypoxic tumor cells.

KW - GDEPT

KW - cytochrome P450

KW - AQ4N

KW - radiation

KW - bioreductive prodrug

KW - CYP3A4

M3 - Article

VL - 10

SP - 40

EP - 48

JO - Cancer Gene Therapy

T2 - Cancer Gene Therapy

JF - Cancer Gene Therapy

SN - 0929-1903

IS - 1

ER -

McCarthy H, Yakkundi A, McErlane V, Hughes C, Keilty G, Murray M et al. Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N. Cancer Gene Therapy. 2003 Jan;10(1):40-48.