Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N

A Yakkundi, V McErlane, M Murray, HO McCarthy, C Ward, Ciara Hughes, LH Patterson, DG Hirst, Stephanie McKeown, T Robson

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Drug metabolizing transgene products, which activate bioreductive cytotoxins, can be used to target treatment-resistant hypoxic tumors. The prodrug AQ4N is bioreduced in hypoxic cells by cytochrome P450s (CYPs) to the cytotoxin AQ4. Previously we have shown that intra-tumoral injection of CYP3A4 and CYP2B6 transgenes with AQ4N and radiation inhibits tumor growth. Here we examine the ability of other CYPs, in particular CYP1A1, to metabolize AQ4N, and to enhance radiosensitization. Metabolism of AQ4N was assessed using microsomes prepared from baculovirus-infected cells transfected with various CYP isoforms. AQ4N metabolism was most efficient with CYP1A1 (66.7 nmol/min/pmol) and 2B6 (34.4 nmol/min/pmol). Transient transfection of human CYP1A1 +/- CYP reductase (CYPRED) was investigated in hypoxic RIF-1 mouse cells in vitro using the alkaline comet assay. There was a significant increase in DNA damage following transient transfection of CYP1A1 compared to non-transfected cells; inclusion of CYPRED provided no additional effect. In vivo, a single intra-tumoral injection of a CYP1A1 construct in combination with AQ4N (100 mg/kg i.p.) and 20 Gy X-rays caused a 16-day delay in tumor regrowth compared to tumors receiving AQ4N plus radiation and empty vector (P = 0.0344). The results show the efficacy of a CYP1A1-mediated GDEPT strategy for bioreduction of AQ4N.
LanguageEnglish
Pages598-605
JournalCancer Gene Therapy
Volume13
Issue number6
DOIs
Publication statusPublished - Jun 2006

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Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP1A1
Neoplasms
Cytochromes
Cytotoxins
Transgenes
Transfection
Cytochrome Reductases
Radiation
Cytochrome P-450 CYP3A
Injections
Comet Assay
Metabolic Activation
AQ4N
Baculoviridae
Prodrugs
Microsomes
DNA Damage
Oxidoreductases
Protein Isoforms

Cite this

Yakkundi, A., McErlane, V., Murray, M., McCarthy, HO., Ward, C., Hughes, C., ... Robson, T. (2006). Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N. Cancer Gene Therapy, 13(6), 598-605. https://doi.org/10.1038/sj.cgt.7700933
Yakkundi, A ; McErlane, V ; Murray, M ; McCarthy, HO ; Ward, C ; Hughes, Ciara ; Patterson, LH ; Hirst, DG ; McKeown, Stephanie ; Robson, T. / Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N. In: Cancer Gene Therapy. 2006 ; Vol. 13, No. 6. pp. 598-605.
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Yakkundi, A, McErlane, V, Murray, M, McCarthy, HO, Ward, C, Hughes, C, Patterson, LH, Hirst, DG, McKeown, S & Robson, T 2006, 'Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N', Cancer Gene Therapy, vol. 13, no. 6, pp. 598-605. https://doi.org/10.1038/sj.cgt.7700933

Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N. / Yakkundi, A; McErlane, V; Murray, M; McCarthy, HO; Ward, C; Hughes, Ciara; Patterson, LH; Hirst, DG; McKeown, Stephanie; Robson, T.

In: Cancer Gene Therapy, Vol. 13, No. 6, 06.2006, p. 598-605.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N

AU - Yakkundi, A

AU - McErlane, V

AU - Murray, M

AU - McCarthy, HO

AU - Ward, C

AU - Hughes, Ciara

AU - Patterson, LH

AU - Hirst, DG

AU - McKeown, Stephanie

AU - Robson, T

PY - 2006/6

Y1 - 2006/6

N2 - Drug metabolizing transgene products, which activate bioreductive cytotoxins, can be used to target treatment-resistant hypoxic tumors. The prodrug AQ4N is bioreduced in hypoxic cells by cytochrome P450s (CYPs) to the cytotoxin AQ4. Previously we have shown that intra-tumoral injection of CYP3A4 and CYP2B6 transgenes with AQ4N and radiation inhibits tumor growth. Here we examine the ability of other CYPs, in particular CYP1A1, to metabolize AQ4N, and to enhance radiosensitization. Metabolism of AQ4N was assessed using microsomes prepared from baculovirus-infected cells transfected with various CYP isoforms. AQ4N metabolism was most efficient with CYP1A1 (66.7 nmol/min/pmol) and 2B6 (34.4 nmol/min/pmol). Transient transfection of human CYP1A1 +/- CYP reductase (CYPRED) was investigated in hypoxic RIF-1 mouse cells in vitro using the alkaline comet assay. There was a significant increase in DNA damage following transient transfection of CYP1A1 compared to non-transfected cells; inclusion of CYPRED provided no additional effect. In vivo, a single intra-tumoral injection of a CYP1A1 construct in combination with AQ4N (100 mg/kg i.p.) and 20 Gy X-rays caused a 16-day delay in tumor regrowth compared to tumors receiving AQ4N plus radiation and empty vector (P = 0.0344). The results show the efficacy of a CYP1A1-mediated GDEPT strategy for bioreduction of AQ4N.

AB - Drug metabolizing transgene products, which activate bioreductive cytotoxins, can be used to target treatment-resistant hypoxic tumors. The prodrug AQ4N is bioreduced in hypoxic cells by cytochrome P450s (CYPs) to the cytotoxin AQ4. Previously we have shown that intra-tumoral injection of CYP3A4 and CYP2B6 transgenes with AQ4N and radiation inhibits tumor growth. Here we examine the ability of other CYPs, in particular CYP1A1, to metabolize AQ4N, and to enhance radiosensitization. Metabolism of AQ4N was assessed using microsomes prepared from baculovirus-infected cells transfected with various CYP isoforms. AQ4N metabolism was most efficient with CYP1A1 (66.7 nmol/min/pmol) and 2B6 (34.4 nmol/min/pmol). Transient transfection of human CYP1A1 +/- CYP reductase (CYPRED) was investigated in hypoxic RIF-1 mouse cells in vitro using the alkaline comet assay. There was a significant increase in DNA damage following transient transfection of CYP1A1 compared to non-transfected cells; inclusion of CYPRED provided no additional effect. In vivo, a single intra-tumoral injection of a CYP1A1 construct in combination with AQ4N (100 mg/kg i.p.) and 20 Gy X-rays caused a 16-day delay in tumor regrowth compared to tumors receiving AQ4N plus radiation and empty vector (P = 0.0344). The results show the efficacy of a CYP1A1-mediated GDEPT strategy for bioreduction of AQ4N.

U2 - 10.1038/sj.cgt.7700933

DO - 10.1038/sj.cgt.7700933

M3 - Article

VL - 13

SP - 598

EP - 605

JO - Cancer Gene Therapy

T2 - Cancer Gene Therapy

JF - Cancer Gene Therapy

SN - 0929-1903

IS - 6

ER -