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

Yakkundi, Anita; McErlane, Verna; Murray, Margaret; McCarthy, Helen; Ward, Claire; Hughes, Ciara; Patterson, Laurence H.; Hirst, David; McKeown, Stephanie

doi:10.1038/sj.cgt.7700933

Cited by 38 publications

(18 citation statements)

References 41 publications

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“…Thus, reduction of AQ4N to the mono N-oxide intermediate AQ4M [ 1-{[2-(dimethylamino-N-oxide)ethyl]amino}-4-{[2-(dimethylamino) ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione] and finally to AQ4 provides a mechanism for selectively generating the active topoisomerase inhibitor within hypoxic cancer cells. Previous studies of a panel of well characterized drug-metabolizing cytochrome P450 (P450) isoforms found that several have sig-nificant activity for the reduction of AQ4N to AQ4 (Raleigh et al, 1998;Yakkundi et al, 2006). Among these, CYP3A4 was the most effective (Raleigh et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

Nishida

Lee²,

Montellano³

2010

Mol Pharmacol

104

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AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N-oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N-oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in solid tumors. CYP2S1 and CYP2W1, two extrahepatic P450 enzymes identified from the human genome whose functions are unknown, are expressed in hypoxic tumor cells at much higher levels than in normal tissue. Here, we demonstrate that CYP2S1, contrary to a published report (Mol Pharmacol 76:1031-1043, 2009), is efficiently reduced by NADPH-P450 reductase. Most importantly, both CYP2S1 and CYP2W1 are better catalysts for the reductive activation of AQ4N to AQ4 than all previously examined P450 enzymes. The overexpression of CYP2S1 and CYP2W1 in tumor tissues, together with their high catalytic activities for AQ4N activation, suggests that they may be exploited for the localized activation of anticancer prodrugs.

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Section: Introductionmentioning

confidence: 99%

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

Nishida

Lee²,

Montellano³

2010

Mol Pharmacol

104

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“…Because there is considerable variability in expression of cytochrome isoforms between tumor types, we hypothesize that low levels of a specific cytochrome isoform needed to activate AQ4N may impair efficient activation in certain experimental systems. Robson and colleagues showed that the antitumor efficacy of AQ4N could be increased by delivery of genes encoding the appropriate drug metabolizing cytochrome enzymes to syngeneic mouse tumors in a gene-directed prodrug therapy strategy (28,29). The PC-3 cell line used in current experiments did not show hypoxia-selective sensitivity to AQ4N and AQ4N/AQ4 accumulation in hypoxic regions of PC-3 xenografts, perhaps due to failure to activate AQ4N to AQ4.…”

Section: Discussionmentioning

confidence: 82%

“…26). The mechanism of enzymatic reduction of AQ4N remains incompletely understood but seems to be mediated by multiple cytochrome P450 enzymes (27,28). Because there is considerable variability in expression of cytochrome isoforms between tumor types, we hypothesize that low levels of a specific cytochrome isoform needed to activate AQ4N may impair efficient activation in certain experimental systems.…”

Section: Discussionmentioning

confidence: 99%

The Hypoxia-Activated ProDrug AQ4N Penetrates Deeply in Tumor Tissues and Complements the Limited Distribution of Mitoxantrone

Trédan

Garbens

Lalani³

et al. 2009

Cancer Research

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Hypoxic tumor cells are likely to be resistant to conventional chemotherapy, in large part because many anticancer drugs are unable to penetrate into poorly oxygenated tumor tissue. Here, we used quantitative immunofluorescence to study the distribution of mitoxantrone and AQ4N in tumor tissue. AQ4N is a prodrug activated under hypoxic conditions to AQ4, which is structurally similar to mitoxantrone and inhibits topoisomerase II. We characterized the penetration of mitoxantrone and AQ4N/AQ4 through multilayered cell cultures (MCC) and in relation to blood vessels and hypoxic regions in human tumor xenografts. We also studied tumor growth delay after treatment with each agent alone and with the combination. In both MCC and xenografts, mitoxantrone is taken up by proximal cells and penetrates slowly to distant regions. In contrast, AQ4N rapidly penetrates MCC and tumor tissue in vivo, and AQ4N (or its reduced form AQ4) is detected at high concentration within hypoxic regions. The targeting of mitoxantrone to oxygenated regions and AQ4N/AQ4 to hypoxic tumor regions results in effective drug exposure over the entire tumor after combined treatment and increases tumor growth delay compared with either drug alone. The combination of a clinically used anticancer drug with limited tissue penetration and a structurally related drug activated in regions of tumor hypoxia is an effective strategy to overcome chemoresistance due to the tumor microenvironment. This study supports clinical evaluation of AQ4N in combination with conventional anticancer agents, such as mitoxantrone.

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“…[1] In the ideal case, treatment with such drugs would not require detailed biochemical knowledge of the diseased cell, using only the genetic information per se, such that complications due to mutations in the target, resistance, or genetic differences between individual patients could be evaded by only changing the sensing part of the encoded drug. Other approaches rely on, for example, the targeting of a gene coding for a prodrug metabolizing enzyme (GDEPT), [2][3] or activation of prodrugs by exogenous enzymes delivered to tumor cells from DNA constructs containing the corresponding gene (ADEPT). [4] Prodrugs can be defined as agents that are transformed into pharmacologically active species after administration.…”

Section: Introductionmentioning

confidence: 99%

Model Systems for Activation of Nucleic Acid Encoded Prodrugs

et al. 2007

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The development of more selective chemotherapeutic agents for benign treatments of malicious diseases is highly desirable. In recent years model systems for the release of small molecule drugs from nucleic acid conjugates by templated chemical or photochemical reactions have been designed. Common for these systems is that the stoichiometric or catalytic drug release is controlled by the highly selective hybridization between complementary strands of nucleic acids. Herein, the concepts of the new field of nucleic acid templated release reactions are outlined.

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

Cited by 38 publications

References 41 publications

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

The Hypoxia-Activated ProDrug AQ4N Penetrates Deeply in Tumor Tissues and Complements the Limited Distribution of Mitoxantrone

Model Systems for Activation of Nucleic Acid Encoded Prodrugs

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