Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent

Patterson, Laurence H.

doi:10.1007/bf00689805

Cited by 133 publications

(100 citation statements)

References 63 publications

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“…In other studies, where reduction was facilitated, potent cytotoxicity was observed in the nM range (Patterson, 1993;Wilson et al, 1996;Smith et al, 1997b). In vitro the differential activity of AQ4N, to its active metabolite AQ4, is considerably greater than any other N-oxide described including DACA-N-oxide and nitracrine N-oxide (Wilson et al, 1996).…”

Section: Tumour Cell and Topoisomerase II Targeting By Aq4nmentioning

confidence: 96%

“…The product should bind non-covalently to DNA with an affinity high enough to produce cytotoxicity and low enough to allow slow diffusion and subsequent cytotoxicity in proximate tumour cells irrespective of their oxygen levels. AQ4N is an N-oxide of a DNA affinic agent that was rationalized to fulfil such requirements (Patterson, 1993).…”

Section: Tumour Hypoxia and Bioreductive Drugsmentioning

confidence: 99%

“…Topoisomerase II targeting by the DNA affinic AQ4 has been well documented (Patterson, 1993;Smith et al, 1997b). In contrast studies have shown that AQ4N was not able to inhibit decatenation of (kinetoplast) DNA by nuclear extract containing topoisomerase II (Patterson, 1993;Smith et al, 1997b).…”

Section: Tumour Cell and Topoisomerase II Targeting By Aq4nmentioning

confidence: 99%

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AQ4N: a new approach to hypoxia-activated cancer chemotherapy

2000

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Summary Preclinical studies demonstrate that in vivo AQ4N enhances the anti-tumour effects of radiation and chemotherapeutic agents with a dose-modifying factor of approximately 2.0. With careful scheduling no, or very little, additional normal tissue toxicity should be observed. AQ4N is a bioreductive prodrug of a potent, stable, reduction product which binds non-covalently to DNA, facilitating antitumour activity in both hypoxic and proximate oxic tumour cells. AQ4N is clearly different in both its mechanism of action and potential bystander effect compared to previously identified bioreductive drugs. In particular AQ4N is the only bioreductive prodrug topoisomerase II inhibitor to enter clinical trials. Targeting this enzyme, which is crucial to cell division, may help sensitize tumours to repeated (fractionated) courses of radiotherapy. This is because in principle, the bioreduction product of AQ4N can inhibit the topoisomerase activity of hypoxic cells as they attempt to re-enter the cell cycle.

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Section: Tumour Cell and Topoisomerase II Targeting By Aq4nmentioning

confidence: 96%

Section: Tumour Hypoxia and Bioreductive Drugsmentioning

confidence: 99%

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AQ4N: a new approach to hypoxia-activated cancer chemotherapy

2000

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“…Several studies have demonstrated indirectly the importance of CYPs in the bioreductive activation and cytotoxicity of AQ4N. 16,17,26 Initially we evaluated a range of CYPs in vitro, to assess which is most efficient in the bioreduction of AQ4N to its toxic species AQ4. Microsomal preparations from baculovirus-infected cells (BTI-TN-5B1) transfected with various CYPs were evaluated for their ability to reduce AQ4N; CYP1A1 was superior to all other isoforms studied, closely followed by CYP2B6.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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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 CYP1A17CYP 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 ¼ 0.0344). The results show the efficacy of a CYP1A1-mediated GDEPT strategy for bioreduction of AQ4N.

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“…One anticancer agent that is of particular interest is AQ4N, an alkylaminoanthroquinone, which is an inhibitor of both topoisomerase I and topoisomerase II (Paterson, 1993). This compound is activated by CYP3A and, in hypoxic conditions, as is likely to exist in tumours, produces a cytotoxic metabolite of high potency, whereas in normo-oxic conditions there is no cytotoxicity (Paterson, 1993).…”

Section: Discussionmentioning

confidence: 99%

Enhanced expression of cytochrome P450 in stomach cancer

Murray

Taylor²,

Burke³

et al. 1998

Br J Cancer

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Summary The cytochromes P450 have a central role in the oxidative activation and detoxification of a wide range of xenobiotics, including many carcinogens and several anti-cancer drugs. Thus the cytochrome P450 enzyme system has important roles in both tumour development and influencing the response of tumours to chemotherapy. Stomach cancer is one of the commonest tumours of the alimentary tract and environmental factors, including dietary factors, have been implicated in the development of this tumour. This type of tumour has a poor prognosis and responds poorly to current therapies. In this study, the presence and cellular localization of several major forms of P450, CYPl A, CYP2E1 and CYP3A have been investigated in stomach cancer and compared with their expression in normal stomach. There was enhanced expression of CYP1 A and CYP3A in stomach cancer with CYP1 A present in 51% and CYP3A present in 28% of cases. In contrast, no P450 was identified in normal stomach. The presence of CYPlA and CYP3A in stomach cancer provides further evidence for the enhanced expression of specific forms of cytochrome P450 in tumours and may be important therapeutically for the development of anticancer drugs that are activated by these forms of P450.Keywords: cytochrome P450; neoplasm; stomach Stomach cancer is one of the commonest cancers of the alimentary tract and has a relatively poor prognosis with limited response to current modes of therapy (Thompson et al, 1993). Environmental factors, particularly dietary factors, are considered to be important in the aetiology and pathogenesis of this type of tumour. The current model for development of stomach cancer proposes that this type of tumour develops from normal stomach through different types of intestinal metaplasia (Correa, 1988).The cytochromes P450 (P450) are a multi-gene family (Nelson et al, 1996) of constitutive and inducible haem-containing enzymes with a critical role in the metabolism of a diverse range of xenobiotics, including many potential carcinogens (Shimada and Guengerich, 1991;Gonzalez and Gelboin, 1994; RobertsThomson et al, 1995) and various anti-cancer drugs (Kivisto et al, 1995a). Thus, the P450s are considered to have a central role in chemical carcinogenesis and are involved in tumour initiation and promotion as they can activate or deactivate most carcinogens (Gonzalez and Gelboin, 1994). Furthermore the P450s can influence the response of established tumours to anti-cancer drugs by metabolizing these drugs both in normal tissues and in tumour cells. In addition, P450s may have a role in cell regulation, in view of their involvement in the metabolism of physiological chemicals active in inter-and intracellular signalling, including steroid hormones, eicosanoids and fatty acids (Capdevila et al, 1992).The liver is the major normal tissue that expresses P450, while specific forms of P450 are expressed in several different normal extra-hepatic tissues, including small intestine, kidney and lung (Schwartzman et al, 1990;Kaminsky and Fasco, 1992; Shima...

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Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent

Cited by 133 publications

References 63 publications

AQ4N: a new approach to hypoxia-activated cancer chemotherapy

AQ4N: a new approach to hypoxia-activated cancer chemotherapy

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

Enhanced expression of cytochrome P450 in stomach cancer

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