NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals.

Bachur, Nicholas R.; Gordon, Sandra; Gee, Malcolm V.; Kon, Hideo

doi:10.1073/pnas.76.2.954

Cited by 467 publications

(286 citation statements)

References 19 publications

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“…It is reduced in cellular cytoplasm by aldehyde and ketone reductases. Detoxification probably occurs by NADPH cytochrome P450 reductase-catalysed reduction of the oxygen-linked glycoside forms to deoxyglycone forms (Difonzo et al, 1971;Bachur et al, 1974Bachur et al, , 1979Bachur, 1975;Benjamin et al, 1977;Oki et al, 1977;Felsted and Bachur, 1980;Gutierrez et al, 1983). DOX and its primary alcohol metabolite doxorubicinol (DOXOL) are excreted unchanged in the bile and to a lesser extent in the urine (Difonzo et al, 1971;Bachur et al, 1974;Bachur, 1975;Benjamin et al, 1977).…”

Section: Doxorubicin (Dox)mentioning

confidence: 99%

An evaluation of hepatic extraction and clearance of doxorubicin

August¹,

Verma²,

Vaertan³

et al. 1995

Br J Cancer

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Section: Doxorubicin (Dox)mentioning

confidence: 99%

An evaluation of hepatic extraction and clearance of doxorubicin

August¹,

Verma²,

Vaertan³

et al. 1995

Br J Cancer

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“…The latter shares a high degree of sequence homology to NADPH:cytochrome P450 reductase (13). Cytochrome P450 reductase and NOSR have been shown to be involved in the metabolism and activation of Adriamycin (14,15) and certain bioreductive drugs including tirapazamine (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N)

Mehibel

Singh

Chinje

et al. 2009

Molecular Cancer Therapeutics

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Tumor-associated macrophages (TAMs) are found in many solid tumors and have often been shown to accumulate in the hypoxic regions surrounding areas of necrosis. TAMs are the major site of expression of nitric oxide synthase (NOS), a heme-containing homodimeric enzyme consisting of oxygenase and reductase domains. The latter has a high degree of sequence homology to cytochrome P450 reductase and a functional consequence of this is the ability of NOS, under hypoxic conditions, to activate the bioreductive drugs tirapazamine and RSU1069. Banoxantrone (AQ4N) is a bioreductive prodrug activated in hypoxia by an oxygen-dependent two-electron reductive process to yield the topoisomerase II inhibitor AQ4. A feature of this process is that the final product could potentially show bystander cell killing. Thus, in this study, we investigated the ability of inducible NOS (iNOS)-expressing TAMs to activate AQ4N and elicit toxicity in cocultured human tumor cells. Murine macrophages were induced to overexpress iNOS by treatment with a combination of cytokines, mixed with HT1080 and HCT116 human tumor cells, and the toxicity of AQ4N was determined under aerobic or hypoxic conditions. The aerobic toxicity of AQ4N toward tumor cells was not affected through coculturing with macrophages. However, under hypoxic conditions, the induction of iNOS activity in the macrophages was associated with an increase in AQ4N metabolism and a substantial increase in tumor cell toxicity, which was dependent on the proportion of macrophages in the culture. This study is the first demonstration of TAM-mediated prodrug activation to result in bystander killing of human tumor cells.

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“…The picture is of course more complex with mitomycin C since toxicity under oxic conditions will arise not only via oxidative stress (Bachur et al, 1979;Pritsos & Sartorelli, 1986) but also through bioreductive activation to DNAalkylating species (Pan et al, 1984;Tomasz et al, 1987). Under hypoxic conditions DNA adducts, including crosslinks, will predominate.…”

mentioning

confidence: 99%