iNOS as a therapeutic target for treatment of human tumors

Fitzpatrick, Brian; Mehibel, Manal; Cowen, Rachel L.; Stratford, Ian J.

doi:10.1016/j.niox.2008.05.001

Cited by 72 publications

(49 citation statements)

References 92 publications

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“…TAMs are the main site of iNOS expression in human breast cancer as shown by Thomsen et al (7). In this type of cancer, we observed a 5-fold increase in total NOS activity in breast tumor biopsies compared with normal breast tissue (48). iNOS expression in human breast tumor models was also confirmed by immunohistochemical analysis and appeared to be localized primarily in areas between viable and necrotic regions of the tumor (an area that is presumably hypoxic; ref.…”

Section: Discussionsupporting

confidence: 58%

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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Section: Discussionsupporting

confidence: 58%

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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“…28,29 Over expression of NOS (Nitric oxide synthase) and presence of p53 are associated with better response to tirapazamine. 30,31 These markers and markers of chronic hypoxia like hypoxia-inducible factor-1alpha(HIF-1alpha), carbonic anhydrase 9 (CA 9) and glucose transporter 1 (GLUT1) may help in judging the role of tirapazamine. 32 Finally, the intracellular pH is also found to be an independent factor, independent of the oxygenation status of the cells in determining the cytotoxicity of tirapazamine.…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of tirapazamine as anti-cancer drug: a meta-analysis of randomized controlled trials

Hiremath

Devendrappa

2018

Int J Basic Clin Pharmacol

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Background: The benefits of achieving better response by adding tirapazamine, a specific hypoxic cancer cell killer to chemo and or radiotherapy is contradictory. This study aims at analyzing the efficacy and safety of tirapazamine, apart from understanding the reasons for its doubtful and inconsistent benefits.Methods: Electronic database search in PUBMED, EMBASE, Cochrane library was conducted using search term “tirapazamine”. Randomized or cross-over studies comparing effects of tirapazamine vs other active treatment or placebo in patients >18yrs with any type of cancers were included under analysis. Overall Survival rate was the primary outcome measure while the incidences of grade-3 and 4 adverse drug reactions were the secondary outcome measure. Inverse variance method and both random and fixed effect models were used in the analysis by RevMan 5.3 software.Results: Total six studies were eligible with 1034 patients included in the analysis. Tirapazamine failed to show significant effect on overall survival rate at the end of one year (HR: 0.96, 95% CI: 0.88, 1.05), two year (HR: 1.04, 95% CI: 0.98, 1.12), three year (HR: 1.01, 95% CI: 0.89, 1.15) and five year (HR: 0.97, 95% CI: 0.77, 1.23) compared to placebo group. There was a significantly higher incidence of muscle cramps (Risk Difference, RD: 0.06, 95% CI: 0.02, 0.11) and dermal adverse events (RD: 0.03, 95% CI: 0.01, 0.06) in tirapazamine group.Conclusions: With the available evidences from clinical trials and preclinical studies, use of tirapazamine may not be justifiable and so is to side line this drug as another failed drug.

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“…Certain cytochrome P450 enzymes (McErlane et al, 2005;Nishida et al, 2010;Xiao et al, 2011) and iNOS (Fitzpatrick et al, 2008;Nishida and Ortiz de Montellano, 2008;Mehibel et al, 2009) can activate AQ4N via a two-step reduction of the di-N-oxide to the di-amino compound AQ4. Other pathways of reductive metabolism demonstrated for related quinones include one-electron reduction to a semiquinone radical and two-electron reduction to a hydroquinone, both of which can be cytotoxic (Nguyen and Gutierrez, 1990;Ross et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Impact of Tumor Blood Flow Modulation on Tumor Sensitivity to the Bioreductive Drug Banoxantrone

Manley

Waxman

2012

J Pharmacol Exp Ther

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We investigated the hypoxia-dependent cytotoxicity of AQ4N (banoxantrone) using a panel of 13 cancer cell lines and studied its relationship to the expression of the quinone reductase DTdiaphorase (NQO1), which is widely found in cancer cells. We also investigated pharmacologic treatments that increase tumor hypoxia in vivo and their impact on AQ4N chemosensitivity in a solid tumor xenograft model. AQ4N showed $8-fold higher cytotoxicity under hypoxia than normoxia in cultures of 9L rat gliosarcoma and H460 human non-small-cell lung carcinoma cells but not for 11 other human cancer cell lines. DT-diaphorase protein levels and AQ4N chemosensitivity were poorly correlated across the cancer cell line panel, and AQ4N chemosensitivity was not affected by DT-diaphorase inhibitors. The vasodilator hydralazine decreased tumor perfusion and increased tumor hypoxia in 9L tumor xenografts, and to a lesser extent in H460 tumor xenografts. However, hydralazine did not increase AQ4N-dependent antitumor activity. Combination of AQ4N with the angiogenesis inhibitor axitinib, which increases 9L tumor hypoxia, transiently increased antitumor activity but with an increase in host toxicity. These findings indicate that the capacity to bioactivate AQ4N is not dependent on DTdiaphorase and is not widespread in cultured cancer cell lines. Moreover, the activation of AQ4N cytotoxicity in vivo requires tumor hypoxia that is more extensive or prolonged than can readily be achieved by vasodilation or by antiangiogenic drug treatment.

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iNOS as a therapeutic target for treatment of human tumors

Cited by 72 publications

References 92 publications

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

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

Safety and efficacy of tirapazamine as anti-cancer drug: a meta-analysis of randomized controlled trials

Impact of Tumor Blood Flow Modulation on Tumor Sensitivity to the Bioreductive Drug Banoxantrone

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