Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia

Guise, Christopher P.; Mowday, Alexandra M.; Ashoorzadeh, Amir; Yuan, Ran; Lin, Wenchu; Wu, Donghai; Smaill, Jeff B.; Patterson, Adam V.; Ding, Ke

doi:10.5732/cjc.012.10285

Cited by 144 publications

(157 citation statements)

References 65 publications

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“…Tirapazamine (TPZ) is the most extensively studied HAP, and it was shown to provide good antitumour enhancement in Phase II clinical trials. 118 This was not confirmed in Phase III trials, which failed to report a significant increase in survival in comparison with conventional therapy. 119,120 However, these patients were not categorized based on their level of tumour hypoxia.…”

Section: Direct Targeting Of Hypoxic Tumour Cells With Hypoxia-activamentioning

confidence: 81%

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

McKeown

2014

BJR

808

712

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Tumour hypoxia is increasingly recognized as a major deleterious factor in cancer therapies, as it compromises treatment and drives malignant progression. This review seeks to clarify the oxygen levels that are pertinent to this issue. It is argued that normoxia (20% oxygen) is an extremely poor comparator for "physoxia", i.e. the much lower levels of oxygen universally found in normal tissues, which averages about 5% oxygen, and ranges from about 3% to 7.4%. Importantly, it should be recognized that the median oxygenation in untreated tumours is significantly much lower, falling between approximately 0.3% and 4.2% oxygen, with most tumours exhibiting median oxygen levels ,2%. This is partially dependent on the tissue of origin, and it is notable that many prostate and pancreatic tumours are profoundly hypoxic. In addition, therapy can induce even further, often unrecognized, changes in tumour oxygenation that may vary longitudinally, increasing or decreasing during treatment in ways that are not always predictable. Studies that fail to take cognizance of the actual physiological levels of oxygen in tissues (approximately 5%) and tumours (approximately 1%) may fail to identify the real circumstances driving tumour response to treatment and/or malignant progression. This can be of particular importance in genetic studies in vitro when comparison to human tumours is required.

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Section: Direct Targeting Of Hypoxic Tumour Cells With Hypoxia-activamentioning

confidence: 81%

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

McKeown

2014

BJR

808

712

View full text Add to dashboard Cite

show abstract

“…In keeping with this, efforts are underway to identify selective inhibitors of HIF-1 and to assess their efficacy as anticancer therapeutics. Currently, two main approaches are used to target hypoxia in tumors, namely bioreductive prodrugs, and inhibitors of molecular targets upon which hypoxic cell survival depends [63,64]. However, several lines of evidence indicate that the HIF pathway is technically extremely challenging to target.…”

Section: The Clinical Significance Of Targeting Hypoxiamentioning

confidence: 99%

The Critical Role of Hypoxia in Tumor-Mediated Immunosuppression

Aouali¹,

Bosseler²,

Sauvage³

et al. 2017

Hypoxia and Human Diseases

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Underestimated for a long time, the involvement of the microenvironment has been proven essential for a better understanding of the cancer development. In keeping with this, the tumor is not considered anymore as a mass of malignant cells, but rather as an organ composed of various malignant and nonmalignant cell populations interacting with each other to create the tumor microenvironment. The tumor immune contexture plays a critical role in shaping the tumor immune response, and it is now well supported that such an immune response is impacted by the hypoxic stress within the tumor microenvironment. Tumor hypoxia is closely linked to tumor progression, metastasis, treatment failure, and escape from immune surveillance. Thus, hypoxia seems to be a key factor involved in creating an immune-suppressive tumor by multiple overlapping mechanisms, including the impairment of the function of cytotoxic immune cells, increasing the immunosuppressive properties of immunosuppressive cells, and activating resistance mechanism in the tumor cells. In this chapter, we review some recent findings describing how hypoxic stress in the tumor microenvironment hijacks the antitumor immune response.

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“…They are activated by enzymatic reduction in hypoxic tissue to form cytotoxins, resulting in hypoxia-selective cell killing [48] .…”

Section: Bioreductive Prodrugsmentioning

confidence: 99%

“…OXY111A is a synthetic allosteric effector of hemoglobin-4 and promotes normoxia in hypoxic tumors [48] . OXY111A has been tested in several cancer animal models, showing beneficial outcomes and low side effect profiles [49] .…”

Section: Bioreductive Prodrugsmentioning

confidence: 99%

Hypoxic microenvironment and hepatocellular carcinoma treatment

Lin¹,

Chang²,

Zhu³

et al. 2018

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Hepatocellular carcinoma (HCC) is one of the most rapidly growing and prevalent cancers in the whole world. The characterized hypoxia region inside the HCC tumors has been recently found as the key driver of HCC malignance and treatment failure, leading to a variety of hypoxia-related biological consequences including angiogenesis, metastasis, metabolism deregulation and drug resistance, which ultimately resulted in treatment failure of HCC. This review will summarize the signaling pathways involved in hypoxia-mediated malignance of HCC and discuss current advances of hypoxia-targeted therapies.

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Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia

Cited by 144 publications

References 65 publications

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

The Critical Role of Hypoxia in Tumor-Mediated Immunosuppression

Hypoxic microenvironment and hepatocellular carcinoma treatment

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