Tirapazamine, Cisplatin, and Radiation Versus Fluorouracil, Cisplatin, and Radiation in Patients With Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02)

Rischin, Danny; Peters, Lester J.; Fisher, Richard; Macann, Andrew; Denham, James W.; Poulsen, Michael; Jackson, Michael; Kenny, Liz; Penniment, Michael; Corry, June; Lamb, David; McClure, Bev

doi:10.1200/jco.2005.01.072

Cited by 225 publications

(129 citation statements)

References 18 publications

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“…Various radiosensitizers have been developed in the past, which were designed to sensitize hypoxic tumor cells to radiation. However, their clinical use was hampered because of their neurotoxicity and low efficacy (Rowinsky, 1999;Zackrisson et al, 2003;Overgaard et al, 2005;Rischin et al, 2005). Recently, Sobhanifar et al (2005) examined human tumor biopsies and human cancer xenografts with expression of HIF-1a and distribution of a chemical hypoxia marker, pimonidazole, which become reactive at less than 10 mm Hg oxygen tension.…”

Section: Discussionmentioning

confidence: 99%

Significance of HIF-1-active cells in angiogenesis and radioresistance

et al. 2007

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Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than the normal tissues. Hypoxia offers resistance to radiotherapy and anticancer chemotherapy, as well as predispose to increased tumor metastases. Furthermore, hypoxia induces hypoxia-inducible factor-1 (HIF-1), which in turn increases tumor angiogenesis. Thus, eradication of HIF-1-active/hypoxic tumor cells is very important for cancer therapy. We have previously reported that procaspase-3 fused with a von Hippel-Lindau (VHL)-mediated protein destruction motif of alpha subunit of HIF-1 (HIF-1a) containing Pro564, named TAT-ODDprocaspase-3 (TOP3), specifically induced cell death to hypoxic cells in vivo as well as in vitro. We now report that TOP3 also eradicates the radiation-induced HIF-1-active tumor cells. HIF-1 activity in the xenografts of human tumor cells, which express luciferase under the transcriptional control of HIF-1, were monitored and quantified daily with an in vivo bioluminescence photon-counting device. HIF-1 activity in tumors was more rapidly increased by ionizing radiation (IR) compared to untreated tumors. TOP3 efficiently decreased the HIF-1-activity in irradiated tumors as well as unirradiated ones, indicating TOP3 eradicated tumor cells with HIF-1-activity induced by IR as well as hypoxia. Eradication of HIF-1-active/hypoxic cells in the xenografts during irradiation exhibited significant suppression in angiogenesis and strong enhancement in a long-term growth suppression of tumor xenografts. These results further strengthen the argument that HIF-1-active/ hypoxic cells play crucial roles in angiogenesis and radioresistance.

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Section: Discussionmentioning

confidence: 99%

Significance of HIF-1-active cells in angiogenesis and radioresistance

et al. 2007

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“…Tirapazamine, is a prodrug that is solely reduced in hypoxic cells, provoking highly genotoxic DNA double-strand breaks. Its use before radiotherapy enhanced 3-year survival rates in phase-II trials (Rischin et al, 2005), but it was found ineffectual in all considered parameters in a multinational phase-III trial (Rischin et al, 2010). On the other hand, astounding results in human cancer patients have been achieved with small-molecule glycolysis inhibitors.…”

Section: The Rise Of Anticancer Therapeutics Targeting Metabolismmentioning

confidence: 99%

Metabolic reprogramming of the tumor

2012

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Cancer is classically considered as a genetic and, more recently, epigenetic multistep disease. Despite seminal studies in the 1920s by Warburg showing a characteristic metabolic pattern for tumors, cancer bioenergetics has often been relegated to the backwaters of cancer biology. This review aims to provide a historical account on cancer metabolism research, and to try to integrate and systematize the metabolic strategies in which cancer cells engage to overcome selective pressures during their inception and evolution. Implications of this renovated view on some common concepts and in therapeutics are also discussed.

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“…Tirapazamine is specifically reduced in hypoxic cells, forming radical species that poison topoisomerase II leading to DNA double-strand breaks 117 . Clinical trials with this agent have demonstrated benefit in patients with lung as well as head and neck cancer, when used in combination with radiation or chemotherapy 118,119 .…”

Section: Therapeutic Implications Of Tumor Hypoxiamentioning

confidence: 99%

The impact of O2 availability on human cancer

2008

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During the last century, it has been established that regions within solid tumors experience mild to severe oxygen deprivation, due to aberrant vascular function. These hypoxic regions are associated with altered cellular metabolism, as well as increased resistance to radiation and chemotherapy. As discussed in this Timeline, over the past decade, work from many laboratories has elucidated the mechanisms by which hypoxia-inducible factors (HIFs) modulate tumor cell metabolism, angiogenesis, growth, and metastasis. The central role played by intra-tumoral hypoxia and HTF in these processes has made them attractive therapeutic targets in the treatment of multiple human malignancies.Oxygen (O 2 ) is required for aerobic metabolism to maintain intracellular bioenergetics and serve as an electron acceptor in many organic and inorganic reactions. Hypoxia, defined as reduced O 2 levels, occurs in a variety of pathological conditions, including stroke, tissue ischemia, inflammation, and the growth of solid tumors. The beginnings of hypoxia research in tumor biology can be traced back to observations made in the early 20 th century by Otto Warburg who demonstrated that, unlike normal cells, tumor cells favor glycolysis, independent of cellular oxygenation levels. He postulated that tumor growth is caused by mitochondrial dysfunction in neoplastic cells, forcing them to generate energy through glycolysis (reviewed in 1 ). This hypothesis appears to be incorrect, but a number of other molecular mechanisms promoting "aerobic glycolysis" have been proposed including mutations and epigenetic changes in genes encoding tumor suppressors (e.g. p53), oncogene activation (e.g. c-Myc), and hypoxic adaptations {Denko, 2008 #6606; Gatenby, 2004 #6608; Deberardinis, 2008 #6609.

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Tirapazamine, Cisplatin, and Radiation Versus Fluorouracil, Cisplatin, and Radiation in Patients With Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02)

Abstract: Both regimens are feasible and are associated with significant but acceptable toxicity profiles in the cooperative group setting. Based on the promising efficacy seen in this trial, TPZ/CIS is being evaluated in a large phase III trial.

Cited by 225 publications

References 18 publications

Significance of HIF-1-active cells in angiogenesis and radioresistance

Significance of HIF-1-active cells in angiogenesis and radioresistance

Metabolic reprogramming of the tumor

The impact of O2 availability on human cancer

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