Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.

Hypoxia — a key regulatory factor in tumour growth

Solid tumours contain regions at very low oxygen concentrations (hypoxia), often surrounding areas of necrosis. The cells in these hypoxic regions are resistant to both radiotherapy and chemotherapy. However, the existence of hypoxia and necrosis also provides an opportunity for tumour-selective therapy, including prodrugs activated by hypoxia, hypoxia-specific gene therapy, targeting the hypoxia-inducible factor 1 transcription factor, and recombinant anaerobic bacteria. These strategies could turn what is now an impediment into a significant advantage for cancer therapy.

Exploiting tumour hypoxia in cancer treatment.

Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.

Drug Resistance and the Solid Tumor Microenvironment

During the past century, the response to hypoxia has emerged as an important phenotypic determinant of a tumour, with repercussions for sensitivity to radiation and chemotherapy. This Timeline provides a historical overview of responses to hypoxia while looking forward to therapeutic strategies that are being developed to exploit them. During the past century it has been established that regions within solid tumours experience mild to severe O2 deprivation owing 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 tumour cell metabolism, angiogenesis, growth and metastasis. The central role played by intra-tumoural hypoxia and HIF in these processes has made them attractive therapeutic targets in the treatment of multiple human malignancies.

The impact of O2 availability on human cancer.

Oxygen supply and diffusion into tissues are necessary for survival. The oxygen partial pressure (pO2), which is a key component of the physiological state of an organ, results from the balance between oxygen delivery and its consumption. In mammals, oxygen is transported by red blood cells circulating in a well-organized vasculature. Oxygen delivery is dependent on the metabolic requirements and functional status of each organ. Consequently, in a physiological condition, organ and tissue are characterized by their own unique ‘tissue normoxia’ or ‘physioxia’ status. Tissue oxygenation is severely disturbed during pathological conditions such as cancer, diabetes, coronary heart disease, stroke, etc., which are associated with decrease in pO2, i.e. ‘hypoxia’. In this review, we present an array of methods currently used for assessing tissue oxygenation. We show that hypoxia is marked during tumour development and has strong consequences for oxygenation and its influence upon chemotherapy efficiency. Then we compare this to physiological pO2 values of human organs. Finally we evaluate consequences of physioxia on cell activity and its molecular modulations. More importantly we emphasize the discrepancy between in vivo and in vitro tissue and cells oxygen status which can have detrimental effects on experimental outcome. It appears that the values corresponding to the physioxia are ranging between 11% and 1% O2 whereas current in vitro experimentations are usually performed in 19.95% O2, an artificial context as far as oxygen balance is concerned. It is important to realize that most of the experiments performed in so-called normoxia might be dangerously misleading.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1582-4934.2011.01258.x

Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia

PURPOSE: A phase III trial, Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non–Small-Cell Lung Tumors (CATAPULT I), was designed to determine the efficacy and safety of tirapazamine plus cisplatin for the treatment of non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously untreated NSCLC were randomized to receive either tirapazamine (390 mg/m2 infused over 2 hours) followed 1 hour later by cisplatin (75 mg/m2 over 1 hour) or 75 mg/m2 of cisplatin alone, every 3 weeks for a maximum of eight cycles. RESULTS: A total of 446 patients with NSCLC (17% with stage IIIB disease and pleural effusions; 83% with stage IV disease) were entered onto the study. Karnofsky performance status (KPS) was ≥ 60 for all patients (for 10%, KPS = 60; for 90%, KPS = 70 to 100). Sixty patients (14%) had clinically stable brain metastases. The median survival was significantly longer (34.6 v 27.7 weeks; P = .0078) and the response rate was significantly greater (27.5% v 13.7%; ...

Tirapazamine Plus Cisplatin Versus Cisplatin in Advanced Non–Small-Cell Lung Cancer: A Report of the International CATAPULT I Study Group

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Tirapazamine Plus Cisplatin Versus Cisplatin in Advanced Non–Small-Cell Lung Cancer: A Report of the International CATAPULT I Study Group