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Pankaj Dinkar Patil*, Raju Tayade
Department of Pharmaceutical sciences and technology,
ICT Mumbai, Maharashtra

Tumor hypoxia is feature of locally advancing solid tumor and also considered as potential therapeutic challenge. It causes solid tumor resistible to the cancer treatment like radiation and chemotherapeutic drugs. The transcription factor HIF-1 is the major player in the regulation of tumor progression into malignant phenotype. We can target this hypoxic conditions using pathophysiological approach for targeted drug delivery for treatment of cancer. This review will focus on various biological aspects of tumor hypoxia necrosis and approaches for targeting hypoxic tumors. This tumor selective treatment will include bioreductive drugs, gene therapy, and recombinant bacteria.


PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 7

Received On: 27/04/2014; Accepted On: 09/05/2014; Published On: 01/07/2014

How to cite this article:PD Patil, R Tayade; A Potent Target for Cancer Treatment – Tumor Hypoxia Necrosis: An Overview; PharmaTutor; 2014; 2(7); 8-28

Hypoxia (also called as Hypoxiation or Anoxemia) is a condition in which the body or a region of the body is deprived of adequate oxygen supply. Hypoxia may be classified as either systemic, affecting the whole body, or local, affecting a region of the body. Hypoxia differs from hypoxemia in that hypoxia refers to a state in which oxygen supply is insufficient, whereas hypoxemia refers specifically to states that have low arterial oxygen supply. Hypoxia is a characteristic feature of locally advanced solid tumors resulting from an imbalance between oxygen (O2) supply and consumption[1]. The presence of hypoxic regions of low levels of oxygen in human tumors was postulated by Thomlinson and Gray some 50 years ago based on their observations of the distribution of necrosis relative to blood vessels.Itwas known at that time that hypoxic cells were resistant to killing by ionizing radiation, and this led to clinical trials with patients undergoing radiotherapy in hyperbaric oxygen chambers, to try to force more oxygen into the blood and into the tumor. Solid tumors comprise approximately 90% of all known cancers like Breast cancer, Prostate cancer, Lung cancer etc. They develop from a single mutated cell and leadto significant morbidity and mortality, either by invading normal tissue or by metastasizing to vital organs, such as the liver, lung, or brain. The process of tumor progression (i.e., proliferation, local invasion, and distant metastasis) is characterized by rapid cellular growth accompanied by alterations of the microenvironment of the tumor cells.In solid tumors, oxygen delivery to the respiring neoplastic and stromal cells is frequently reduced or even abolished by deteriorating diffusion geometry, severe structural abnormalities of tumor micro vessels, and damaged microcirculation. Sustained hypoxia in a growing tumor may cause cellular changes that can result in a more clinically aggressive phenotype. During the process of hypoxia-driven malignant progression, tumors may develop an increased potential for local invasive growth, perifocal tumor cell spreading, and regional and distant tumor cell spreading.

To grow beyond a diameter of approximately 1 mm, newly developing tumors must form their own vascular network and blood supply, which they accomplish either by incorporating preexisting host vessels or by forming new microvessels through the influence of tumor angiogenesis factors. However, the newly formed vascular network differs greatly from that found in normal tissue, typically displaying a broad range of structural and functionalabnormalities, including dilations, incomplete or absent endothelial linings and basement membranes, leakiness, irregular and tortuous architecture, arteriovenous shunts, blind ends and a lack of contractile wall components and pharmacological/physiological receptors. These abnormalities lead to irregular and sluggish blood flow, therebydiminishing the delivery of O2(and nutrients) to the tumor cells, with the resultant development of hypoxic or even anoxic areas. The oxygenation status of the tumor can beworsened further by increases in diffusion distances, which occur when the tumor cells spread beyond the distance that allows adequate delivery of O2 by the blood vessels (>70 µm)[2].

For many years, tumor hypoxia has been recognized as a potential therapeutic problem because of its adverse impact on the effectiveness of radiation therapy. However, hypoxia has recently emerged as a major factor that influences tumor proliferation and malignant progression. Additionally, hypoxia may induce downregulation of adhesion molecules, thereby facilitating tumorcell detachment. Hypoxia-induced or hypoxia-mediated changes of the proteome (i.e., the complete set of proteins within a cell at a given time) of the neoplastic and stroma cells and the genome of the genetically unstable neoplastic cells may explain the fact that tumor oxygenation is associated with disease progression, a link that has been demonstrated for a variety of human malignant tumor types. The aim of this review is to compile current details of hypoxia and the phenomena of malignant progression and resistance toward oncologic treatment and how one can exploit pathophysiological conditions for targeted drug delivery [3].

Tissue hypoxia results from the inadequate supply of oxygen that compromises biologic functions. Oxygen passively diffuses in the lung alveoli according to a pressure gradient. Oxygen diffuses from the breathed air, mixed with water vapour, to arterial blood, where its partial pressure is around 100 mmHg (13.3kPa). In the blood, oxygen is bound to hemoglobin, a protein in red blood cells. The binding capacity of hemoglobin is influenced by the partial pressure of oxygen in the environment, as described in the oxygen–hemoglobin dissociation curve. A smaller amount of oxygen is transported in solution in the blood.In peripheral tissues, oxygen again diffuses down a pressure gradient into cells and their mitochondria, where it is used to produce energy in conjunction with the breakdown of glucose, fats and some amino acids.Hypoxia can result from a failure at any stage in the delivery of oxygen to cells[3]. This can include decreased partial pressures of oxygen, problems with diffusion of oxygen in the lungs, insufficient available hemoglobin, problems with blood flow to the end tissue, and problems with breathing rhythm. Experimentally, oxygen diffusion becomes rate limiting (and lethal) when arterial oxygen partial pressure falls to 40 mmHg (5.3kPa) or below.

Causes of hypoxia:
Ischemia meaning insufficient blood flow to a tissue can also result in hypoxia. This is called 'Ischemic hypoxia’. An example of insufficient blood flow causing local hypoxia is gangrene that occurs in diabetes.

Hypoxemic hypoxia
It is specific hypoxic state where the arterial content of oxygen is insufficient.

Problems with hemoglobin
Almost all the oxygen in the blood is bound to hemoglobin, so interfering with this carrier molecule limits oxygen delivery to the periphery. Hemoglobin increases the oxygen-carrying capacity of blood by about 40-fold,with the ability of hemoglobin to carry oxygen influenced by the partial pressure of oxygen in the environment, a relationship described in the oxygen hemoglobin dissociation curve. When the ability of hemoglobin to carry oxygen is interfered with, a hypoxic state can result.

Hemoglobin plays a substantial role in carrying oxygen throughout the body and when it is deficient, anemia can result, causing 'Anaemic hypoxia' if tissue perfusion is decreased. Iron deficiency is the most common cause of anemia. As iron is used in the synthesis of hemoglobin, less hemoglobin will be synthesized when there is less iron, due to insufficient intake, or poor absorption.

Carbon monoxide poisoning  andCyanide poisoning
Carbon monoxide competes with oxygen for binding sites on hemoglobin molecules. As carbon monoxide binds with hemoglobin hundreds of times tighter than oxygen, it can prevent the carriage of oxygen.Histotoxic hypoxia results when the quantity of oxygen reaching the cells is normal, but the cells are unable to use the oxygen effectively, due to disabled oxidative phosphorylation enzymes. This may occur in Cyanide poisoning.

Biochemists usually define hypoxia as O2-limited electron transport .Physiologists and clinicians define hypoxia as a state of reduced O2availability or decreased O2 partial pressures below critical thresholds, thus restricting or even abolishing the function of organs, tissues, or cells. Anoxia describes the state where no O2is detected in the tissue (O2 partial pressure 0 mm of mercury [mmHg]).

Hypoxia can be categorized into two main types- Acute hypoxia and chronic hypoxia.These two subtypes can lead to completely different hypoxia-related responses within the tumor, which could have a direct effect on tumor development and response to treatment. In order to accurately assess the specific biological consequences, it is important to understand which time frames best define acute and chronic hypoxia.

Acute hypoxia
It is also called as perfusion limited hypoxia. It is caused by inadequate blood flow in tissues. Because of structural and functional abnormalities in tumor micro vasculatures such as disorganized vascular network, dilations, an incomplete endothelial lining etc. It leads to ischemic hypoxia.

Chronic hypoxia
It is called as diffusion limited hypoxia characterized by diffusion distances with tumor expansion. This leads to inadequate O2 supply for cells distant from nutrition blood vessels. Chronically hypoxic cells are usually situated remotely from capillaries.

Figure 1The vascular network of normal tissue versus tumor tissue[3]

Tumors contain regions of hypoxia and necrosis because their vasculature can’t supply oxygen and other vital nutrients to all the cells. Whereas normal vasculature (a) is hierarchically organized, with vessels that are sufficiently close to ensure adequate nutrient and oxygen supply to all cells, tumor vessels (b) are chaotic, dilated, tortuous and are often far apart and have sluggish blood flow. As a consequence, areas of hypoxia and necrosis often develop distant from blood vessels. In addition to these regions of chronic (or diffusion-limited) hypoxia, areas of acute (or perfusion-limited) hypoxia can develop in tumors as a result of the temporary closure or reduced flow in certain vessels[4].

Hypoxia is property of solid tumors.Robust tumor growth requires the presence of a local vascular network that supplies both oxygen and nutrients to tumor cells.

Figure 2 Tumor growth[3]

The basic difference between normal and tumor tissues is that they lack vasculature.

Figure 3 Normal vs. tumor tissues[3]

Properties of solid tumors:
1. High Heterogeneity
2. Low oxygen tension
3. Low pH
4. Low glucose concentration

Oxygenation status in tumors
Oxygen levels are typically very heterogeneous, both among patients and within individual tumors. Following Table 1depicts critical O2partial pressures below which adequate metabolic functions in solid tumors (metabolic hypoxia) cannot be maintained.


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