Cancer is the uncontrolled proliferation of the cells. The term cancer is an umbrella term which incorporates a wide range of diverse diseases. Essentially cancer is a disease which results from the uncontrolled proliferation of cells that have the ability to spread from their primary site, a process known as metastasis; this property is usually what gives cancer its high morbidity and lethality. The unregulated cell growth arises from faults in the DNA sequence or the manner in which this is regulated. There will be further discussion on the pathways involved in cancer in an attempt to relate this to the role of NQO2 in the cell. Below is a table adapted from Hannah and Weinberg: The six hallmarks of cancer (2000), it attempts to give six properties that are true of almost every cancer cell and is widely cited and respected in the literature.
Normal functioning cell
Growth signal autonomy
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Outside signalling needed to initiate cell growth.
The cell itself can stimulate cell division without any influence from the cells environment; mutation has led to short-circuiting of the cell growth pathways.
Evasion of growth inhibitory signals
Evasion of apoptosis (programmed cell death)
Unlimited replicative potential
Angiogenesis (formation of new blood vessels)
Invasision and metastasis
The cell shows sensitivity to the mechanisms in place to stop cell growth if necessary.
Usually a cell reaches a point in time when it discovers it can't continue anymore such as when it receives damage to its DNA; programmed cell death occurs to get rid of the cell.
The chromosomal ends (telomeres) become shorter after every cellular division; limiting the amount of times the cell can divide.
The amount of bloody supply providing oxygen and nutrients is sensed and proteins are produced to induce angiogenesis accordingly.???
It is desirable to move for a normal differentiated cell.
Mutations allow the cell to not respond to pathways that are in place to control cell growth.
As a result of mutation, cancer cells have mechanisms in place to overcome this barrier to survival.
Mutations have allowed the cell to maintain the length of their chromosomes, resulting in the possibility of endless cellular replication.
The balance of angiogenic inducers and inhibitors is shifted towards inducers, resulting in more nutrients and oxygen for the demanding cancer cells; favouring tumour survival and assisting metastasis
Mutations result in changes of enzymes and cell adhesion properties, this allows the cancerous cell to migrate from the primary site to secondary/tertiary sites.
Histopathology of cancer
The term neoplasm corresponds to a new cancerous growth that results in an abnormal mass of cells with deregulated cellular proliferation. The cell population within the tumour has arisen from one cell, where genes controlling cell division and survival were altered due to DNA damage of some kind. A tumour is made up of two components; firstly the proliferating cells, known as the parenchyma and the supportive blood vessels and connective tissue, known as the stroma. When a cancer becomes relatively advanced then metastasis is more likely. Tumour nomenclature depends on three things; the region involved, the ability to metastasise and the tissue type involved. A malignancy of the epithelial cells (the most common type of cancer) is known as a carcinoma where as a cancer of the connective tissue is known as a sarcoma.
What causes cancer?
Cancer can be caused by chemical, physical or biological factors1. Chemical carcinogesis involves a series of DNA mutations due to exposure of a carcinogen such as the cocktail found in cigarette smoke. Physical causes incorporate DNA damage resulting from ionizing radiation. Whereas biological causes are those cancers caused by gene deregulation due to oncogenic (cancer causing) viral infections; such as certain strains of the Human papilloma virus, which have been directly implicated in cervical cancer. It is important to realise that once the initial cancer has developed, the tumour is not linear and stationary; further genetic instability leads to variation and progression to favour tumour growth. Furthermore there is involvement of regulatory systems containing cancer genes. Mutations in these genes cause deregulated cell growth and a decreased repair of cell damage2; resulting in cancer.
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Treatment of cancer
The treatment of cancer relies on the golden bullet approach of trying to selectively kill/remove tumour cells without damaging normal cells to try and minimise the side effects of the therapy.
**It is important to realise the difference between tissue necrosis and apoptosis (programmed cell death), this is because different chemotherapeutic drug classes will causes cancer degradation in different ways. Apoptosis occurs for reasons such as DNA damage or the removal of growth factors, targeting single damaged cells in order to recycle cellular components and prevent DNA alterations leading to cancer. Necrosis, however, happens to groups of cells as a result of harsh living conditions or where inflammatory processes
Invasion and metastsis
The ability of a cancer to metastasise depends on expression of barrier degrading enzymes and the amount of angiogenesis the cells have been able to recruit. as well as......(what else can favour a tumour to metastisise). **
When a cell becomes malignant (draw figure 2.1) How a cell becomes cancerous and the mechanisms that are in place to protect the cell from such an event is an important area to study if we are to gain new targets and new classes of anti-cancer agents.
Each year in the United Kingdom there are more than 285,000 people diagnosed with cancer, this equates to one in three people developing cancer in their life time; unfortunately despite increased efficacy of medicines, the ageing population in the UK means that cancer will continue to be a major health problem in the foreseeable future.
There are over 200 types of cancer but the more prevalent forms are lung, breast, colorectal and prostate; which make up over half of the 285,000 new cases diagnosed per year in the UK. Rates of cancer vary depending on age, gender, genetics and environmental factors. For example, Cancer of the prostate is the most common in males, followed by lung cancer. Whereas in the female population, cancer of the breast is the most common form, making up for a third of all female cancers. Males are nearly twice as likely to develop lung cancer compared to females. The risk of developing cancer increases significantly with age; in the 25-34 age group the risk of developing cancer is approximately 2000 per 100,000 people as opposed to 50,000 per 100,000 people in the 75+ age group. Cancer is the cause of approximately a quarter of deaths in the UK, and the incidence itself is fairly constant; however certain cancers such as malignant melanoma are on the rise due to increased UV exposure in certain populations. Lung, colorectal, breast, prostate and oesophagus are responsible for approximately half of cancer related deaths in the UK; cancer survival rates (surviving longer than 5 years after diagnosis) vary significantly depending on the cancer type, for example testicular cancer has a 95% survival rate as opposed to Lung cancer which has the much lower survival rate of 6%. Survival rate decreases with increasing age of the population, this could be for a variety of reasons such as co-morbidities or the fact that elderly patients are less readily entered in to phase 1 clinical trials. Early detection and therefore initiation of treatment positively affected cancer survival rates in the UK, particularly in the breast cancer population; there were 15,625 deaths in 1989 compared to 12,319 deaths in 2006 this is largely attributed to new awareness and screening initiatives within the NHS.
Different methods of treating cancer
Adjuvant, neo adjuvant etc.
Classical anti-cancer agents are separated in to groups depending on their mode of action and where they act in the cell cycle.
Mode of action
Cell cycle phase affected
Via various methods an unstable ethyleneimonium ion intermediate is generated that forms covalent bonds with DNA. Guanine base alkylation occurs most frequently.
Cell cycle independent
Nitrogen mustards (melphalan);
Alkyl sulphonates (busulphan)
Platinum based (cisplatin)
These have a similar structure to bases in DNA, they are therefore taken up by the DNA
Planar molecules co called because the lead compounds were produced by bacteria. They act by intercalating between base pairs or binding to the external grooves of the DNA double helix.
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Cell cycle independent
Anthracyclines (daunorubicin) quinone see arley
Interfere with the stability of the mitotic spindle resulting in disruption of mitosis
Vinca alkaloids (vincristine);
Hormonal anticancer agents
Used to antagonise cancers that rely on hormones for growth such as neoplasms of the breast and prostate.
Cell cycle independent
Oestrogen antagonists (tamoxifen);
Aromatase inhibitors (anastrazole);
Inhibit an enzyme involved in DNA replication
Toposisomerase I inhibitor (camptothecin);
Toposisomerase II inhibitor
An enzyme is a protein which allows reactions in the body to require a lower activation energy and essentially at a faster rate. The enzyme's tertiary structure gives rise to a so called 'active site', a unique layout of functional groups to that specific enzyme. An active site is where the starter molecule known as the substrate is converted to a molecule known as the product. Enzymes, like other catalysts, are not altered during the formation of the product. Enzymes are diverse and essential for metabolic pathways inside the cell, this is because most metabolic pathways wouldn't otherwise have the facility or sufficient speed. This important feature of enzymes presents them as valuable and effective drug targets that can have profound effects on human biology, and as a result, the majority of highly efficacious drugs are enzyme inhibitors. Many enzymes require molecules called co-factors to allow or enhance the activity of the active site. Small organic molecules that act as cofactors are called coenzymes3. Enzymes have been classified in to six classes, NQO2 belongs to oxidoreductases class. These enzymes are involved in oxidation and reduction3 of other molecules and often require cofactors to supply or sequester electrons. Potentially go in to detail about free energy page 309 of berg. Enzymes are able to make a reaction more favourable by lowering the energy required to activate the process; they do this by facilitating the formation of transition states via an enzyme substrate complex. The active site of an enzyme is the part of the protein that binds specifically to the substrate (and cofactor if required). The active site is a 3-dimensional cleft which is formed by groups that come from different parts of the amino acid sequence3. A substrate binds to this active site via multiple weak attractions3; the specificity of the enzyme for the substrate depends on the precisely defined arrangement of atoms in an active site3. Induced fit vs lock and key page 318 berg diagrams.
The main role of an enzyme is to increase the rate of reaction of a process inside a living organism; it is therefore advantageous to study the kinetics of individual enzymes in order to gain a better understanding of their role and the processes they are involved in. V0 is the rate of catalysis and is defined by the number of moles of product formed per second3. Rate constants are assigned that represent the different rates involved in the processes that lead to the formation of the product.