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Saturday, 13 June 2015

Question 5: How might a patient's white blood cell count be affected by a drug that reduces cell division, and how may this person be treated differently to compensate for this effect?

*These posts are from coursework answers for my degree, but the Figures that are referred to in the text didn't scan well and have already been handed in. These long posts would probably not interest most people but if you enjoy quite in-depth reading of scientific problems then this may be for you.

Question 5: If a patient with an inoperable cancer is treated using a drug that reduces the rate of cell division, how might the patient’s white blood cell count change?  How might the patient’s environment be modified to compensate for the effects of these changes?

Answer:


If a drug that reduces the rate of cell division is given to a cancer patient, one would expect a decrease in that person’s white blood cell count (Prinjha, and Tarakhovsky, 2013).This is because not only would the cancer cells have their rate of cell division stunted, but the immune cells would also.
A drug which inhibits cancer cell growth and is given to a patient with an inoperable cancer is likely to be a form of targeted therapy in regard to cancer treatment. These drugs are more specialised in choosing cancer cells to exhibit their effects. Older drugs find it harder to differentiate between healthy and cancerous cells, and given that their effect usually increases depending on the rate of cell reproduction (advantageous because cancer cells tend to rapidly reproduce), these older drugs commonly cause much harm to fast-growing cells such as the skin and digestive tract. However, targeted therapies still have substantial side-effects, particularly fatigue, nausea, skin and clotting problems as well as elevated blood pressure. These forms of drugs, however, would have less effect upon the white blood cell count than ordinary drugs (National Cancer Institute, 2014).
Chan, Koh and Li (2012), state that cancerous cells are most vulnerable during mitosis and that the use of drugs centred on cell division is therefore of high importance to cancer treatment. They also state that drugs producing antimitotic effects tend to be highly specific, but that the body reacts unpredictably when exposed to them.
According to Schmidt (2000 pp. 112-115), the production of thymidylate and dihydrofolate are of substantial importance in the role of DNA synthesis. Given that cancer is fundamentally a cellular error causing uncontrolled replication, the inhibition of DNA synthesis plays a pivotal role in treating cancer. A compound called 5-fluorouridine bears strong similarity to the substrate acted upon by thymidylate synthase, once it has been phosphorylated by a nucleoside kinase (the only difference is that this product contains a fluorine where the natural substrate, dUMP, contains hydrogen). However, once this end-product (called 5-fluorouridine monophosphate) binds with thymidylate synthase, the fluorine stays bonded to the enzyme, causing it to no longer function. Since the 5-fluorouridine monophosphate reacts with the enzyme, and the enzyme can no longer function afterwards, it is called a “suicide substrate”. DNA necessary for cell division can also be reduced by decreasing the reduction of dihydrofolate to tetrahydrofolate. When N5,N10-methylene tetrahydrofolate donates a methyl group to deoxy-UMP under the supervision of the thymidylate synthase enzyme, thymidylate (deoxy-TMP) is formed. This reaction is illustrated in figure 5.1.

Since the tetrahydrofolate compound in this reaction is oxidised to dihydrofolate, the converse of this (reduction of dihydrofolate by dihydrofolate reductase (DHFR)), will consequently lead indirectly to thymidylate production. Thus, the inhibition of DHFR will also reduce thymidylate production. Substrates which are competitive inhibitors of folates are called folate antagonists, where an antagonist is a substance that binds to a receptor, without producing the receptor’s activity. Thus, a substance binding to a folate-receptor, may not produce the same effect as a folate-containing substance binding to it. The antagonists in this example will attempt to out-compete the folate substrates involved in activating the DHFR enzymes, thus preventing the chemical reactions leading initially to the reduction of dihydrofolate to tetrahydrofolate and eventually to the production of thymidylate, which would increase DNA synthesis and allow cell division to occur.
From Schmidt (2000, p. 230), information is given about the G1 phase of cell division. This particular phase is actually a point of non-division, in which various biochemical reactions take place, but the cell does not actively divide. Many animal cells can spend years in the G1 phase without dividing, which makes it highly important in cancer treatment. If the G1 phase could be clearly understood, then cells could be encouraged to remain within it, not dividing, and consequently not resulting in cancer formation. An unfortunate consequence of decreasing cell division non-specifically however, is that all cells in the body which take in a particular drug that decreases cell division will have their rate of replication decreased. This makes it more difficult for the body to combat infections which are not affected by the drugs, given that the body cells may be subjected to division-inhibition for many weeks or months before encountering a new infection, its immune cells are likely to be lower in number and therefore not be as capable of combating the threat.
If the number of white blood cells that a patient has, decreases, then that person is more susceptible to all possible infections as these cells fight them.
Among the white blood cells or leukocytes, the form most important during consideration of possible infections is the neutrophil. This is the type of white blood cell most abundant in plasma, constituting roughly 54-62% of the overall number of circulating leukocytes (Mescher 2013, p. 235). Neutrophils are relatively small phagocytic immune cells that are produced in vast quantities every day (roughly 126 billion enter the digestive tract daily, according to Seeley, VanPutte, Regan and Russo, 2011, p. 791), and are often the first of the immune cells to reach infected regions in great numbers. Once at an infected site, neutrophils are responsible for increasing immune cell activity and inflammation at this area. This is brought about by their release of cytokines which encourage the proliferation and differentiation of immune cells, and by chemotactic agents, respectively (Seeley, VanPutte, Regan and Russo, 2011, p. 792).
The test for abundance of circulating neutrophils is called the absolute neutrophil count (ANC), and is considered the most important risk factor for both bacterial and fungal infections, according to Johnston and Spence (eds, 2003, p. 253). The diagnosis of neutropenia (a deficiency of neutrophils), is stated as an ANC of less than 500 per millilitre of plasma, or expected to fall to this level within the next 24 hours of being tested. These writers also state that risk increases as neutrophil count decreases, and that the rate at which neutrophil count is decreasing, as well as how long neutropenia has presented, also play a pivotal role in contracting bacterial and fungal infections. The more rapidly neutrophil count is falling, and the longer a person has had neutropenia, the more likelihood there is of becoming infected, and the more severe the infection is likely to be. Thus, it is highly important to consider neutropenia, although B-cell and T-cell function is also compromised in cancer treatment, usually due to chemotherapy, but further exacerbation can occur via concomitant utilisation of steroids (Johnston and Spence, eds, 2003, p. 246). These authors also explain that the use of catheters in immunocompromised cancer patients poses a significant risk of subsequent infection, this is due to the ease with which microbial colonies can form within the synthetic catheter, possibly migrating into the host and causing infection. Therefore, it is of the utmost importance that catheters be monitored and if possible, sampled, in order to gauge microbial growth.
There are many other types of immune cell that are important in the response to infection. This first section deals with those cells which are an integral part of the innate immune system, i.e. the branch of the immune system acts in a non-specific manner:
Neutrophils fall into this category but are explained in detail above.
Monocytes are white blood cells that circulate the body and are enticed by chemo-attractants to enter damaged tissue and differentiate into macrophages which are important for consuming toxic substances and cells that may damage the body, they may also stimulate B-cell and T-cell activity during infection (Seeley, VanPutte, Regan and Russo, 2011, p. 791). Macrophages are roughly 5 times the size of monocytes, and have additional lysozymes and mitochondria. They are larger, longer-lasting, and are capable of engulfing larger particles than neutrophils, though they appear at the site of infection a little later than neutrophils. Thus, they are most used in the later stages of infection. Their large size makes them ideal for engulfing cellular debris, and even whole neutrophils which have died earlier on during the immune response. Macrophages may also secrete various substances such as interferons, complement, and prostaglandins. The roles of interferons and complement are discussed elsewhere, but prostaglandins have a variety of actions, perhaps most importantly of which are its function in increasing the permeability of blood vessels (which can allow immune cells to permeate vascular and reach infected or damaged tissue, and also in causing vasodilation, again allowing immune cells to reach a particular site by aiding blood flow to the affected region. This is shown by Seeley, VanPutte, Regan and Russo, 2011, pp. 789, 792.
Both basophils (motile) and mast cells (nonmotile) are immune cells that promote inflammation within tissues through the release of various chemicals, e.g. leukotrienes and histamine. This inflammatory response can increase blood flow to the area, signal other leukocytes to arrive on the scene, and encourage the formation of either a platelet plug or clot to seal off the affected region to further damage and/or infection. Conversely, eosinophils are motile immune cells that enter tissues and inhibit the inflammatory response. They do this by breaking down the substances secreted by the basophil and mast cells. Therefore, eosinophils are produced in larger quantities during immune reactions where a large inflammatory response occurs, such as in allergies. Additionally, eosinophils have the ability to kill some forms of parasites (Seeley, VanPutte, Regan and Russo, 2011, pp. 791-793).
Finally, NK (natural killer) cells are important in the attack on cancer cells. NK cells contain enzymes that can chemically lyse or split tumour cells, preventing the growth spread of cancer, one of their preferred mechanisms of actions is to chemically lyse the plasma membrane of harmful cells (Seeley, VanPutte, Regan and Russo, 2011, p. 791-792).
The adaptive immune system then, deals with specific and personalised threats to the body. This branch of the immune system is capable of responding to a specific substance, called an antigen. These antigens may be produced by the body, for example, a tumour cell (a self-antigen), or produced by a foreign invader or microbe which has found its way into the body and may cause harm (a foreign antigen). Within the umbrella term of adaptive immunity, there are two main categories of immune response; cell-mediated immunity and antibody-mediated immunity. Antibody-mediated immunity is brought about by the production of antibodies (these are released by cells that result from the differentiation of B-cells) that bind with antigens to form antigen-antibody complexes that inhibit the actions of harmful cells. On the other hand, cell-mediated immunity arises from the activity of T-cells, which can destroy whole cells instead of inhibiting vital components. This is highly useful for infections from viruses, which essentially ‘hijack’ the biochemical reactions of a cell for their own needs (Seeley, VanPutte, Regan and Russo, 2011, p. 794-806).
The adaptive immune system almost entirely consists of B-cells and T-cells to combat infection:
B-cells can be stimulated by antigens on the cell surface membrane of a pathogen and differentiate to produce either a plasma cell or memory B-cell. The plasma cell in this scenario would produce antibodies complementary in shape to the harmful antigen which would inhibit the effectiveness of the pathogen and signal for its lytic destruction by neutrophils, eosinophils, macrophages or monocytes. The memory B-cells formed by differentiated of B-cells can promote a rapid and lasting immune reaction to a specific form of pathogen. If this pathogen were to enter the body, memory B-cells would mass-produce antibodies that would inhibit its actions. (Seeley, VanPutte, Regan and Russo, 2011, pp.791, 803).
There are many types of T-cells; delayed hypersensitivity T-cells promote inflammation through the release of cytokines, helper T-cells stimulate the activity of effector T-cells and B-cells, Suppressor T-cells do the opposite, inhibiting the action of both T-cells (effector forms) and B-cells, and lastly, memory T-cells are similar to memory B-cells in their ability to maintain a lasting immunity towards a particular antigen that has been previously encountered. (Seeley, VanPutte, Regan and Russo, 2011, p. 791).
Finally, dendritic cells activate both B-cells and T-cells after recognition of a harmful antigen (Seeley, VanPutte, Regan and Russo, 2011, p. 791).
Another area of concern is the mucous membrane throughout the digestive tract. This membrane can become inflamed and mouth, stomach and other ulcers can result from the use of both chemotherapy and radiotherapy (depending on where the latter is targeted to), these ulcers and general damage to the mucous membrane can facilitate the harbouring of pathogens which can infect the body (Johnston and Spence, eds, 2003, p. 253). Further to this, though beyond the scope of this essay, is the effect of the underlying cause or simultaneous condition with regard to cancer. Chronic lung or liver diseases as well as AIDS, can independently compromise immune function, which would only be worsened by cancer treatment.
Care must be taken to ensure proper health of skin, teeth and the general oral cavity. Healthy skin and mucous membranes in the oral cavity produce secretions that prevent bacterial infection. For example, skin secretes oils and has an acidic pH due to the actions of sebaceous and sweat glands. Saliva in the oral cavity contains many antimicrobial agents, including the protein lysozyme, which destroys the cells walls of bacteria. These are some examples of nonspecific barriers (methods that provide a broad-spectrum of defence not limited to a single pathogen at a time). See Houghton Mifflin Harcourt (2014). Broken skin, infected gums and rotting teeth can all harbour bacteria that can lead to an infection the immunocompromised patient. Antibiotics may be taken to control overall and in particular, digestive bacteria, lest these should turn pathological.
According to Pack (2001, pp. 210-212), there are three types of barrier preventing infections to the body. These are the nonspecific barriers, the nonspecific defences, and the specific defences of the body. Many of the nonspecific barriers have already been covered, these are; skin, sweat, proteins such as lysozyme, cilia, digestive juices, and commensals (symbiotic organisms exist in and on the human body that can compete against harmful microbes). These barriers prevent the inward movement of harmful substances and microbes into the body.
The nonspecific defences are responsible for nonspecific removal and destruction of threats that have found their way into the body. Examples include phagocytes (white blood cells that engulf and digest pathogens, neutrophils, eosinophils, macrophages and monocytes are included in this category). Natural killer cells, are also on the list, as well as interferons and a defensive chemical called “complement”. Interferons are released by cells that are infected by viruses, and help the immune system recognise when a viral infection has occurred. Interferon is also aptly named for its ability to interfere with the production of viruses (Seeley, VanPutte, Regan and Russo, 2011, p. 789). Complement is a compound formed by roughly 20 proteins bonded together which attracts phagocytic immune cells to the site of an infection, as well as lysing cells by its own actions (Pack, 2001, p. 211).
The immune system forms the specific defence system against foreign microbes (Pack, 2001, p. 213). Some of the nonspecific defences such as natural killer cells and phagocytes are used for specific defence, particularly when an antigen has become part of an antigen-antibody complex and immune cells are signalled to engulf it.
On page 254 (Johnston and Spence, eds, 2003), the authors make known the vices of surgical removal of the human spleen, which can take place occasionally as part of cancer treatment. They state that the spleen is necessary for removal of opsonized pathogens (those bound by antibodies in the preparation of phagocytosis) and erythrocytes which have been infected with parasites. Surgical removal of the spleen also reduces the body’s ability to develop immune reactions to previously unencountered antigens. According to Pack (2001, pp. 204-209), the spleen is the largest organ in the lymphatic system. It contains two distinct regions; the white pulp and the red pulp. The white pulp contains many lymphocytes (T cells and B cells), as well as reticular fibres, whereas the red pulp contains many venous sinuses that act as a reservoir of red blood cells. The spleen has several main functions; filtering the blood of pathogens and debris from dead and aged cells, the destruction of old erythrocytes and subsequent recycling of organelles and nutrients, acting as a reserve for blood, and providing a site of T cell and B proliferation (T cells reproduce before returning to attack non-self cells and B cells produce antibodies and plasma cells which go on to inactivate harmful antigens. Thus, its removal can have dangerous consequences.
The above effects combined produce a patient who is highly susceptible to infection. They mention several bacteria whose infections are more commonly and severely present in immunocompromised patients, there are; Streptococcus pnuemoniae, Capnocytophaga canimorsus and Babesia microti (a bacterium that presents with malaria-like symptoms such as fever, chills, sweating, and head and body aches information that is elaborated upon by the Centers for Disease Control and Prevention, 2014a).
Wigglesworth (2003) gives a lot of information on the use of environment changes for immunosuppressed patients. If such patients are currently residing in a hospital then they can be separated from the main hospital population and wads, usually by keeping them in a single room. Hygiene is of particular importance to ensure that no pathogens are transferred from care workers to the patient. Hand-washing is a must in this scenario.
According to the University of Utah Health Care (2003), proper hand-washing is the most important action in the prevention of infectious diseases. The amount of visitors that a person meets during the day and the foods that they eat must be monitored to ensure there is little risk of infection. Certain foods are considered high-risk when it comes to patients with a weakened immune system, extra care must be taken to avoid these foods. Soft cheeses and anything made with raw eggs are a hazard for such patients. Therefore, mayonnaise was also be avoided.
Additionally, the use of vaccinations before a person is likely to become immunocompromised can decrease the likelihood of infection. This has been proposed as a strategy for persons likely to exhibit lower immune function for a number of different reasons including cancer and HIV (Tolan, et al, 2013).
The Centers for Disease Control and Prevention recommend that any sign of fever in patients receiving chemotherapy be treated as an emergency, even if it is the only symptom (Centers for Disease Control and Prevention, 2014b). Further safety precautions can be taken to reduce the chance of infection can be taken. One can avoid sharing any personal items, such as cups or utensils or anything that requires insertion into the mouth, e.g. toothbrushes. Daily washing should be done with unscented lotions. Lotions which are scented can damage or dry the skin, allowing pathogens to colonise or pass through this layer. Meat and eggs must be cooked thoroughly, raw fruit and vegetables must be washed carefully, gloves should be worn around pets and for gardening, and care must be taken to avoid damaging the gums during tooth-brushing (thus a soft toothbrush is highly recommended), see Centers for Disease Control and Prevention, 2014c. This same source provides ample knowledge of the warning signs of infection in order to warn immunocompromised patients. Some of the more noticeable signs are; a fever of >38oC for over one hour, sore throat, burning or other pain upon urination, shortness of breath, diarrhoea, vomiting and increased urination.
Finally, the Centers for Disease Control and Prevention also note that white blood cell usually drops to its lowest value as a result of chemotherapy around 7 to 12 days after the chemotherapy dose has finished, and from this point the low count can last for around a week before increasing again. This lowest point is when most vigilance is required in protecting oneself from infection, as the immune system will be most weakened and unable to respond adequately (Centers for Disease Control and Prevention, 2014d).

Question 5 References:
Centres for Disease Control and Prevention, 2014a. Babesiosis FAQs, [online] Available at: <http://www.cdc.gov/parasites/babesiosis/gen_info/faqs.html#symptoms> [Accessed 13 April 2015].
Centres for Disease Control and Prevention, 2014b.Emergency Room Personnel, [online] Available at: < http://www.cdc.gov/cancer/preventinfections/pdf/er_personnel_poster.pdf > [Accessed 13 April 2015].
Centres for Disease Control and Prevention, 2014c. How can I prevent an infection? [online] Available at: < http://www.cdc.gov/cancer/preventinfections/pdf/neutropenia.pdf > [Accessed 13 April 2015]. 
Centres for Disease Control and Prevention, 2014d. Protect: Know the Signs and Symptoms of Infection, [online] Available at: <http://www.cdc.gov/cancer/preventinfections/symptoms.htm> [Accessed 13 April 2015].
Chan, K.S., Koh, C.G., and Li, H.Y., 2012. Mitosis-targeted anti-cancer therapies: where they stand. [online] Available at: <http://www.nature.com/cddis/journal/v3/n10/full/cddis2012148a.html> [Accessed 7 April 2015]. 
Houghton Mifflin Harcourt 2014. Nonspecific Barriers, [online] Available at: <http://www.cliffsnotes.com/sciences/anatomy-and-physiology/the-immune-system-and-other-body-defenses/nonspecific-barriers> [Accessed 7 April 2015]. 
Johnston, P.G., and Spence, R.A.J., eds. 2003, Oncologic Emergencies. United States, New York: Oxford University Press Inc.
Mescher, A.L., 2013. Junqueira’s Basic Histology Text & Atlas, 13th ed. China: The McGraw-Hill Companies.

National Cancer Institute, 2014. Targeted Cancer Therapies, [online] Available at: <http://www.cancer.gov/cancertopics/treatment/types/targeted-therapies/targeted-therapies-fact-sheet> [Accessed 7 April 2015].
Pack, P.E., 2001.  Anatomy and Physiology, Hoboken, NJ: Wiley Publishing, Inc.
Prinjha, R., and Tarahovsky, A., 2013. Chromatin targeting drugs in cancer and immunity. [online] Available at: <http://genesdev.cshlp.org/content/27/16/1731.full> [Accessed 7 April 2015].
Schmidt, F., 2000. Biochemistry II, New York, NY: Wiley Publishing, Inc.
Tolan, R.W., Brook, I., Windle, M.L., Domachowske, J., Rauch, D., and Steele, R.W. 2013. Infections in the Immunocompromised Host, [online] Available at: <http://emedicine.medscape.com/article/973120-overview> [Accessed 7 April 2015].
University of Utah Health Care, 2003. Prevention of Infectious Diseases, [online] Available at: < http://healthcare.utah.edu/healthlibrary/related/doc.php?type=85&id=P00644> [Accessed 7 April 2015].
Wigglesworth, N., 2003. The use of protective isolation, [online] Available at: <http://www.nursingtimes.net/nursing-practice/specialisms/infection-control/the-use-of-protective-isolation/205720.article> [Accessed 7 April 2015].



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