Discuss about the Prognostic Factors and Poor Clinical.
The cells of the cancer have specific characteristics different from the normal cells in a number of ways and this is what enable them to grow very uncontrollable and becomes more invasive. These cell (cancer cell) are known to be less specialised as compared to the normal cells. This basically means that while the normal cells grow into very district cells that later perform specific functions, cancer cells never observe this concept. This is part of the reason why cancer cells continue to divide without stopping.
These cells deliberately ignore the signals that usually alert the cells to stop dividing or that usually trigger the coordinated cell death commonly known as apoptosis that assist the body to remove the unwanted cells. The cancer cells are able to dictate the operation of the normal cells, blood vessels and the molecules that surround and provide nutrients to the tumour. The surrounding of the tumour is called microenvironment. In some cases, the cancer cells can induce the nearby cells to form capillaries that supply the tumour with the nutrients and oxygen which is necessary for growth. The capillaries also remove the waste products for the tumour (Alexandrov et al 2014)
The cancerous cells are capable of attacking the immune system, a group of the special cells that are meant to safeguard the body against germs. Although the immune system is normally capable of removing the damaged cells or those cells that are abnormal from the body system, some cancer cells are capable of hiding from the immune system.
Tumours can also utilise the very immune system to stay alive and have their growth facilitated. For instance, with the assistance of the specific immune system with the cells that prevent a runway immune system response and this actually keeps the cancer cells immune to the body immune system.
This is a genetic disease because it is caused by the changes that take place to those genes that control the functions of the cells specifically on their growth and division. The changes in the genes that causes cancer can be passed on from the parents to their offspring. It can also surface in the persons lifetime as a result of the errors in the division of the cells. The errors may result from the damage of the DNA due to the environmental exposure. The environmental exposure that results into the development of the cancer may include chemicals of tobacco and UV radiations from the sun.
Every person’s cancer has a very unique genetic changes combinations. Additional changes will continue to occur even as the cancer continuous to grow. It is important to note that even within the same the same tumour, the genetic changes can still be different. Generally, the cancer cells constitute very many genetic changes such as the mutations in the DNA as opposed to the normal cells. Most of these changes may not lead to cancer but they may be as a result of the cancer itself.
The changes in the genetic make up that usually lead to the development of cancer basically affect three major kinds of the genes. These include the DNA repair genes, tumour repair suppressor genes and the Proto-oncogenes. These changes are commonly referred to as the driver of the growth of the cancer. The Proto-oncogenes are known to be responsible for the normal cell growth and division. However, when there is alteration in these genes, the cells may become more active than normal hence becoming cancer causing genes that is, oncogenes thereby allowing cancer cells growth and survival when they should not. Tumour suppressors are responsible for controlling the cell division and growth.
The cell with different changes in the tumour suppressor genes can divide in a way that is not under any control. The damaged DNA are being fixed by the DNA repair genes. The cells that experience mutations within such genes tend to develop other mutations in other genes. The end result of these changes is the development of the cancerous cells.
The researchers have indicated that there is a lot of changes in the molecules that lead to cancer. Most mutations commonly occur in very many different kinds of the cancer. Because of this, the cells of the chancer usually possess characteristics of changes that are believed to be the motivators of the cancer.
Metastatic cancer is known to spread from the place of its origin to other parts of the body. The spreading of cancer from one part of the body to other parts is called metastasis. The naming of the metastatic cancer is usually tied to its place of origin, for instance the breast cancer that spreads to other parts of the body including lung will just be called by the name of the origin as cancer which has spread from the breast and not original lung cancer.
The spreading cancerous cells resemble the cells of the very first or the initial cancer. Besides, metastatic cancerous cells and those of the original cancer posse’s similar properties of their molecules e.g. the chromosomes. Treatment may help the individuals suffering from cancer to have prolonged lives.
Colorectal cancer is the most threading type of cancer coming position three. The annual reports indicate that over millions of people die of this disease (Kim et at 2012) The disease mortality rate is at 33%The disease is increasing in the Asian countries due to the changes in the dietary and the living standards. It however regrettable that the molecular system that usually facilitate the development of the CRC has jus remained very elusive. Change nuclear morphosis including the enlargement and the increased in the numbers of the nucleoli are common in the cells of the cancers including CRC.The nucleoli are the points or the sites where the transcription of the rDNA and the biogenesis of the ribosomes occur.
Colorectal cancer can be malignant, on-cancerous or just a benign. A malignant cancer is known to move to various parts of the human body where they cause damage to them thoroughly.
Several factors will affect the treatment of the colorectal cancer including the size of the cancer, the stage and the size and whether it is recurrent or not. The available options include chemotherapy, radiotherapy and surgery Cancer (Genome Atlas Network 2012).
In an attempt to get the best cancer therapies, a combination of the therapy of STI571(an inhibitor of the Bcr and the one used in the clinical treatment of the chronic myelogenous leukaemia was adopted. The colon cancer (HCT116) was treated with STI571 and TRAIL. The viability of the cell was determined MTT assay and the appearance of the sub-G1. Western blotting was used was used to determine the protein expression and the kinase phosphorylation.c-Abl was found to be inhibited by the target-specific small interference
TRAIL was obtained from the Pepro Tech London. The STI571 was obtained from the Norvatis Phama AG. other reagents included rabbit monoclonal antibodies for the specific capacious antibodies for c-Abl. The human colon cancer (HCT116) was grown in the DMEM.The medium was supplemented with 10 % heat inactivated FBS,100U/ml penicillin and ug/streptomycin.
The cells were incubated at a temperature of 37 degrees Celsius, atmosphere that is humidified at least 5% of carbon dioxide gas and routinely sub cultured after every 3 days. The viability of the cell was determined using dimethylthiazol-2-yl,5-diphenytetrazolium bromide (MTT) for a period of 30 minutes. The cell was later dissolved in the 100% DMSO.The net absorbance was obtained and the activities of the enzymes in the mitochondrion together with the cell productivity recorded.
After the drug treatment, the cells were all collected and washed thoroughly with PBS at least twice and then fixed in ice that was 70% ethanol. It was then stored then stored at Avery low temperature of -20 degrees Celsius overnight. The DNA extraction buffer was then added for thirty minutes at the room temperature. This was followed by an incubation in PBS that had propidium iodide (PI) also for thirty minutes in the dark place at room temperature. Utilisation of FACs can flow cytometer technique aided in the counting of the cells and the recorded reduces DNA amount than that of the G0/G1 stages showed apoptotic cells (Nikiforov et al. 2014).
Cells were then lysed through adding cold RIPA buffer and fresh solution of the protease and the cell lysate was centrifuged for 20 minutes. There was denature of the protein in the sample buffer and then it was separated on the SDS-PAGE and later transferred to polyvinylidene difluoride membranes with the help of a moist trans-blow system.
These blots were stagnated for a period of one hour at room temperature together with Tris -Buffered saline containing 5% non-fat milk. These blots were then washed at least three times with the TBST and later incubated at a temperature of 4 degrees Celsius overnight. The cells were then incubated the following day for another period of 1hr at the room temperature with the secondary antibody. In order to have the equal amount, protein sample was applied for the electrophoresis process, the internal control was achieved using B-actin.
The study showed that the advantages of cytotoxic effects of STI571 and TRAIL against k562 cells. The model prototype of CML. Biochemical and pharmacological approaches was used in the verification of the reduction of TRAIL-induced cell deaths by the STI571 which was involved a caspase-independent apoptotic route or line of operation.
It was found out that apan-caspse inhibitor fully changed the TRAIL-induced cell death but with little effect on the STI571.In addition, STI571 had reduction effects on TRAIL-induced sub-G1 fractions but with similar effect on the MTT assay. The analysis was also done on the processing of procaspase 3 and the results indicated a TRAIL treatment could only lead to the processing of procaspase 3. In the case of pre-treatment using STI571, the proteolysis of the procaspase3 was reduced.
TRAIL is a very potential agent of anticancer. The combination with other drugs improves its effectiveness and this has probably given it much attention. In this regard, its benefits that is associated in the STI571 was indicated in the CML and the melanoma. The respective death resistance that is observed in the CML can be overcome by collectively using TRAIL and STI571.
It was observed that the co-treatment with STI571 enhanced the cells susceptibility to TRAIL. The action of the TRAIL in the cancer of the colon was found to be very reactive to sad, this confirmed the process of apoptosis. However, the reduction in the viability by STI571 did not feel the effects of the zVAD and this completely ignored the process of apoptosis (Ryerson et al. 2014).
The study that is a cell proliferation analysis showed that STI571 can prevent the growing of the cell of HCT116.This was clearly indicated in the HT19 colon cancer cells. The antagonising results were obtained when the HCT116 was treated with STI571 and TRAIL. This possibly pointed out that STI571 can effectively regulate the death of TRAIL (Letourneau et al. 2013). The antagonistic effects of STI571 exhibited the concentration dependent at a value of 0.1-1um.The same effects however were not shown by the higher concentration of STI571 say 10um.In this particular study, it was clearly demonstrated the caspase-dependent c-Abl cleavage and activation in the colon cell lines treated with TRAIL. Most researches done showed that phosphorylation of c-Abl at Tyr412 by getting indications from Src kinases, the index full c-Abl activation was illustrated through receptor tyrosine kinases. In addition-Abl can easily be cleaved by caspase that is found in the C-terminal.
The above-mentioned cleavage basically happens in the cytoplasmic compartment and leads to the generation of a 120-kDa fragment. This can possibly lead to the increased activity of kinase and its subsequent accumulation in the nucleus. The current results indicated the occurrence of both phosphorylation activation and proteolytic activation of the c-Abl that resulted from stimulations in the HCT116 cells. Besides, all mechanisms of activities that are mediated by the caspase routes. The increase of Try412 phosphorylation was recorded on the residual non-cleaved c-Abl. It is important to note that STI571 did not change the c-Abl cleavage that resulted from TRAIL but to some extend lowered the effects of Tryr412 phosphorylation.
The results that were obtained indicated the presence of c-Abl autophosphorylation at Tryr412 cells stimulated through TRAIL. This also implied a cleavage- independent, but a caspase-mediated means for the activation of c-Abl.
STI571 did not alter the opennes of other types of the cancerous cell that were used as the control experiments in the lowered TRAIL reaction in the colon cancer cells. It was therefore possible to completely rule out the effects of the STI571 on the protein expressions related to c-Abl (Lin et al. 2012).
(A) Cell viability of the FEMX-1 as indicated in the black bars and WM239 cells as indicated in the white bars treated with 0.75ng/ml lexatumumab and 40nM azinomycin for 48 hours by the the MTS of the values p=0.0042 and p=0.0041.
Colorectal cancer continues as one of the prevalent and possibly killer tumour types in both women and men in the whole world. This is happening despite the efforts that have been put in place including the preventive screening and other advanced treatment methods. Even though significant steps have been made in the cytotoxic and therapy of targeted points, there has been a lot or resistance to the options available including the chemotherapy. This has led to many cases of death as the tumours accumulate the means of avoiding treatment.
Metastatic disease has been known for no cure except for the patients with the condition known as oligometastatic lesions that is only confined or restricted to the tissues of the lungs and the liver that can have mastectomy. People are normally issued with a combination of cytotoxic chemotherapy together with the therapy of the target when the treatment that aims to cure is found not to be of help.
Although several steps have been made in the systematic therapy, the survival rate that is taken after very five years still remain at 12.5%. The main reason that is put forward for the treatment failure is the resistant that has been acquired to the therapy which takes place in 90% of all the individuals with the spreading cancer. The resistance especially to the targeted therapy is evident by the disease progression that is normally seen or recognise within 3 to 12 months on the epidemical growth factor receptor (EGFR) antagonist and this calls for the provision of the other means of treatment (Eheman et al.2012).
The malignant tumours can have intrinsic resistance or to the solutions. It is very crucial in the in the determination of the original or initial treatment and the subsequent lines of this treatment’s resistance is normally observed on the early development. In some cases, the innate resistance may not e understood up to the point retrospective. For example, the resistance to EGFR targeted therapies was panitumumab. The required education on the application and operations. RAS mutations in the CRC is a full clarification on the unknown resistance to those therapies and have their clinical usage changed.
Different means of the acquired resistance can be of varying characteristics. The acquired resistance can be in the existence for the activities such as cytotoxic therapy and the targeted position. In most of the cases the resistance that is developed to one drug will translate this resistance to other drugs which may be working in the similar way.
The solution to this effect is the use of a concept that is known as a complex resistance drug. In general, the resistance to those traditional cytotoxic therapy is usually managed effectively by lowering the drug delivery to the cancer cells. This can be achieved either through the increased cells ability to remove substances that has had its content mediated by the transporters that depends on it. This is achieved through reduction of the uptake into the cell or by alteration of the cell that is responsible for the metabolisms.
Also, the resistance within the cells can be transmitted by the changes that takes place within the cells themselves during the genetic modification that can possibly change the sensitivity of the drug.
Resistance to the specific targeted therapies happens by different means including the upregulation, activation of the downstream or the mutation that will trigger the signalling’s molecules that are found within the specific pathway. The knowledge of the means of the acquired resistance to the targeted therapies is very important in the development of the novel and Avery solid combinations of the treatment that will definitely provide a proper guidance to the expected therapies. With the existence of the markedly improved genomic sequencing and the technique of the molecular biology, a plethora of new putative means of resistance and the effective therapies have been obtained.
This has been the major way of treating the patience with the lymph nodes that are positive and with the metastatic disease. Its effectiveness was first discovered in the United States of America. It has since then showed the benefits over the 5FU a part from the surgery andesine the adoption of the of the use of chemotherapy in the handling of the Cruciferin drugs have been checked and approved for use including capecitabine among others resulting to their use into the practice guidelines and even their applications in the cancer clinics
Fluoropyrimidines (FPs) asnda 5-FU capecitabine will create a n antitumor activity through inducing of deficiency of the thymidylate thereby putting imbalance in the pool of the nucleotide. This results into the impaired replication of the DNA structures, the repair and finally death of the cells (Siegel, Miller and Jemal 2013). The 5-FU was a mong the reported drugs that were known to have anticancer activity. After its first publication on its characteristics and effectiveness in the cancer treatment of the colon, it has since then become the mainstay of the related diseases.
The 5-flourouracil whose pathway is Thymidylate synthesis uses the increased expression as a means of resistance thereby resulting into the higher target of the 5-FU prevention. There is also lowered unwanted feedback by the TS-FdUMP that operates on its equation alone.
In the methylene tetrahydrofolate reductase (MTHFR), the increased operations of the MTHFR lowering the amount of the compound CH2THF presence needed for the inhibition process of the TS becomes the mechanism of the resistance (Forman and Bray 2013).
Thymide phosphorylase, TP uses increased equations or expressions that is postulated and this may possibly lead to the increased salvage route of the nucleotide. Very low expressions connect with the higher reaction to the 5-FU therapy (Siegel, Miller and Jemal 2015).
Oratate phosphoribosyl transferase which is commonly known as OPRT uses the lowered or the decreased expression that is postulated since very high expressions are associated with sensitivity. Dihydropyridine dehydrogenase that is commonly referred to as the DPD will have the increased expression leading to high degradation
As the knowledge about the biology of cancer and general genetics increases, the new methods of the treatments targets have been discovered and the new drug been found that affect the cancerous cells in a very perfect way that interfering with the entire cells in that particular cycle. These improvements have led to the treatments that give good results and response that is associated with the least toxic side effects. This is in comparison with the previous methods (Byrne et al.2012). The main categories of the targeted therapies are the monoclonal antibodies and the small molecules inhibitors. These are known to be different in their targets of action and even in their modes of the application or administration.
Although the agents that is targeted may lift expectations for the more useful therapy, there exist a very significant advantage and just like other ancient chemotherapy, they are subject to primary and other subsequent resistance that will definitely give no results in the treatment. Some of the properly understood pathways or the operation routes may include EGFR and VEGFR.
Resistance cases are observed through the constructive activation paths which may be as a result of the mutation or the receptor over expression’s receptor and the activating ligand can be potentially targeted through proper identification of the ligands or the receptors that participates in the cell growth or the cell survival. Most of the known mechanisms of the resistance are associated with the changes of the target itself the details of the pathways are as illustrated in the diagram below.
Although the relationship that exist between the EGFR mutations or the changes in the genetic make ups and the feedback mechanism or the responses are never made clear yet, there is enough proof that the higher number of the receptors of the EGGFR as shown in the hybridization (FISH) is likely to be a positive indicator of the response to the treatment.
This operation may extend from cetuximab and panitumumab. Similarly, the expressions of the low level are purported as a means of the intrinsic resistance to the therapy although this has not been clinically shown in most of the practices.
Activating KRAS have been discussed widely as one of the means of both acquired resistance and the intrinsic resistance. In the serious and large analysis, EGRF which is known to be sensitive to the cell lines of the primary colon tumours is actually characterised with the several changes in the molecular compositions, mostly through mutations. This particular study indicated that the KRAS changes could be found in the samples of the blood as early as 10 months prior to the radiographic evidence of the disease an indication that this particular resistance may occur very early in the development stages. The changes in the NRAS are usually replaces each other with the changes that takes place in the KRAS and in the BRAF (Siegel, Miller and Jemal 2016).
Although there is already a lot that is known in relation to the cancers and other tumours, there exist a group of tumours still that do not respond to the treatment. This could be a very positive indicator to the unseen innate or the intrinsic resistance. Apparently, it is a requirement that test should not only lead to KRAS mutation detections but also NRAS mutations before the patient can be exposed to anti-EGFR therapy.
Chemotherapy still remain the most problem in the clinics that deals with the cancer treatments. Also, the chemotherapy resistance has been the other major challenge to the efforts that have been put in place by the researchers. The has been a decline in the response from the patient’s body especially when exposed to the chemotherapy drugs for more than ones. This therefore means that there is an urgent need to come up with the novel drugs that will increase this response rates that is truly worrying.
The studies therefore focused on the idea of repurposing the existing drugs in the trial within the clinics that have chemotherapy resistant colorectal cancer patients followed by the suggestions of the trial designs that possibly could be used to have those repurposed drugs tested for use.
In today treatment of the cancer, the resistance to the drugs remains to be the major challenge. This has led to the cases of the patients being subjected to chemotherapy but without any benefit at all. This step of the chemotherapy does not spare the patients the side effects of the chemotherapy activities. It has been estimated that the response to the cancer drugs by the cancer patients has far gone down to be below 25%. The best way to solve this particular problem is to develop and use the drugs that have bio marks that can be used to locate the treatment to the correct patient at the correct time.
The predictive bio marks will seem to have a lot of impact in the early treatment since most of the patients that were treated earlier will tend to develop resistance to the drugs. Surgery still remain the effective way to treat the patients of CRC.
The success of the surgical treatment will however depend on the stage of the disease. The procedure of the operation will continue up to the last and final stage. There is no standard in the third line therapy but the chosen treatment by the oncologist can effectively induce the short increase within the progression but without overall survival seriously affected.
The problem can therefore be effectively being eliminated in very many ways including the early diagnosis of the patients, use of the promising predictive bio marks, repurposing the already existing drugs and the optimized administration of the drugs on the regular basis. The study focusses on the possibility of using a repurpose drug (Cerami et al.2012).
Repurposing of the drugs refers to the alternative that is provided other than the already existing pool of drugs that no longer trigger response from the cancer patients. The repurposing technique has got two advantages. Firstly, there is prior knowledge that is the toxicities and the dosing can be thoroughly be used in the repurposing of the drug.
The patients that uses this particular option for the cancer treatment of the cancer incur very low costs as opposed to the expensive already existing cancer drugs. Obviously, the patient or the candidate that is under the repurposing in CRC must be tested in a proper clinical set up. When repurposing a drug that has never been used in the treatment of cancer, there is a potential risk that the used drug has a combination with the other chemotherapy with toxic effects. There is therefore a requirement of the three+ three dose escalating in order to minimise the effects of these risks. The main idea here is that the patients are included in the cohorts of at least three progressively higher amounts or dose levels of the repurposed drugs. All the patients will be given a combination of the standard concentration of the chemotherapy and the repurposed drug.
At the initial stages, there are three patients that are under the treatment of the chemotherapy in the combination with 50% of the previously made maximum tolerated dose. (MTD) In case the dose limiting toxicity is observed in any of the individuals under the test, more patients will be included in the program (Weinstein et al 2013). The program of the dose escalation will only continue as long as there is experience of the DLT. If the next step is to e taken which in this case is round three, then 75% of the MDT will be used. Six patience will be included at the highest dose of the repurposed drug. These same individuals will also be included in the next phase 2 study so that there is minimised number of the individuals in the trial. This will continue towards the perfection of the results (Torre et al. 2015).
In conclusion, it has been shown that the combined treatment of the anisomycin with other elements like lexatumumab improves the effects of the drugs. This was evident when the apoptosis was enhanced in the melanoma cell lines. The synergic effects results from higher caspase cascade indications and motivated cleavage while it lowered the concentration of apoptotic protein Livin. Collectively these results indicate that anisomycin treatment might be a good way for enhancing the response or the reaction of the cell called melanoma to TRAIL-R2 targeted therapies. What is the modalities of cell death that can anisomycin induce and what is the molecular target that is responsible for that?
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