Cancer Health Care Assignment

Cancer Health Care Assignment

This is a solution of Cancer Health Care Assignment in which we discuss  about Chronic myeloid leukaemia.

Abstract

Chronic myeloid leukaemia is a cancer that mainly targets bone marrow and blood.Itconsist an oncogene BCR/ABL that is not present in normal cells. This gene makes a protein BCR/ABL that supports the growth of CML cells.Presence of point mutations in BCR-ABL1 has been implicated as a mechanism for development of imatinibresistance .In order to access the amino acid sequence of the target protein, the protein Abl 1 (Abelson murine leukemia viral oncogene homolog 1) searched in the protein data base on NCBI. Various hits appeared out of which the protein with PDB.On examining the structure of protein, it revealed that there are nine peptide ligand binding sites present in the protein structure while it also carries one large and two small pockets for polypeptide binding.The introduction of TKIs and their implementation in the treatment of CML have changed the management and outcome of this disease dramatically.

Introduction-

Chronic myeloid leukaemiais a cancer that mainly targets bone marrow and blood. Production of too many granulocytes interfers with normal cell production. It has a gradual development and have three phases – chronic, accelerated and blast phase. Though , it is a rare disease accounting 0.03 % of all cancers, it proves to be fatal. CML consist an oncogene BCR/ABL that is not present in normal cells. This gene makes a protein BCR/ABL that supports the growth of CML cells.It is a cytoplasmic 210 kD protein (Valent 2007) that is essential for the growth of leukemic cells. It shows tyrosine kinase activity and thus triggers several downstreaming signaling molecules. There has been a drastic change in the treatment of chronic myeloid leukemia with the emergence of the Abl tyrosine kinase inhibitor, imatinibmesylate. Primary and secondry resistance has been reported particularly in patients at advanced stage of disease. Treatment of chronic myeloid leukemia (CML) has changed drastically with the emergence of the Abl tyrosine kinase inhibitor (TKI), imatinibmesylate. However, primary and secondary resistance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the Abl kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. In order to override this resistance, several second generation ATP-competitive Abl TKIs including dasatinib, nilotinib, bosutinib and INNO-406 have been developed.(Bentov et al 20011) Despite promising clinical results from these novel Abl TKIs for most mutations, the frequently observed mutant T315I is not effectively targeted by any of these agents. Thus, identification of novel agents and the development of new strategies for the effective treatment of CML patients with the T315I mutation are important and challenging tasks.argeted therapy with the Abl kinase inhibitor imatinib has markedly improved the outlook for patients with chronic myeloid leukemia (CML). Breakpoint cluster region (Bcr)-Abl signaling is reactivated at the time of resistance, predominantly due to mutations in the kinase domain of Bcr-Abl that interfere with drug binding. The T315I mutation results in an amino acid substitution at position 315 in BCR-ABL1, from a threonine (T) to an isoleucine (I). Presence of point mutations in BCR-ABL1 has been implicated as a mechanism for development of imatinib resistance ( Sovereni 2011).Several groups have succeeded in identifying at least eighteen different mutations in leukaemiccells from patients who had developed resistance to imatinib. Mutations have been described at positions 244, 250, 252, 253, 255, 289, 311, 315, 317, 343, 351, 355, 359, 379, 382, 387, 396, and 486 (Oliver 2005). The two most frequently occurringmutations were those aminoacids E255 and T315 at position 255, glutamine is substituted by either a lysine (E255K) or a valine (E255V), and at position 315, threonine is substituted by an isoleucine residue. {See more: Ethical Decision Making in Healthcare}

Methodology

For comparison of protein kinase domain primary structure multiple sequence alignment will be done. The alignment is splitted into four parts – gathering sequence,calculation of multiple sequence alignment,rendering the alignment and analyzing the alignment. During gathering BLAST & FASTA will be done. Several bioinformatics server like NCBI,EMBL etc. are to be used during calculation. In order to access the amino acid sequence of the target protein, the protein Abl 1 (Abelson murine leukemia viral oncogene homolog 1) searched in the protein data base on NCBI. Various hits appeared out of which the protein with PDB ID: 1ABQ_A and gen pept accession number is 157829786 which represented the crystal structure of unligandedAbltyrosin kinase Sh 3 domain was selected (http://www.ncbi.nlm.nih.gov/protein/1ABQ_A). The FASTA format of the amino sequence was accessed by clicking on FASTA link (http://www.ncbi.nlm.nih.gov/protein/157829786?report=fasta ). {Look At this-: Rural Health Nursing Assignment Help}

Cancer Health Care Assignment

Result &Analysis:

The protein consists of 62 amino acids, isolated from Musmusculus. On examining the structure of protein, it revealed that there are nine peptide ligand binding sites present in the protein structure while it also carries one large and two small pockets for polypeptide binding. PDB data base (http://www.rcsb.org/pdb/explore/explore.do?structureId=1ABQ ) provides further information regarding the motifs present on the protein structure. It has one proline rich domain and one F actin rich domain while a DA binding domain also exists in the structure. Secondary structural features include eighteen ? helix while eleven alpha helix.

Discussion-

The introduction of TKIs and their implementation in the treatment of CML have changed the management and outcome of this disease dramatically. They have transformed this disease from an immediately life-threatening leukemia, with a 10–20% mortality rate per year, to a chronic disease, managed with oral medications, and with 1–2% mortality per year.Mutational analysis should be performed in those with imatinib failure, escalatingBCR-ABL transcript levels and those with suboptimal response(Jabbaur et al 2013). Mutational data also help in choosing the right second-generation TKI based on the point mutations that led to imatinib failure. {Read more-: How to Motivate Health Care Employees}

References-

1. Valent P. (2007). Imatinib resistance chronic myeloid leukemia, current concepts on pathogenesis and new emerging pharmacologic approaches. Biologics targets and therapy. 2. Bentov R. B. et al. Mechanism of Drug resistance in Kinases. Expert OpinInvestig Drugs 2011 (2): 153–208. doi:10.1517/13543784.2011.546344. 3. Soverini S.., et al. (2011) Validation of the new European LeukemiaNet (ELN) recommendations for Bcr-Abl kinase domain mutation analysis in chronic myeloid leukemia: an analysis of the GIMEMA CML Working Party Studies. Blood118: abstract 112. 4. Marc oliver. Conformational Plasticity in Drug Design: Towards the Development of Inhibitors of Oncogenic Fusion Proteins with Protein Tyrosine Kinase Activity (2005). 5. (http://www.ncbi.nlm.nih.gov/protein/1ABQ_A) 6. (http://www.rcsb.org/pdb/explore/explore.do?structureId=1ABQ) 7. Jabbaur E. (2013).Management of imatinib-resistant patients with chronic myeloid leukemia.TherAdvHematol. 2013 Apr; 4(2): 103–117.

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