Essay Example on Introduction and Clinical Features Chronic myeloid leukemia









1 Introduction and Clinical Features Chronic myeloid leukaemia CML is a cancer that affects both the blood and the bone marrow It is characterized by neoplastic proliferation of mature myeloid cells especially granulocytes and their precursors CML results from a reciprocal translocation of ABL gene chromosome 9 long arm to BCR chromosome 22 long arm i e t 9 22 q34 q11 2 with the resulting BCR ABL gene fusion creating the so called Philadelphia chromosome 1 2 This fusion results in a constitutive tyrosine kinase activity which leads to the phosphorylation and activation of various downstream proteins that promote cellular proliferation whilst inhibiting apoptosis 3 Approximately 15 of leukemias in adults are chronic myeloid leukemia CML with an incidence of 1 2 100 000 individuals 4 and a median age of diagnosis at 60 65 years 5 As much as 50 of patients with CML present asymptomatically and are diagnosed incidentally after routine check ups 6 Moreover even in symptomatic cases symptoms are not always specific For example around 50 to 75 of patients complain of left upper quadrant pain owing to splenomegaly Patients may also experience early satiety display symptoms of anemia and night sweats Other symptoms may include bleeding due to platelet dysfunction and thrombocytosis 6 7 A minority of patients 5 may present with hyperviscosity symptoms due to the high degree of leukocytosis 7 This review aims to compile and discuss current advancements in Nanomedicine in which nanoparticles are used as drug delivery systems for the treatment of CML Both the chemical properties of nanoparticles and their clinical applications will be detailed in this work 2 Conventional methods in CML treatment Advantages and drawbacks 

The majority of current therapeutic approaches for CML treatment include tyrosine kinase inhibitors TKIs such as imatinib 8 Although TKIs are the most successful pharmaceutical treatment for CML complete cure from CML cannot be achieved without bone marrow transplantation 8 Other than the lack of complete curative effect of the present chemotherapeutic agents drug resistance and cancer relapse are major disadvantages in the current treatment approaches 9 Therefore employing new agents in combination with existing treatments is of critical importance to improve cancer cells response to drugs to prevent later relapse and to successfully cure CML without the need for transplantation The need to overcome current drugs drawbacks has pushed researchers to develop new treatment strategies with nanotechnology emerging as a possible new approach in the management of CML 10 3 Multidrug resistance One of the major reasons of chemotherapy failure and cancer relapse in hematological malignancies is multidrug resistance MDR In MDR cancerous cells develop complex mechanisms conferring resistance against the cytotoxic effects induced by various types of drugs via various mechanisms of action 

Although drug resistance is initiated a certain type of drugs the resistance is not drug-specific 11 Mechanisms of MDR include downregulation of the production of apoptosis-related proteins such as Bax and Bcl 2 12 drug excretion recovery from drug-induced DNA damage and alterations in the activity of enzymes functioning in drug metabolism 13 Nevertheless the most important mechanism of MDR is drug excretion via permeability glycoprotein P gp 14 an ATP dependant transmembrane efflux pump encoded by the Mdr1 gene which functions to decrease intracellular drug concentrations by actively transporting drugs out of the cells 15 16 17 The overexpression of Mdr1 gene leads to excessive production of P gp increasing resistance to chemotherapeutic drugs and increasing the chance of cancer recurrence thus worsening prognosis 18 With an ever-increasing rate of resistance to treatment new methods of therapeutic targeting must be developed The employment of nanoparticles as drug delivery systems has emerged as promising approach to overcome the resistance phenomenon 4 Nanomedicine in CML treatment While designing a drug delivery system several measurements must considered to ensure success 

A drug delivery system must ensure an efficient delivery of its constituents to the targeted cells whilst preserving the drug molecular bioactivity Moreover the kinetics of the drug loading and drug release should be controlled to achieve a desirable and adequate loading and release of the drug 19 20 Nanoparticles NPs present several advantages when used as drug delivery systems For example drug delivery via NPs improves the water solubility of the drug in cancer cells Moreover drug delivery by NPs enhances the intracellular uptake of the drug and also aids in preserving its metabolic stability The circulation time of the drug is also enhanced when it is delivered via NPs NPs allow targeted drug delivery thus sparing normal cells of the cytotoxic effect of the drug 21 22 In short when loaded into nano carriers chemotherapeutic drugs can escape degradation while displaying lower toxicity superior efficacy and solubility 23 24 25 

However using NPs requires a deep understanding of the various parameters that determine NP function inside a living entity such as a cell or the entire human body The toxicity uptake and half life of NPs depends on factors that are both intrinsic such as surface charge particle size and shape zeta potential and surface area as well as others that are extrinsic to the NP such as the activity of the reticuloendothelial system RES and renal clearance 26 The half life of NPs is highly dependent on their interaction with the reticuloendothelial system especially macrophages 27 Reducing NP clearance by macrophages could be achieved for example by Coating NPS with a hydrophilic layer using polymers such as polyethylene glycol through a process called PEGylation 28 29 Finally when NPs reach the targeted tissues endocytosis is the main mechanism by which these hydrophilic nanoparticles are transported into cells

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