Mechanisms drug resistance to cancer chemotherapy

Mechanisms drug resistance to cancer chemotherapy Introduction Cancer is one of the major causes of death in the developed world and statistics show that one in three people will be diagnosed with cancer during their lifetime [1]. Cancers are malignant tumours and can be distinguished from normal cells by four characteristics; uncontrolled proliferation, dedifferentiation and loss of function, invasiveness, and ability to metastasise [2]. These characteristics are caused by altered gene expression, as a result of genetic mutations that inactivate tumour suppressor genes and / or activate oncogenes. Most cancer chemotherapeutic drugs affect only one characteristic aspect, which is uncontrolled proliferation [3]. In many cases the antiproloferation action is caused by damage to DNA, which initiates apoptosis and cell death [4]. As their main target is cell division, they affect all rapidly dividing cells, including normal cells. This produces general toxic effects, such as myelosuppression, alopecia, damage to gastrointestinal epithelium, sterility and severe nausea and vomiting. Besides the toxic effects of chemotherapy, another major problem is chemoresistance [5]. Resistance to chemotherapy is when the cancer cells do not respond to the drugs. It can be inherented, as a genetic mutation, or it can be acquired, as a cellular response to drug exposure. Mechanisms of resistance include: increased efflux or decreased influx of cytotoxic drugs; insufficient activation of the drug; increased inactivation of the drug; increased concentration of target enzyme; rapid repair of DNA lesions; or mutations in various genes. When patients develop resistance, multiple drugs with different pathways of entry and different cellular targets are used. However, cancer cells can become multidrug resistant, a phenomenon due to cells expressing mechanisms that cause simultaneous resistance to many different, structurally and functionally, unrelated drugs [6]. Multidrug resistance, generally, results from over expression of ATP-dependent efflux pumps [5]. These pumps have broad drug specificity and belong to a family of ATP-binding cassette (ABC) transporters, of which P-glycoprotein (PGP) is one of the most important members. Increased drug efflux, via these transporters, lowers intracellular drug concentration, allowing cancer cells to escape the toxic effects of the drugs. PGP inhibitors are being developed to overcome multidrug resistance and two that have reached clinical trials are varapamil, a calcium channel blocker, and cyclosporin A, an immunosuppressant [7]. The remainder of this review will focus on the different chemotherapeutic agents currently being used for the treatment of cancer and their mechanism of action. Also the main mechanism of resistance to these drugs will be explored, particularly focusing on the role of P-glycoprotein and how it can be modulated to reverse drug resistance. Drugs used in cancer chemotherapy Drugs used in the treatment of cancer are summarised in table 2. They are grouped into: cytotoxic drugs, which preferentially but not exclusively target rapidly dividing cancer cells; hormone therapy, which is a more specific form of treatment used for tumours derived from hormone sensitive tissues; and miscellaneous agents, which include a number of recently developed drugs such as monoclonal antibodies. Cytotoxic drugs Cytotoxic drugs can be further divided into the following; alkylating agents, which act by forming covalent bonds with DNA and impeding replication; antimetabolites, which block one or more of the metabolic pathways involved in DNA synthesis; cytotoxic antibiotics, which are of microbial origin and prevent cell division by directly acting on DNA; and plant derivertives, which affect microtubule function and hence the formation of the mitotic spindle. Alkylating agents Alkylating agents form carbonium ions, which are highly reactive and interact instantaneously with nucleophilic sites such as N7 of guanine in DNA [8]. They are bifunctional, which means they have two alkylating groups, and can cause intra- or inter-chain cross-linking between DNA strands. This prevents strand separation for DNA synthesis or transcription. They can also cause base mispairing between strands, which interferes with the progression of the replication fork [3]. These actions block DNA synthesis, causing a block at G2 phase and subsequently apoptotic cell death. Alkylating agents currently being used in chemotherapy primarily belong to the following families: nitrogen mustards (Cyclophosphamide, Chlorambucil, Melphalan, Ifosfamide, Busulfan); nitrosoureas (Carmustine, Lomustine, Fotemustine); aziridines (Thiotepa); Dacarbazine and platinum compounds (Cisplatin, Carboplatin, Oxaliplatin) [9]. Nitrogen mustards, nitrosoureas and aziridines are believed to kill tumour cells by inducing DNA inter-strand cross-links, while platinum compounds induce intra- and inter-strand cross-links, as well as DNA-protein cross-links under certain circumstances [8]. Resistance to these drugs can develop as a result of cancer cells rapidly repairing drug induced lesions [10], which will be discussed in detail later. Antimetabolites Antimetabolites interfere with the metabolic pathways involved in DNA synthesis. An example of an antimetabolite is Methotrexate, which is a folate antagonist [11]. Folates are essential for the synthesis of purine nucleotides and thymidylate, which in turn are essential for DNA synthesis and cell division. Folates are actively taken up into cells by the reduced folate carrier (RFC), where they are converted to polyglutamates. Polyglutamate folates are then reduced to tetrahydrofolate (FH4) by the enzyme dihydrofolate reductase (DHFR). Methotrexate exerts its action by being taken up into cells by the follate carrier, and like folate being converted to the polyglutamate form. It has a higher affinity for DHFR than the endogenous folate and thus inhibits the enzyme, depleting intracellular FH4, and therefore hindering DNA synthesis. Another example of an antimetabolite is Fluorouracil, which is a pyrimidine analogue [12]. It interferes with DTMP synthesis by forming a ternary complex with thymidylate synthetase (TS); the enzyme that produces DTMP. DTMP is required for the synthesis of DNA and purines, so the irreversible inhibition of the enzyme by fluorouracil results in is inhibition of DNA but not RNA or protein synthesis. Fludarabine is a purine analogue, which is another group of antimetabolites [13]. It is metabolised to its triphosphate form, which inhibits DNA polymerase. As well as the general side effects associated with chemotherapy, patients may develop resistance to antimetabolites; due to a decreased amount of drug uptake [14] or altered concentration of target enzymes [15], which will be discussed later. Cytotoxic antibiotics Cytotoxic antibiotics, such as the anthracyclines (Doxorubicin, Idarubicin, Daunorubicin, Epirubicin, Aclarubicin, Mitoxantrone) bind to DNA and inhibit both DNA and RNA synthesis [16]. Their main cytotoxic action is mediated through an inhibitory effect on topoisomerase II, the activity of which is markedly increased in proliferating cells. During DNA replication, reversible swivelling needs to take place around the replication fork in order to prevent the daughter DNA molecule becoming inextricably entangled during mitotic segregation [17]. The swivel is produced by topoisomerase II, which nicks both DNA strands and subsequently reseals the breaks. Doxorubicin intercalates in the DNA, and its effect is in essence, to stabilise the DNA-topoisomerase II complex after the strands have been nicked, thus halting the process at this point [18]. Dactinomycin is also a cytotoxic antibiotic, which intercalates in the minor groove of DNA, interfering with the movement of RNA polymerase along the gene and thus preventing transcription [19]. Bleomycins are a group of metal-chelating glycopeptide antibiotics that degrade preformed DNA, causing chain fragmentation and release of free bases [20]. This action is thought to involve chelation of ferrous iron and interaction with oxygen, resulting in the oxidation of iron and generation of superoxide and/or hydroxyl radicals. They are most effective in the G2 phase of the cell cycle and mitosis, but are also active against non-dividing cells, that is cells in the G0 phase. This class of drugs cause resistance by altered activity of topoisomerase II, aswell as reduced uptake of the drugs [21]. Plant derivatives One sub group of plant derivatives is the vinca alkaloids, which includes Vincristine, Vinblastine, Vindesine and Vinorelbine [22]. They bind to tubulin and inhibit its polymerisation into microtubules. This prevents spindle formation in dividing cells, which causes arrest at metaphase. They also inhibit other cellular activities that involve microtubules, such as leucocyte phagocytosis, chemotaxis and axonal transport in neurons. They are relatively non-toxic in comparison to the previously mentioned cytotoxic drugs. Another group of plant derivatives is the taxanes, which include Paclitaxel and Docetaxel [23]. They act on microtubules by stabilising them, in effect freezing them in the polymerised state, which achieves a similar effect to that of the vinca alkaloids. Campothecins is another group of plant derivatives and include Irinotecan and Topotecan [24]. They bind to and inhibit topoisomerase I; high levels of which occur throughout the cell cycle. Hormone therapy Tumours derived from hormone sensitive tissues may be hormone dependent [25]. This is due to the presence of steroid receptors in the malignant cells. Their growth can be inhibited by agents with apposing actions, hormone antagonists or drugs that inhibit the endogenous hormone synthesis. The most important group of drugs used to treat cancer are the steroids, namely the glucocorticoids (Prednisolone and Dexamethasone), oestrogens (Diethylstilbestrol and Ethinyloestradiol) and gonadotrophin-releasing hormone analogues (Octreotide and Lanreotide), as well as agents that antagonise hormone action (Tamoxifen, Toremifene and Fulvestrant). Such drugs rarely act as a cure but do mitigate the symptoms of the cancer and thus play an important part in the clinical management of sex-hormone-dependant tumours. Miscellaneous agents Crisantaspase Crisantaspase is a preparation of the enzyme asparaginase and therefore, like asparaginase, can break down asparagine to aspartic acid and ammonia [26]. It is active against tumour cells, such as those of acute lymphoblastic leukaemia, which have lost the capacity to synthesise asparagine and therefore require an exogenous source. As most normal body cells are able to synthesise asparagine, the drug has a fairly selective action and very little suppressive effect on the bone marrow, the mucosa of the gastrointestinal tract or hair follicles. Monoclonal Antibodies Antibodies are immunoglobulins that react with defined target proteins expressed on cancer cells. This activates the hosts immune response, which kills cancer cells by complement-mediated lysis or by killer cells. Monoclonal antibodies can also attach to and activate growth factor receptors on cancer cells, thus inhibiting the survival pathway and promoting apoptosis. Rituximab is a monoclonal antibody that is licensed (in combination with other chemotherapeutic agents) for treatment of certain types of lymphomas [27]. It lysis B lymphocytes by binding to the calcium- channel forming CD20 protein and activating completment. It also sensitises resistant cells to other chemotherapeutic drugs. Trastuzumab (Herceptin) is a humanised murine monoclonal antibody that binds to a protein termed HER2 (the human epithelial growth factor receptor 2); a receptor with integral tyrosine kinase activity [28]. It induces the host immune response as well as inducing the cell cycle inhibitors p21 and p27. Imatinib Mesylate Imatinib is an inhibitor of signalling pathway kinases [29]. It inhibits the platelet-derived growth factor (PDGF); a receptor tyrosine kinase, and the Bcr/Abl kinase; a cytoplasmic kinase. These are considered to be unique factors in the pathogenesis of chronic myeloid leukaemias. Imatinib is licensed for the treatment of this tumour when it has proved to be resistant to other therapeutic strategies, as well as for the treatment of some gastrointestinal tumours that are not susceptible to surgery. Resistance to Anticancer Drugs As mentioned previously patients can develop resistance to many chemotherapeutic agents. This can be caused by a number of mechanisms, which are summarised in figure 1. A decrease in the amount of drug taken up by the cell Resistance can develop as a result of decreased drug uptake. This can be due to the loss of transporter function, for example RFC [30]. Decreased influx of Methotrexate in tumour cells has been widely associated with decreased RFC gene expression. Down-regulation of the transporter protein is due to alterations in the transcription and translation factors. Transcriptional factors, such as the Sp1 family, CREB (cyclic AMP-response element binding protein) and p53, regulate RFC gene expression [31]. Therefore loss of function of these transcription factors cause silencing of the RFC gene, which results in reduced protein level. Also post-translational modifications of transcription factors alter phosphorylation patterns, which abolishes Sp1 and CREB function thereby resulting in loss of RFC gene expression and subsequently resistance [32]. Mutations in the human RFC gene can also decrease drug influx. Jensen et al (1998) have reported a mutation that causes marked changes in the kinetic properties of RFC mediated transport of folates [14]. The structurally altered RFC was functionally characterized by a 9- and 31-fold increased affinity for transport of reduced folate cofactors and folic acid, respectively. This allowed the accumulation of intracellular folates, which sustained cell growth and DNA replication, allowing cancer cells to escape the cytotoxic effects of antifolate drugs. Altered concentration of target enzyme Increased expression of target enzyme is a common mechanism of acquired resistance. For example Methotrexate resistance can develop as a result of DHFR gene amplification and subsequent enzyme overexpression [15]. Gene amplification is thought to occur as a consequent of antifolate inhibitors binding to DHFR, which causes a conformational change that alters the translational autoregulatary negative feedback mechanism, wherein DHFR protein specifically interacts with its own mRNA and negatively controls translational efficiency. The drug concentration will be limited to the dose administered, which will not be able to block the additional enzyme that is synthesised, resulting in cancer cells overcoming the inhibitory effect of the drug. Insufficient activation of the drug Some drugs require metabolic activation to manifest their antitumour activity for example Cytarabine has to undergo catalytic conversion, by the action of deoxycytidine kinase, to an active form [33]. So under expression or mutation of this drug-metabolising enzyme can reduce drug efficacy and cause resistance. Another example of resistance due to insufficient activation of the drug is Mercaptopurine, which is a prodrug [34]. Mercaptopurine is activated by hypoxanthine guanine phosphoribosyl transferase (HGPRT) and mutations that reduce the activity of this enzyme will allow the cancer cells to escape the toxic effects of the drug. Increase in inactivation Resistant to Mercatopurine can also develop as a result of increased inactivation of the drug [35]. The mechanism behind this is thiopurine s-methyltransferase (TPMT), which inactivates Mercaptopurine and thereby prevents the formation of the active drug. Mutations in the TPMT gene will alter its activity and may cause resistance. Rapid repair of drug-induced lesions Patients can develop resistance as a result of cancer cells recognizing DNA lesions and rapidly initiating repair pathways [9]. This is the main cause of resistance to alkylating agents as their mechanism of action is DNA damage There are several repair pathways and include the Direct Repair (DR) pathway, Base Excision Repair (BER) pathway, Nucleotide Excision Repair (NER) pathway, Homologous Recombination (HR) pathway and Non-Homologous End Joining (NHEJ) pathway. The DR pathway is mainly mediated by the DNA repair protein: O6-alkylguanine DNA alkyltransferase (AGT) [36]. AGT transfers the alkyl adducts from the nucleotides to the cysteine residue within its active site, independently from other proteins and without causing DNA strand breaks. The BER pathway recognizes and accurately removes bases that have been damaged by alkylation [37]. A damaged base is removed by a damage-specific DNA glycosylase, leading to the formation of a potentially cytotoxic apurinic or apirimidinic site intermediate. This is then processed by an AP endonuclease (APE1), which generates a strand break that is further processed by Poly ADP-Ribose Polymerase (PARP), DNA polymerase b (Polb) and ligase III to restore the damage. The NER pathway deals with the repair of bulky DNA lesions formed by DNA-alkylating agents such as Cisplatin, which distort the DNA double helix and block DNA replication and transcription [38]. Two major mechanisms of DNA repair have been recognized in this pathway: the transcription-coupled repair, which specifically targets at and removes lesions that block the progression of RNA polymerase II, and the global genome repair, which deals with lesions in the rest of the genome. Generally, nucleotide repair is a complex multi-step process that sequentially deploys a group of proteins to reorganize the lesion, remove the damage, and support new DNA synthesis. The HR and NHEJ pathways are involved in the repair of DNA double strand breaks, commonly considered to be the most lethal of all DNA lesions. Double strand breaks are induced by chemotherapeutic agents such Bleomycin, and Etoposide. In the HR pathway, ATM (ataxia talagiectasia mutated kinase) and its related ATR proteins sense the severe DNA lesions, and are mobilized to phosphorylate a wide range of substrate proteins [39]. Also a number of regulatory proteins, including BRCA1, BRCA2 and p53, are recruited to coordinate the DNA repair. The NHEJ pathway involves the alignment of the broken ends followed by recruitment and activation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and DNA ligase IV to complete the ligation step [40]. Mutations Mutations in various genes can give rise to resistant target molecules, for example the p53 gene [41]. The p53 protein is an important regulator of the cell cycle and is sensitive to any DNA damage caused during replication. Following DNA damage it will normally induce G1 arrest and/or apoptosis to prevent the production of defective cells. Mutations in this gene will cause the loss of p53 function, which will allow cells with damaged DNA to continue replicating, resulting in resistance to DNA damaging drugs. Other genes, such as h-ras and bcl-2/bax, involved in the apoptotic pathway, have also been implicated in resistance [42]. Resistance due to mutations in genes will affect a wide range of anticancer drugs as all cells contain the same genetic material. It also potentially increases the proportion of surviving mutant cells, which leads to greater tumour heterogeneity. Increased expression of efflux pumps Resistance to natural hydrophobic drugs, such as vinca alkaloids and taxanes, as well as the cytotoxic antibiotics, such as anthracyclines and Dactinomycin, occurs due to the over expression of ATP-dependent efflux pumps in cancer cells [5]. These pumps belong to a family of ATP-binding cassette (ABC) transporters, which are divided into eight distinct subfamilies, shown in table 1. Of these subfamilies PGP, also known as MDR1, has a broad drug specificity, which explains the cross-resistance to several chemically unrelated compounds. It is a multidrug efflux pump that has 12 transmembrane regions, which bind hydrophobic drug substrates that are either neutral or positively charged [6]. It also has two ATP-binding sites, as hydrolysis of two ATP molecules are needed for the transport one drug molecule [43]. Binding of substrate to the transmembrane regions stimulates the ATPase activity of PGP, causing a conformational change that releases substrate to the extracellular space. Hydrol ysis at the second ATP site is required to re-set the transporter so that it can bind substrate again, completing one catalytic cycle. Increased expression of the PGP transporter in cancer cells increases the amount of catalytic cycles that occur, which increases the amount of drug effluxed [5]. This lowers the intracellular drug concentration below a cell-killing threshold, which results in resistance. Not all multidrug-resistant cancer cells express PGP. Resistance in these cells was discovered to be linked with the expression of the multidrug-resistance-associated protein 1 (MRP1) [44]. MRP1 is similar to PGP in structure (table 1) but, unlike PGP, it recognizes neutral and negatively charged hydrophobic natural products, and transports glutathione and other conjugates of these drugs, or, in some cases, such as for Vincristine, co-transports unconjugated glutathione. Some anticancer drugs, such as Mitoxantrone, are poor substrates for PGP and MRP1. Mitoxantrone resistance is due to a more distant member of the ABC transporter family, MXR (Mitoxantrone-resistance gene) [45]. This transporter is thought to be a homodimer of two half-transporters, each containing an ATP-binding domain at the amino-terminal end of the molecule and six transmembrane segments (table 1). Resistance can also develop as a result of increased expression of ABC transporters in the apical membrane of the gastrointestinal tract [46]. ABC transporters play a key physiological role, where they extrude toxins thus forming a protective mechanism and a first line of defense. Increased expression of these transporters decreases drug uptake and therefore decrease drug bioavailability. Examples of chemotherapeutic agents that develop resistance by this mechanism include antimetabolites, such as Methotrexate and Fluorouracil, and alkylating agents, such as Cisplatin. Also water-soluble drugs that piggyback on transporters and carriers or enter by means of endocytosis can fail to accumulate as they will not be able to enter the body. Additionally, PGP actively secretes intravenously administered drugs into the gastrointestinal tract [47]. Resistance due to increased levels of PGP transporters in the gastrointestinal tract is illustrated by MDR1a/MDR1b-knockout mice, which have shown to have increased tissue concentrations of PGP substrates. Studies have also shown increased tissue absorption of PGP substrates, following oral administration, when co-administered with a PGP inhibitor. Reversal of drug resistance in cancer Ways to overcome multidrug resistance due to the over expression of ABC transporters are being researched. Some of the main approaches include developing PGP inhibitors, antibodies against the PGP transporter, antisense oligonucleotides and liposome-encapsulated drugs. Drugs that can reverse multidrug resistance, such as PGP inhibitors, could be useful interventions to improve bioavailability, by increasing oral uptake of anticancer drugs and decreasing drug excretion, thereby reducing dosing requirements [7]. Two inhibitors that are used in the laboratory and in clinical trials that attempted to reverse drug resistance are the calcium channel blocker, verapamil and, the immunosuppressant, cyclosporin A. Another method that can be used to inhibit PGP is by competitive inhibition [48]. PGP binds many different hydrophobic compounds so any drug that interacts with the substrate-binding region is likely to be a competitive inhibitor of other drugs. Thus, two drugs that are transported by PGP will compete for this transport, resulting in increased oral absorption of both, decreased excretion, and redistribution. This kind of drug interaction can be used to inhibit the multidrug transporter, when the inhibitor drug has little or no other pharmacologic e ffect. Monoclonal antibodies (MAbs) against PGP have been used to kill multidrug resistant cells [49]. MAbs are of therapeutic use as they can activate the immune response, which results in complement mediated lysis or antibody dependent cellular cytotoxicity of the cells. An example of a MAb is MRK-16, which has shown selective toxicity towards tumours that are over expressing PGP. Molecules, which are normally involved in signal transduction on T and B cells can also be targeted for antibody therapy [50]. Such molecules include CD19, which is a membrane receptor involved in signal transduction and potentiates the response of B cells to antigens. MAbs directed against CD19 can induce cell-cycle arrest due to negative growth signals that cross-link immunoglobulin M and CD19. Antisense drugs work by down regulating gene expression [51]. This occurs by sequence-specific blinding of either DNA or RNA, which inhibits transcription or translation, respectively. Different antisense-oligodeoxynucleotides have been reported to chemosensitize resistant tumour cells to anticancer drugs through down regulation of PGP expression and thus increasing the intracellular accumulation of anticancer drugs in the cancer cells. The efficiency of a synthetic oligodeoxynucleotide (ODN) in regulating gene expression in living cells depends on its thermodynamic stability, resistance toward nucleases and cellular uptake [52]. A number of studies indicate that a synthetic ODN coupled with a DNA intercalator such as acridine, naphthyl imide, psoralen or pyrene might act to increase stability. Novel drug delivery systems such as liposome-encapsulated drugs have also been developed to overcome multidrug resistance [53]. Liposome formulations contain a small fraction of polyethylene glycol (PEG)-derivatised phospholipid, which has been shown to dramatically alter the pharmacokinetic properties of certain anticancer drugs. These pharmacokinetic alterations include long elimination half-life and small volume of distribution. Another formulation developed to bypass PGP transporters is anionic liposomes, which are internalised by certain cells and are able to provide drug release in intracellular compartments. Conclusion Cancer is prevalent in the western world and much research is dedicated to produce effective chemotherapy. Current chemotherapy includes alkylating agents, antimetabolites, cytotoxic antibiotics, plant derivertives, hormone therapy and monoclonal antibodies. However the efficacy of these chemptherapeutic agents is limited to patients developing multidrug resistance. This is mainly due to the over expression of ABC transporters, particularly the PGP transporter, as they have broad drug specificity so can bind many structurally unrelated drugs [5]. Techniques to reverse multidrug resistance are being developed and include co-administration of PGP inhibitors, which prevent the binding of anticancer drugs the transporter [7], the use of antibodies, which kill cells over expressing the PGP transporter [49], antisense oligonucleotides that down regulate PGP expression [51] and liposome-encapsulated drugs, which alter the pharmacokinetic properties of anticancer drugs [53]. A better understanding of the mechanism by which ABC transporters efflux chemotherapy and further analysis, in clinical trials, of known mechanisms of multidrug resistance would increase the development of agents that reverse multidrug resistance. Also improved imaging techniques used in clinic to screen cancer cells would enhance the ability of practitioners to prescribe individualised treatment according to the patients level of resistance. One approach that can be developed is to produce fluorescent antibodies against all 48 human ABC transporters and use them in conjunction with a specialised fluorescent microscope to monitor the levels of ABC transporters in cancer cells. References Office for National Statistics (2005) Cancer Statistics registrations: registrations of cancer diagnosed in 2006, England. http://www.statistics.gov.uk/downloads/theme_health/MB1-37/MB1_37_2006.pdf [accessed December 2009] Weinberg RA (1996) How Cancer Arises. Scientific American; 275: 42-48 Lawley PD and Phillips DH (1996) DNA adducts from chemotherapeutic agents. Mutation Research; 355: 13-40 This article is not included in your organizations subscription. 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Continuous improvement Essay

What is continuous improvement means in the context of organisational success Continuous improvement is a quality philosophy that assumes further improvements are always possible and that processes should be continuously re-evaluated and improvements implemented. It is also the seeking of small improvements in processes and products, with the objective of increasing quality and reducing waste. It is believed that an organization must constantly measure the effectiveness of its processes and strive to meet more difficult objectives to satisfy customers. Continuous improvement is an ongoing effort to improve products, services or processes. These efforts can seek â€Å"incremental† improvement over time or â€Å"breakthrough† improvement all at once How it is possible to lead continuous improvement systems and processes -Encouraging and supporting team members to participate in decision-making processes: Quality management is a process in business that requires participation from everyone, from senior management to those on the shop floor. Quality management can only be effective if everyone participates and contributes ideas for the overall improvement of a business. Without active participation by everyone, you are not getting everything you could get from the process. You need to involve everyone; you need to ensure that you listen to everyone’s ideas. After all, often it is not just management who know how to make improvements. Those on the shop floor deal with problems on a daily basis, and this puts them in the best position to find ways of making improvements. In this section we will look at ways of working with your team to ensure that you are getting the active participation of all team members. There are a range of tools that can be used to ensure that your team is encouraged to participate in the continuous improvement process. oBrainstoming oCheck sheets oMind mapping oCause and Effect diagram oNorminal Group technique oConsensus oVoting -Ensuring continuous improvement processes are communicated to stakeholders: In order to be successful, it is important that quality initiatives and the general concept of quality management is promoted throughout an organisation. Quality management requires solid commitment on the part of management and all staff members in order to be regarded as successful, and promotion is an extremely useful means of showing, and developing, this commitment. We will examine promotion of quality through a cyclic approach. In a sense, this approach can be likened to the idea of quality management, as it involves continuous improvement of ideas. The four major means of communicating and promoting quality initiatives within an organisation are: oNewsletters oWorkshops oForum groups oPresentations -Developing effective mentoring and coaching processes: Many industries have very high worker turnover and recruiting staff and more importantly retaining them can be quite difficult to achieve. Having a coach or mentor in place can help relieve much of the stress that new staff feel when they begin a new job. New staff may lack experience or some of the core skills required to undertake a specific job and by having a coach or mentor there to provide assistance, you can assist in reducing the stress felt by new staff undertaking a new job. The process of having a coach or mentor assigned to your new staff is not a new idea, but one which can provide significant advances in improving overall quality in the workplace. They also enhance the individual employees performance. There are a number of different methods that can be used when creating a coaching or mentoring scheme in your workplace. These include: -Personal coaching programs employing external or internal coaches -Traditional’ or peer-to-peer mentoring schemes -Buddy schemes, a form of two-way peer-to-peer mentoring The method that you decide to utilise when working towards improving quality in your work place will be entirely dependant on what you are trying to fix and the type of skills that are already present in your workplace. You may also need to consider the organisation and its culture. Some organisations simply do not have the kind of culture that allows for one individual to assist another easily without the staff feeling uncomfortable. It is therefore extremely important to consider the effects of the company’s culture on any systems that you may decide to implement into the workplace. Competition, for example, among employees for reaching sales targets or earning commission may mean that there is a lack of willingness to act as an effective mentor or coach. Coaching and mentoring are generally used to provide on-job training, however it can be a lot wider than this. Coaches in the workplace can become an integral strategy in improving quality by developing staff on a continuous rather than one off basis. How an organisational leader would contribute to and implement continuous improvement initiatives It is fundamental to the success of the Management System and to the implementation of continual improvement throughout the organization that senior managers provide strong leadership; visible and active support; and, demonstrated commitment. To encourage improved individual and organization performance, executive sponsors should empower and make individuals accountable for their work. The role of senior management in continual improvement includes the following responsibilities. -Establishing a vision for continual improvement -Establishing overall goals for continual improvement -Creating the motivation for change -Establishing commitment and alignment of the senior management team -Managing the continual improvement programme -Creating a continual improvement culture -Impact on staff involved in continual improvement -Recognizing staff for continual improvement success -Openness and honesty A specific example approaches used for continual process improvement (CPI): TEPCO – JAPAN In TEPCO the following 10 steps outline the process improvement methodology: -Step 1: Determine the boundaries of the process that requires improvement, Organize, Capture â€Å"as-is† SIPOC (Suppliers, inputs, process, outputs, customers). -Step 2:Benchmark the process against industry â€Å"Best Practices†. – Set goals. -Step 3: Capture the current â€Å"as-is† process.

Possible Warning Signs on Essay Helper Free You Need to Know About

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Data Analysis and Application for Unit 9 Essay - 571 Words

Data Analysis and Application Unit 9 Section 1 The research article writer used for this assignment was one on heavy metal music and adolescent suicidality. The participants were adolescents in high school, 121, between tenth to twelfth graders from the Midwest. The scales of measurement that were used in this study were,RFL(Reasons for Living Inventory, a music survey, and SRQ (Suicidal Risk Questionnaire).The journal article is relevant to my area of specialization, of child and adolescent developmental psychology, because it involves adolescents and their well-being. Section 2 The researchers in the article used ANOVA, they hypotheses that heavy metal fans had weaker reasons for living, overall, than†¦show more content†¦The major question posed in the study was whether heavy metal music fans are more vulnerable to suicide, the hypothesis was supported, the hypothesis was further supported from findings that a significantly greater percentage of heavy metal music fans, compared to non-fans thought about killing themselves (Scheel Westefeld, 1999). Section 5 The conclusion from the statistical test supports the findings of the hypothesis. Writer however does not necessarily agree wholeheartedly with the research article. Writer feels they are some limitations to the study, it does not account for other factors in the adolescents life, besides their chose in music that may lead to suicidal thoughts and feelings. There could be several factors that could be the cause of the suicidal thinking, attempts, problems at home, abuse, alcohol and drug abuse, problems in school. Writer feels these teens may seek out this kind of heavy metal music because these negative themes reflect their feelings about their life in general (Scheel Westefeld, 1999). Also it was never discussed in the findings if any of these adolescents had any previous mental health inpatient admissions, and how long they were in the care. It could be many of these teens were clinically depressed for a long period of time, and been in and out of hospital, treatment facilities, and never truly had there depression adequately under control ,had therefore it was just a matter ofShow MoreRelated2121 unit information1576 Words   |  7 PagesETF2121/ETF5912 Data Analysis in Business Unit Information – Semester 1 2014 Coordinator and Lecturer - Weeks 7-12: Associate Professor Ann Maharaj Office: H5.86 Phone: (990)32236 Email: ann.maharaj@monash.edu Lecturer - Weeks 1-6: Mr Bruce Stephens Office: H5.64 Phone: (990)32062 Email: bruce.stephens@monash.edu Unit material: No prescribed textbook Unit Book: available on the Moodle site. Exercises: available on the Moodle site. Software: EXCEL. Recommended Reference Books BerensonRead MoreEssay about A Proposed ICA Algorithm1443 Words   |  6 Pagesdirections rather than searching for the solution in a random manner. 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