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t increases Mdm2 mRNA andproteins levels on the order of twoto fourfold can be a strongly correlated (-)-MK 801 with poor prognosis. Further, deletion of one allele of Mdm2 or Mdmx in mice suppresses Bcell lymphomadevelopment induced by the oncogene cMyc. These data taken with all the fact that signaltransduction pathways:are responsible for the nuclear import and export of Mdm2,alter Mdm2 ubiquitin ligase activity,affect Mdm2 binding partners andaffect Mdm2regulatory functions suggests that selectively targeting the kinases that modulate Mdm2 andMdmx activity would defend and activate p53. Hence offering novel therapeutic targets.The classic example of a rationally developed kinase inhibitor is the Abelson tyrosine kinaseinhibitor imatinib.
The use of imatinib to treat chronic myelogenous leukemiapresents a case study in the will need for a careful understanding in the diseasemechanism and drug action (-)-MK 801 in predicting drug applicability for other indications. Imatinibinhibits the Abl kinase activity in the constitutively active mutant BCRAbl fusion kinaseprotein by blocking ATP binding. Moreover, imatinib is minimally toxic to nondiseasecells. BCRAbl is the result of a gene fusion amongst the breakpoint cluster regiongene and cAbl kinaseor Philadelphia chromosome. BCRAblis present in 95% of patients diagnosed with CML. BCRAbl functions as an oncogeneby dysregulating intracellular signaling leading to aberrant proliferation and resistance toapoptosis. The clinical outcome in the BCRAbl fusion gene item is an abundance ofmyeloid progenitor and differentiated cells.
At the time of diagnosis, CML patients typicallyhave peripheral blood counts almost 20fold greater than normal. Blood cells harboringthe BCRAbl BI-1356 fusion gene item initially keep their normal activity but at some point losetheir ability to differentiate leading to blast crisis. Imatinib is much much less powerful following blastcrisis presumably due to the presence of multiplehitsto the cell. Imatinib providespositive cellular response in 6590% of patients with CML and up to 8090% responsewhen patients are in early chronic phase. Imatinib is usually effectively tolerated withfew side effects compared to common cytotoxic chemotherapy. Low peripheral blood countsare a common side effect with imatinib treatment when nonhematologic reactions are minor. Imatinib can be a good results story of rationalized drug style but additionally illustrates a will need formultifaceted approaches in cancer treatment.
The initial excitement of imatinib's good results was dampened by the early identification ofresistance mutations HSP primarily within the BCRAbl kinase domain. Resistance to imatinib inCML is generally by the reactivation of BCRAbl signal transduction. Imatinib resistance inCML develops rapidly, and some argue inevitably, since the selective pressures on cellstreated with single target therapies is high. Since cells exposed to single target therapies onlyneed to overcome a single source of inhibition, a further point mutation is generally adequate todevelop resistance. And due to the rapid proliferation of cancer cells, the rise of resistancemutations generally occurs inside a clinical setting.Imatinib has also been utilised on a limited basis for treatment of other tumors with mixedsuccess.
Imatinib exhibited a lack of response in at BI-1356 least one study with metastatic Leydigcell tumor. Further, inside a mouse model of mammary adenocarcinoma cells, imatinib treatment lead to accelerated tumor growth. These final results suggest thatthe reported in vitro and animal model findings for imatinib may not be directly applicablefor added indications. These disparate final results suggest that a much more complicatedsignaling cascade is at play in different tumor models. Since CML is typified by hyperactiveAbl kinase activity, imatinib is helpful in lowering the degree of Abl kinase activity within the cellto a much more normal physiological level. Nevertheless, pressures for tumor growth eventuallyovertake (-)-MK 801 the action in the drug and resistance mutants develop.
The action of imatinib BI-1356 incells that have normal Abl signaling would produce a whole distinct range of signalingevents that may possibly or may not be advantageous as cancer therapeutics. In this context,treatment of tumors harboring wildtype p53 with imatinib would not most likely present benefitsince p53 levels would be negatively impacted through inhibition of Abl kinase activity.Furthermore, blocking Abl phosphorylation of Mdmx would result in the formation of Mdmxp53complexes, rendering p53 transcriptionally inactive.4. ConclusionsThe application of kinase inhibitors for the treatment of cancer is currently a major focus indrug development. These compounds have fairly couple of side effects and show really goodinitial efficacy. Nevertheless, development of compounds with further specificity can be a challengeand the rise of resistance mutations limits the clinical impact of any single target compound.Rational use of several compounds that selectively target many kinases inside a singlecascade may possibly present a mechanism to lessen drug resistance in th