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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,have an effect on Mdm2 binding partners andaffect Mdm2regulatory functions suggests that selectively targeting the kinases that modulate Mdm2 andMdmx activity would shield and activate p53. Hence providing novel therapeutic targets.The classic example of a rationally created kinase inhibitor could be the Abelson tyrosine kinaseinhibitor imatinib.
The use of imatinib to treat chronic myelogenous leukemiapresents a case study with the need to have to get a careful understanding with the diseasemechanism and drug action (-)-MK 801 in predicting drug applicability for other indications. Imatinibinhibits the Abl kinase activity with the constitutively active mutant BCRAbl fusion kinaseprotein by blocking ATP binding. Moreover, imatinib is minimally toxic to nondiseasecells. BCRAbl could be the result of a gene fusion among the breakpoint cluster regiongene and cAbl kinaseor Philadelphia chromosome. BCRAblis present in 95% of individuals diagnosed with CML. BCRAbl functions as an oncogeneby dysregulating intracellular signaling leading to aberrant proliferation and resistance toapoptosis. The clinical outcome with the BCRAbl fusion gene product is an abundance ofmyeloid progenitor and differentiated cells.
At the time of diagnosis, CML individuals typicallyhave peripheral blood counts almost 20fold greater than typical. Blood cells harboringthe BCRAbl BI-1356 fusion gene product initially keep their typical activity but ultimately losetheir ability to differentiate leading to blast crisis. Imatinib is substantially much less efficient right after blastcrisis presumably as a result of the presence of multiplehitsto the cell. Imatinib providespositive cellular response in 6590% of individuals with CML and up to 8090% responsewhen individuals are in early chronic phase. Imatinib is normally nicely tolerated withfew side effects in comparison with standard cytotoxic chemotherapy. Low peripheral blood countsare a prevalent side effect with imatinib therapy whilst nonhematologic reactions are minor. Imatinib can be a accomplishment story of rationalized drug style but also illustrates a need to have formultifaceted approaches in cancer therapy.
The initial excitement of imatinib's accomplishment was dampened by the early identification ofresistance mutations HSP primarily in the BCRAbl kinase domain. Resistance to imatinib inCML is usually by the reactivation of BCRAbl signal transduction. Imatinib resistance inCML develops quickly, 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 as a result of the rapid proliferation of cancer cells, the rise of resistancemutations generally occurs in a clinical setting.Imatinib has also been employed on a limited basis for therapy of other tumors with mixedsuccess.
Imatinib exhibited a lack of response in at BI-1356 least one study with metastatic Leydigcell tumor. Further, in a mouse model of mammary adenocarcinoma cells, imatinib therapy result in accelerated tumor growth. These results suggest thatthe reported in vitro and animal model findings for imatinib may not be directly applicablefor additional indications. These disparate results suggest that a much more complicatedsignaling cascade is at play in numerous tumor models. Since CML is typified by hyperactiveAbl kinase activity, imatinib is useful in lowering the level of Abl kinase activity in the cellto a much more typical physiological level. On the other hand, pressures for tumor growth eventuallyovertake (-)-MK 801 the action with the drug and resistance mutants develop.
The action of imatinib BI-1356 incells that have typical Abl signaling would generate a entire various selection of signalingevents that could or may not be advantageous as cancer therapeutics. In this context,therapy of tumors harboring wildtype p53 with imatinib would not likely present benefitsince p53 levels would be negatively impacted by means of inhibition of Abl kinase activity.In addition, blocking Abl phosphorylation of Mdmx would lead to the formation of Mdmxp53complexes, rendering p53 transcriptionally inactive.4. ConclusionsThe application of kinase inhibitors for the therapy of cancer is presently a major focus indrug development. These compounds have fairly few side effects and show really goodinitial efficacy. On the other hand, 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 various compounds that selectively target many kinases in a singlecascade could present a mechanism to lessen drug resistance in th