H is Alvocidib Flavopiridol inhibitors of PARP are available. So far, two PARP inhibitors therapeutic applications in cancer therapy: the chemo / radiopotentiator and as a stand-alone therapy for tumor types that are already deficient in certain types of mechanisms of DNA repair. Slightly damaged in the first application, the combination of PARP inhibitors with DNA Ended chemotherapy or radiation k Can repair mechanisms of cancer cell DNA entered into compromise Ing genomic dysfunction and cell death. In fact, the first clinical phase I trial a PARP inhibitor with AGO14699 2003-2005 was carried out in combination with the methylating agent temozolomide in patients with advanced solid tumors.
Phase I, Phase II and Phase III clinical trials with other PARP inhibitors in combination with chemotherapy are ongoing. An important breakthrough in the field of PARP inhibitors come KW-2478 in 2005 when two separate independent Have Independent groups, the sensitivity of BRCA1 and BRCA2 deficient cell lines to PARP inhibitors, the support for the first time the potential use of inhibitors shown , PARP as individual therapeutic agents types of cancer cells to a deficiency of certain types of mechanisms of DNA repair. This approach is based on the concept that inhibition of PARP leads to an increase Increase the SSB is closing Lich lead to the DSB by the collapse of replication forks and repair of the DSB in tumor cells that have lost, adversely Are made more prominent based BRCA1 and BRCA2, essential components of the HR pathway, leading to chromosomal aberrations and genomic instability t cell death.
This synthetic lethal approach, defined as a situation where a mutation in a cellular gene is Lead re sensitivity, but the loss of the two t Is harmful, seems to be a promising approach in the development of therapies against cancer. Several clinical trials have been initiated to test the effectiveness of this approach. Tats Chlich, a study with an orally active PARP inhibitor Olaparib a clinical benefit in the BRCA1 or BRCA2 mutation. Moreover, the lack of tumor-homologous proteins In other Rekombinationspfad sensitive to PARP inhibitors. For example, recent findings have shown that cells with PTEN mutations are sensitive to PARP inhibitors.
In Similar way PALB2-deficient cells are also sensitive family of transcription factors, MYC, including normal c-myc Myc Myc and N L, the functionally redundant transcription factors known deregulated in most human cancers. Myc regulates a variety of genes, cells, and a reply by reprogramming cellular Rer functions, including the cell cycle progression, cell growth and metabolism, all the features of tumor progression and cell transformation. Fortunately, the most important mechanisms of tumor suppression are used to protect the cell from deregulated oncogenes such as myc. Two of them, oncogene induces apoptosis and senescence, must be related to tumor progression occur.2, 3 tumor progression on a certain amount of genomic instability t accumulate mutations in tumor suppressor genes bypass the main, such as control positions Tp53.
4 the contr The genomic stability t of Myc is a transcription factor, h frequently in human cancers. The mediation process Myc cell transformation with genomic proliferating cells and rapid inh Pensions instability t associated to b invasive survive what Sartigen neoplasms, with a poor prognosis for this. Independent Independent transcription functions of Myc z Select the stimulation of replication. above the strength Myc expression stimulates replication of the reaction is associated, that DNA-Sch the signals via the phosphoinositide 3-kinase protein kinases ATM and ATR. These related in turn activate the DNA-Sch The Chk1 and Chk2 converter. Here we show that Myc can stimulate transcription indirectly CHEK2 in vitro and in B cells of transgenic M λ Myc mice or intestinal APCmin the mouse. It is not important Chk2 Myc, the F Ability to transform cells in vitro