As BAD, BIM, MCL 1, caspase-9 and BCL 2 and so regulates apoptosis. 2.1. RAS target for inhibiting melanoma RAS family of small G proteins K consists RAS Cyt387 RAS H and N is the. Activation of MAPK proteins, such as behind the PI3K and RAF HRAS and KRAS genes were identified as human homologues of viral oncogenes in the proto Harvey and Kirsten rat sarcoma virus. RAS proteins Act as molecular switches embroidered l proliferation and survival of the cell. In human tumors, RAS mutation, loss of CAP 1 or NF RAS by upstream Rtigen activation of cell surface Activated surface receptors. Oncogenic mutations of RAS family members have been reported in one-third of all human cancers. In melanoma, the replacement of leucine for glutamine at residue 61 of the h Most frequent aberration is observed in N RAS.
Ras mutant lacking GTPase activity t and remains active, what Uncontrollable cell proliferation Lee and transformed Isoliquiritigenin Ph Genotype. In melanoma, the introduction of activated RAS in melanocytes lead to melanoma tumors in M Nozzles. Au Addition, the expression of RAS remove tumor suppressor p16INK4a, p53 and p14 ARF and H Removable RAS expression by siRNA can lead to regression of melanoma in melanoma tumor model inducible. Therefore, the RAS is a potentially important target in melanoma. 2.2. Therapeutic Targeting RAS works melanoma Efforts pharmacologically inhibit RAS or its regulatory components in the treatment of cancer, were far less successful. Since the activation of Ras requires farnesylation of the cysteine residues Carboxyl farnesyltransferase was found that.
Using targeting FT farnesyltransferase inhibitors of farnesyl cysteine or mimetics as farnesyl derivatives Thiosalicyls Acid can effectively prevent growth of melanoma However, these agents have failed in clinical trials due to nonspecific reactions, such as FTS farnesylate many other proteins Than RAS, other mechanisms by which RAS proteins Activated which are developing resistance to inhibitors, and the presence of fortune assets and other oncogenic proteins. For example, the N RAS proved geranyl geranyl transferase from geranylated was his. Target FT and GGT completely together Inhibit constantly all forms of Ras activation was found to be toxic, because they. Activation of many other proteins With RAS inhibitor In a phase II study of 14 patients with metastatic melanoma, was oral administration of FT inhibitor R115777 toxic and lack of therapeutic efficacy although FT is a potent inhibitor.
Another potent inhibitor FT, SCH 66336 has been shown to induce G1 phase of the cell cycle and the inactivation of the retinoblastoma protein, melanoma cells to t Ten. In addition, the combination of SCH 66336 Thiosalicyls Acid and farnesyl cisplatininduced apoptosis significantly improved activity T chemosensitizer FTI. Another inhibitor of farnesyl-called Lonafarnib tested alone or in combination with chemotherapeutic agents as regulators of melanoma cell invasion, proliferation and survival. Lonafarnib was not able to inhibit the growth of metastatic melanoma cells and tested to sensitize chemotherapeutics. In contrast, significantly Lonafarnib Erh Ht