Ultimately, these specific and curative treatment proce dures selleck chemicals shall remove symptomatic and often unspecific therapies with potentially severe side effects. The first promising Inhibitors,Modulators,Libraries experimental data are giving hope but need to be carefully validated in clinical trials for practicability, safety, and efficiency. Introduction Incidence of cutaneous melanoma has increased during last decades in Western population. Several risk factors have been reported. A light phototype, a large number of ac quired common nevi, and the occurrence of atypical nevi have been associated with a higher Inhibitors,Modulators,Libraries risk of melanoma. Among others, family history of melanoma confers the highest risk for the development of the disease. Nevertheless, patients with cutaneous melanoma present a higher incidence of second or even additional melanomas.

However, subsequent primary melanomas have been found to be significantly thinner than index lesions, possibly due to increased surveil lance and not to differences in tumor biology. In patients with multiple primary melanoma, the disease staging is based on the melanoma with the worst prognostic Inhibitors,Modulators,Libraries features. From the pathogenetic point of view, the mitogen acti vated protein kinase signal transduction pathway has been reported to play a major role in both the development and progression of melanoma. The increased activity of ERK12 proteins, which is constitutively activated in melanomas mostly as a con sequence of mutations in upstream components of the pathway, has been implicated in rapid melanoma cell growth, enhanced cell survival and resistance to apoptosis.

Oncogenic mutations of BRAF all Inhibitors,Modulators,Libraries constituted by single amino acid substitutions, have been found in approximately 8% of all types of human cancer, including colorectal, ovarian, thyroid, and lung cancers as well as in cholangiocarcinoma and hepatocellular carcinoma, but their highest rates remain those observed in melanoma. Overall, slightly less than half of melanomas carry activating mutations in the BRAF gene, regardless of the mutation screening approach used. The affirmation of new drugs inhibiting some mediators of the MAPK pathway, including mutated BRAF and activated Inhibitors,Modulators,Libraries MEK, has led to major advances in the treatment of patients with melanoma. A less common primary pathway which stimulates cell proliferation, without MAPK activation, seems to be the reduction of RB activity by CyclinD1 or CDK4 amplification or RB mutation. Nevertheless, impairment of the p16CDKN2A protein, which acts as an inhibitor of melanocytic proliferation by binding the CDK46 ki nases and blocking sellectchem phosphorylation of the RB protein, may also lead to uncontrolled cell growth as well as to increased aggressiveness of transformed melanocytic cells.