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Evaluation of the expression profile of genes modulated by TNF and melphalan in mixed cultures of endothelial cells, melanoma cells and macrophages

Grant number: 10/10493-6
Support type:Regular Research Grants
Duration: September 01, 2010 - August 31, 2012
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Vladmir Cláudio Cordeiro de Lima
Grantee:Vladmir Cláudio Cordeiro de Lima
Home Institution: Hospital A C Camargo. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

Melanoma is a cancer that originates in melanocytes and their primary sites include skin, uvea, leptomeninges and mucous membranes, skin being the most common site of involvement (90%). Its incidence has increased in recent decades. In Brazil, the estimate is 5930 new cases in 2010, with 1990 cases in the state of Sao Paulo. The risk of death is higher in patients with melanoma detected in late stage, with 50-10% survival at 5 years and median survival 6-9 months in stage IV. Over the past 30 years, the survival rate has not changed and the most used drug in the treatment is dacarbazine (DTIC), with response rates between 50-20% and survival free of disease progression from 1.5 to 1.6 month, without gain in overall survival. To improve these results, several strategies have been studied and used. Immunotherapy, which aims to eliminate the tumor by stimulating the host immune response, using interleukin-2 (IL2) and interferon (IFNa) and offering objective responses in about 17%, but no gain in overall survival. Another strategy, biochemotherapy combining chemotherapy with immunotherapy, with higher response rate for chemotherapy or immunotherapy alone, but without an increase in survival. Two to 10% of advanced melanomas of limbs manifest as locoregional recurrence, remaining confined to the limb. The standard treatment options for this type of recurrence include surgical excision or ablation electrodissection, cryotherapy or CO2 laser. In some cases amputation is needed by the extent of commitment. An alternative, less mobid is the isolated limb perfusion (ILP), saving the limb of amputation by providing anti-neoplastic agents in high doses through the State, after cannulation of the vessels that irrigate, achieving local concentrations of chemotherapy 30 times higher than systemic administration. Melphalan (MEL) and tumor necrosis factor (TNF) are the drugs most used in this treatment, with objective responses ranging from 48-95%. Melphalan is a bifunctional alkylating chemotherapeutic agent, which acts forming crosslinks with the nitrogenous bases of DNA, interfering in the processes of synthesis and replication. TNF is a cytokine with pleiotropic action of anti-tumor activity in some tumor cell lines by direct cytotoxic effect or damage of tumor vasculature. A study from our institution (PhD Vladmir C. C. Lima) sought to identify the molecular targets of action of MEL and TNF in melanoma and was given the gene expression profile of cutaneous melanoma in response to treatment with these drugs. Was identified, using the oligonucleotide microarray technique, a set of genes whose expression was modulated in melanoma after treatment with MEL MEL + TNF and TNF in a murine tumor model in vivo. Administration of MEL promoted slower tumor growth and this was not modified by co-administration of TNF. Treatment with MEL or MEL + TNF was associated with increased progression-free survival. Among the genes whose expression was modulated by the treatments are Arhgef6, Pard3, FABP4, Flt1, and Ifi202b Igf2bp3. These genes plays a crucial role at various stages of tumorigenesis (proliferation, adhesion, migration, apoptosis and angiogenesis). Melanoma is composed of neoplastic cells and stromal (fibroblasts, endothelium, macrophages and lymphocytes). Today, it is known that tumor macrophages are maestros of inflammation in the tumor microenvironment and clinical studies associated them with tumor progression, hence their importance as a therapeutic target. It is also known that angiogenesis is a critical event for tumor progression and metastasis. In this context, endothelial cells can express many genes, in addition to acquiring abnormalities, becoming resistant to chemotherapy. A better understanding of these processes could allow subsidies for treatments less toxic and more effective. (AU)