STAT family proteins are localized Vandetanib structure primarily in the cytoplasm, but upon activation they dimerize and localize to the nucleus to regulate genes involved with cellular growth, proliferation and metastasis. STAT3 is phosphorylated on a tyrosine residue by Janus kinases. Abnormal JAK activity is primarily responsible for the constitutive activation of STAT3 and the development of a tumorigenic phenotype in various cancers, including colon. Therefore, disrupting the activation of STAT3 has the potential to enhance chemotherapy induced apoptosis and treatment outcomes. Interleukin 6 is an inflammatory chemokine released by a variety of cells, including T cells and macrophages, which binds and signals through the IL 6 receptor and the B receptor subunit glycoprotein 130.
IL 6 stimulation through gp130 activates the JAK STAT pathway, leading to cell prolifera tion and survival. IL 6 has been linked to metasta sis into bone and elevated IL 6 levels have been observed in various tumors and cell lines. Thus, aberrantly high IL 6 levels cause the phosphorylation of STAT3, leading to cancer cell survival. In colon cancer, the membrane bound IL 6 receptor expres sion was found to be decreased, whereas the production of soluble IL 6 receptor was increased, leading to greater STAT activation and the induction of pro survival proteins. IL 6 signaling has been shown to be TGF beta dependent, where suppression of TGF beta led to decreased STAT activation and the prevention of in vivo tumor progression. Currently, patients with node positive or metastatic colon cancer demonstrate an overall survival benefit when treated with a fluoropyrimidine based regimen.
Colon cancer patients with metastatic disease receiving an OXP combination chemotherapy are about twice as likely to respond to treatment compared to the same drug combinations without OXP. It has also been demonstrated that these patients survive longer. Over the last decade, similar fluoropyrimidine combinations have been evaluated in patients with node positive disease, and unlike patients with metastatic colon cancer, improvement in clinical outcome was only demonstrated in regimens of a fluoropyrimidine alone or in combination with OXP, also referred to as FOLFOX. Unfortunately, the survival benefits of patients treated with a combination of 5 fluorouacil leucovorin, and, the CPT analog, irinotecan is restricted to stage IV colon cancer, and the response rate in this patient population is roughly about 50%.
The benefits of FOLFOX post operative systemic therapy has been clearly demonstrated in stage III disease, the value in stage II is small but present, and on subgroup analysis, patients with high risk stage II tumors demonstrated a trend toward improved disease free survival. Current standard, supported by the National Comprehensive Cancer Network is FOLFOX and consists of 5 fluorouracil, http://www.selleckchem.com/products/carfilzomib-pr-171.html leucovorin, and oxaliplatin.