Sorafenib (BAY 43-9006) in hepatocellular carcinoma patients: from discovery to clinical development.

Angiogenesis and signaling through the RAS/RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinoma (HCC). Sorafenib (Nexavar), a novel bi-aryl urea BAY 43-9006, is an orally administered multikinase inhibitor with activity against RAS/RAF kinases multikinase inhibitor with activity against RAF kinases and several receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. It is involved in angiogenic pathway and cell proliferation. Sorafenib has demonstrated potent anti-tumor activity in in vitro studies, preclinical xenograft models of different tumor types and human clinical trials. This review summarizes the history of sorafenib from its discovery by the medicinal chemistry approach through to clinical development and ongoing trials on the combination between sorafenib and trans-arterial chemoembolization (TACE) in HCC patients.

A possible role of thymidine phosphorylase expression and 5-fluorouracil increased sensitivity in oropharyngeal cancer patients.

Thymidine Pi deoxyribosyltransferase (TP) is an enzyme involved in DNA synthesis up-regulated in tumours and it is also a pro-angiogenic factor. TP cannot activate capecitabine, because capecitabine first needs conversion by carboxylesterase and cytidine deaminase into 5-deoxy-fluorouridine. This compound can be activated by TP to 5-fluorouracil (5-FU). Although TP is not necessary for 5-FU toxicity, experimental data suggest that high levels of TP correlate with an enhanced response to 5-FU therapy. In this study, we have analysed by immunohistochemistry CD34, CD68 and TP positive cells in bioptic samples from 53 patients with T(1-3) N(0-1) M(0) oropharyngeal squamous cell carcinoma (OSC) and from 24 patients with non-dysplastic oropharyngeal leukoplakia (NDOLP). Results showed that the mean of TP-positive cells, CD68 positive macrophages and CD34 positive endothelial cells eval-uated as microvessel density (MVD) was significantly higher in OSC than in NDOLP. Moreover, at a median follow-up of 19 months, patients with TP expression and higher MVD showed a better survival rate as compared to those with low MVD, probably as a consequence of 5-FU-based therapy.We hypothesized a role for TP in oropharyngeal tumourigenesis and 5-FU activation in the adjuvant setting of OSC patients.