In a recent meta-analysis, Ciliberto et al. [51] described a statistically superiority in terms of survival and response rate for gemcitabine-based combination compared to gemcitabine alone. Moreover, this advantage was marginal and at the cost of an increased toxicity. The authors concluded that in the era of targeted therapy new approaches were possible only in presence Inhibitors,research,lifescience,medical of solid preclinical

findings. A report by von Hoff et al. [31] demonstrated in a phase I/II study an interesting activity of gemcitabine/nab-paclitaxel combination at gemcitabine 1000mg/m2 and nab-paclitaxel at 125mg/m2 doses weekly for three doses in a 4 week schedule. A 48% response rate was achieved at MTD. The authors additionally demonstrated that SPARC-expressing tumors appeared more sensitive to the drug combination. An interesting finding from a preclinical study reported that nab-paclitaxel demonstrated the Inhibitors,research,lifescience,medical capacity of increasing the gemcitabine bioavailability inside the tumors. These findings led to the design of a phase

III study where gemcitabine/nab-paclitaxel was compared to gemcitabine alone showing an Inhibitors,research,lifescience,medical advantage in OS, PFS, and RR. This study, presented to ASCO GI 2013 (American Society of Clinical Oncology, Gastrointestinal Cancer Symposium) by von Hoff, is clearly a changing practice study and the gemcitabine/nab-paclitaxel, which led to an almost two month longer OS should be now compared to FOLFIRINOX combination (Table 2). The biological bases of the synergistic interaction between nab-paclitaxel and gemcitabine have recently been elucidated by an in vivo study in animal models. In detail, the combination treatment was administered to KPC mice that develop advanced Inhibitors,research,lifescience,medical and metastatic pancreas ductal adenocarcinoma. The authors have demonstrated an increase of intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase

protein in cultured cells through reactive oxygen species-mediated ABT-888 order degradation, Inhibitors,research,lifescience,medical resulting in the increased stabilization of gemcitabine. These findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PC [52]. This study provides mechanistic insight into the Thiamine-diphosphate kinase clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer. Table 2 Randomized phase I/II and III trials with nab-paclitaxel in aPC. 5. Other Areas of Nab-Paclitaxel Development Melanoma represents 5% and 4% of all cancers in males in females, respectively. However, the rates of incidence of melanoma are steadily increasing in the USA as in most parts of Europe [53]. The survival rates of melanoma become worse with advancing stage. Therefore, early diagnosis in addition to surgical treatment before its spread is the most effective treatment.