Although each single trial had failed to demonstrate the superiority of gemcitabine/platinum combination over gemcitabine single agent in the prolongation of the survival in patients with advanced pancreatic cancer, however, the survival benefit of gemcitabine/platinum doublets was demonstrated in a pooled, meta-analysis survival with a hazard ratio of 0.81, p = 0.031 (22). It is also well known that the use of cisplatin is frequently

limited by its nephrotoxicity, peripheral sensory neuropathy, ototoxicity and the aggravation of hematological toxicity while in combination with other cytotoxic agents. Therefore, several liposomal formulations of cisplatin have Inhibitors,research,lifescience,medical been developed aiming to reduce its toxicity profile and hopefully Inhibitors,research,lifescience,medical to enhance it activity. Based on previous experience of gemcitabine/cisplatin combination and the result of meta-analysis, several liposomal formulated cisplatin have been evaluated in patients with pancreatic cancer. Lipoplatin is one of the pegylated liposome cisplatin, whose nanoparticulate liposomes are reverse-miscelles, composed of dipalmitoyl phosphatidyl

glycerol (DPPG), soy PF-01367338 manufacturer phosphatidyl choline (SPC-3), cholesterol and methoxy- Inhibitors,research,lifescience,medical polyethylene glycol-distearoyl phosphatidylethanolamine (mPEG2000-DSPE). Lipoplatin exhibits the fundamental pharmacologic characteristics of pegylated liposomal agents, for Inhibitors,research,lifescience,medical example, protecting from the engulfment of reticuloendotheralial system to prolong circulating time, and extravasating from the fenestrate between endothelial cells of tumor vasculature to preferentially localize in per-tumor interstitial tissue and uptake by tumor cells. The anionic, fusogenic nature of the DPPG lipids enables lipoplatin to cross cell membranes more easily than native cisplatin. In addition, with intraperitoneal injection of a “sheath” liposomes wrapped reporter β-galactosidase gene, which had same structure like lipoplatin, into human tumor bearing nude mice, Boulikas et al were able to demonstrate the preferential expression of the reporter gene in the

tumor and the tumor neo-vasculature. The findings Inhibitors,research,lifescience,medical indicate the potential antiangiogenic activity of the lipoplatin (23). In phase I trial of lipoplatin monotherapy, the drug was diluted in 5% glucose water and administered as 8 hour intravenous infusion every 14 days. Linifanib (ABT-869) The dose was escalated from 25 mg/m2 to 125 mg/m2. Even at the targeted dose of 125 mg/m2, only grade 1-2 gastrointestinal and hematological toxicities were observed, but neither nephrotoxicity nor neuropathy. Higher doses, 200, 250 and 300 mg/m2, were also tested in one each patient, respectively. The half-life of lipoplatin was estimated ranging from 60 – 117 hours. Of the 27 accruals (19 with pretreated, advanced pancreatic cancer) in this phase I trial, the objective tumor response rate and disease control rate were 11.1% and 63.0%, respectively.