Many gemcitabine resistance mechanisms including altered levels of its activation enzyme, decreased intracellular drug transport, increased drug metabolism, and increased expression of DNA repair enzymes have been proposed as contributing to the failure of gemcitabine therapy (35)-(38). Evidence published in early 2009 from the RTOG9704 trial confirmed that increased intra-tumoral expression of human equilibrative nucleoside transporter (hENT1), the major protein believed to be responsible for transporting gemcitabine into cells, was associated with an improved overall and disease-free survival in patients Inhibitors,research,lifescience,medical with resected pancreatic cancer treated with gemcitabine as compared

with those receiving 5-fluorouracil (39). Preclinical evaluation in lung cancer has demonstrated that overexpression of ribonucleotide reductase regulatory subunit M1 (RRM1), a DNA repair enzyme, may also be a marker of poor Inhibitors,research,lifescience,medical response to gemcitabine therapy (40).

Previous clinical studies have suggested that gemcitabine therapy has less efficacy in patients with advanced tumors expressing high levels of RRM1 (41), (42). Further immunohistochemical study of RRM1 correlates overexpression of protein levels with a worse overall survival and disease control than those patients with RRM1-negative Inhibitors,research,lifescience,medical tumors (43). Recently, the clinical significance of single nucleotide polymorphisms (SNP) of gemcitabine metabolic genes was evaluated in pancreatic cancer by our group (44). Okazaki et al examined 17 SNPs of eight genes in 154 patients with potentially resectable pancreatic adenocarcinoma treated with neoadjuvant concurrent gemcitabine and radiation therapy Inhibitors,research,lifescience,medical with or without cisplatin. Though none of the SNPs was significantly associated with overall survival (OS) individually, a combined genotype effect was

observed, in which the risk of death was increased for patients with variant gemcitabine metabolic genes. Moreover, hematologic toxicity due to gemcitabine Inhibitors,research,lifescience,medical was associated with polymorphisms of the cytidine deaminase and deoxycytidine Axl signaling pathway inhibitors kinase genes. This study suggests that the clinical outcome of pancreatic cancer patients treated with gemcitabine-based chemotherapy results, in part, from variations in however genes responsible for gemcitabine metabolism and elimination. The results of this study support the investigation of pharmacogenetic profiling to individualize gemcitabine-based therapy for pancreatic cancer. An effort is being made to expand pharmacogenetic profiling for other agents that are considered effective in pancreatic cancer. Although gemcitabine has been the mainstay of chemotherapy for pancreatic cancer for the past decade, the beneficial effects from gemcitabine are mostly palliative and survival gains from this agent are limited.