ABSTRACT
Pancreatitis is a significant clinical problem and the lack of effective therapeutic options means that treatment is often palliative rather than curative. A deeper understanding of the pathogenesis of both acute and chronic pancreatitis is necessary to develop new therapies. Pathological changes in pancreatitis are dependent on innate immune cell recruitment to the site of initial tissue damage, and on the coordination of downstream inflammatory pathways. The chemokine receptor CXCR2 drives neutrophil recruitment during inflammation, and to investigate its role in pancreatic inflammation, we induced acute and chronic pancreatitis in wild-type and Cxcr2(-/-) mice. Strikingly, Cxcr2(-/-) mice were strongly protected from tissue damage in models of acute pancreatitis, and this could be recapitulated by neutrophil depletion or by the specific deletion of Cxcr2 from myeloid cells. The pancreata of Cxcr2(-/-) mice were also substantially protected from damage during chronic pancreatitis. Neutrophil depletion was less effective in this model, suggesting that CXCR2 on non-neutrophils contributes to the development of chronic pancreatitis. Importantly, pharmacological inhibition of CXCR2 in wild-type mice replicated the protection seen in Cxcr2(-/-) mice in acute and chronic models of pancreatitis. Moreover, acute pancreatic inflammation was reversible by inhibition of CXCR2. Thus, CXCR2 is critically involved in the development of acute and chronic pancreatitis in mice, and its inhibition or loss protects against pancreatic damage. CXCR2 may therefore be a viable therapeutic target in the treatment of pancreatitis.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Pancreas/drug effects , Pancreatitis, Chronic/prevention & control , Pancreatitis/prevention & control , Peptides/pharmacology , Receptors, Interleukin-8B/antagonists & inhibitors , Acute Disease , Animals , Ceruletide , Cytoprotection , Disease Models, Animal , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Infiltration/drug effects , Neutrophils/drug effects , Neutrophils/immunology , Neutrophils/metabolism , Pancreas/immunology , Pancreas/metabolism , Pancreas/pathology , Pancreatitis/chemically induced , Pancreatitis/genetics , Pancreatitis/immunology , Pancreatitis/metabolism , Pancreatitis/pathology , Pancreatitis, Chronic/chemically induced , Pancreatitis, Chronic/genetics , Pancreatitis, Chronic/immunology , Pancreatitis, Chronic/metabolism , Pancreatitis, Chronic/pathology , Receptors, Interleukin-8B/deficiency , Receptors, Interleukin-8B/genetics , Receptors, Interleukin-8B/immunology , Signal Transduction/drug effects , Time FactorsABSTRACT
PURPOSE: This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies and determined the safety, tolerability, and pharmacokinetic (PK) profile of selumetinib and its active metabolite N-desmethyl-selumetinib in fed and fasted states. METHODS: A single dose of 75 mg selumetinib was to be taken with food on Day 1 followed by a single dose of 75 mg after fasting for at least 10 h on Day 8, or vice versa, followed by twice daily dosing of 75 mg selumetinib from Day 10. Plasma concentrations and PK parameters were determined on Days 1 and 8. Patients could continue to receive selumetinib for as long as they benefitted from treatment. RESULTS: In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of C(max) and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (t(max)) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated. CONCLUSIONS: The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population.
Subject(s)
Benzimidazoles/administration & dosage , Food , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Neoplasms/drug therapy , Adult , Aged , Benzimidazoles/adverse effects , Benzimidazoles/pharmacokinetics , Biological Availability , Cross-Over Studies , Female , Humans , Male , Middle AgedABSTRACT
The past 25 years have seen unparalleled advances in our understanding of the molecular basis of cancer. As a result, novel molecular targets have been identified that provide great potential for the development of new cancer diagnostics and therapies. Four key features of cancer cells distinguish them from their normal counterparts: loss of cell-cycle regulation, loss of control over invasion and metastasis, failure of apoptotic mechanisms, and bypass of senescence. This review examines our understanding of the bypass of senescence and the process of immortalization during carcinogenesis. In addition, the realistic opportunities for telomerase in cancer diagnostics and the challenges faced in clinical trial design for telomerase therapeutics are discussed.
