Schroeder, Mark A.

Purpose Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. Methods Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m2 intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. Results Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. Conclusion This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.

Abstract Cells experience plasma membrane stress failure when the matrix to which they adhere undergoes large deformations. In the lung, such a mechanism might explain mechanical ventilation–associated cell injury. We have previously shown that in alveolar epithelial cells, deformation induces lipid trafficking to the plasma membrane, thereby accommodating the required increase in the cell surface area. We now show that cell wounding is strain amplitude and rate dependent and that under conditions of impaired exocytosis strain-induced cell wounding is significantly increased. In addition, the susceptibility of cells to mechanical injury was not correlated with changes in cell stiffness. Using a dual-labeling technique, we differentiated between cell populations that were reversibly and irreversibly injured and showed that interventions that impair deformation-induced lipid trafficking also reduce the likelihood of plasma membrane resealing. Our findings suggest that cell plasticity and remodeling responses such as deformation-induced lipid trafficking are more important for cytoprotection from strain injury than are the innate mechanical properties of the cell. We also conclude that in deformation experiments, tests of cell membrane integrity cannot be interpreted as tests of cell viability because an intact plasma membrane after deformation does not mean that no injury had occurred.