The effect and mechanism of M402 on gemcitabine uptake into pancreatic tumors.

215 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which has been attributed to high interstitial pressure and poor drug delivery. In nonclinical studies, M402 affected multiple growth factors, adhesion molecules, and chemokines, inhibiting tumor progression, metastasis, and angiogenesis by clearing heparin-binding factors from the tumor microenvironment. We hypothesized that M402 could modulate tumor-stroma interactions in an orthotopic pancreatic cancer model (rich in desmoplasia), decreasing the fibrotic response and in turn increasing tumor perfusion and drug delivery. Methods: Capan-2 human PDAC cells were injected into the pancreata of nude mice. M402 (40 mg/kg/day, s.c.) or saline began Week 5. Gemcitabine (GEM; 30 mg/kg, i.p. biweekly) started Week 7. At different time points, primary tumors were analyzed for mRNA arrays, immunohistochemistry (ECM components, CD31), and functional tumor vasculature. GEM tumor uptake was evaluated by quantifying the i...