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2006 Abstracts: PKC 412 - A Pan-Antiangiogenic Compound From Bench To Bedside
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PKC 412 - A Pan-Antiangiogenic Compound From Bench To Bedside
Peter Buechler, Jamael El-Fitori, Yun Su, Klaus Felix, Markus W. Buechler, Helmut Friess; General Surgery, University of Heidelberg, Heidelberg, Germany

INTRODUCTION: Pancreatic cancer is an aggressive malignancy with a poor prognosis. Currently there is no effective therapy. The increasing awareness of the role of tumor neoangiogenesis in growth of solid tumors resulted in a consensual opinion that abrogated neoangiogenesis may cause tumor growth arrest. Angiogenesis is also necessary for local and systemic tumor progression both hallmarks of pancreatic cancer. PKC412 is a novel pan-inhibitor of mutated FLT3, PKC, KDR, c-KIT, PDGFRα, and PDGFRβ. The aims of this study were to analyse the therapeutic efficiency of this novel multi target compound in vitro and in vivo using a novel orthotopic model for experimental pancreatic cancer. METHODS: Five human pancreatic cancer cell lines AsPc-1 (A1), Capan-1 (C1), HPAF-2 (HP2), PANC-1 (P1) and MIA PaCa-2 (MP2) were analyzed. RT-PCR was used for FLT3 mutation in pancreatic cancer cells. Anchorage dependent cell growth was quantified with the MTT assay. Soft agar assays were used to study anchorage independent growth. Cell cycle progression was analyzed by flow cytometry. In vivo HP2 and AsPC-1 cells were used to induce orthotopic tumors in a novel murine model for pancreatic cancer (each n=12). Animals received every day 10 mg/kg PKC412 i.p. for 8 weeks. Immunohistochemistry (anti CD31) was used to quantify microvessel density. RESULTS: No FLT3 mutation could be detected in any of the pancreatic cancer cell lines. Cell growth was inhibited in all cell lines tested; PKC412 resulted in a dose and time dependent growth suppression. In flow cytometric analysis a strong G2/M-phase arrest was detectable. Anchorage independent growth was also significantly reduced in a dose dependent and time dependent manner. The in vivo correlate was a significant growth reduction of orthotopic tumors growth in both cell lines tested. Growth suppression in vivo was mediated not only by antimitogenic activity but also by suppression of tumor neoangiogenesis since the number of blood vessels in treated animals was significantly lower. CONCLUSION: PKC412 is a highly promising new compound with strong anti-mitogenic and in vivo antiangiogenic activity. This dual efficiency will likely be of therapeutic value for patients with pancreatic cancer.


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