Chemosensitivity testing and test-directed chemotherapy in human pancreatic cancer

Human pancreatic cancer is a devastating disease with poor prognosis. In many cases it is diagnosed at stages in which a complete resection is not possible. However, even after complete resection most tumors recur. Therefore, several chemotherapeutic strategies have been developed, so far, with little impact on the clinical outcome. Because one of the hallmarks of human pancreatic cancer is its general resistance to chemotherapeutic agents, it seems important to develop strategies to individualize chemotherapy and to render cells more sensitive to chemotherapeutic agents. In this summary we describe our methods of in vitro chemosensitivity testing using the human tumor colony-forming assay for pancreatic cancer in comparison with other solid tumors and describe how the in vitro results influence chemotherapy. Furthermore, we point out new developments of mRNA quantitation of chemoresistance target enzymes based on real-time PCR, which may help in the future to individualize chemotherapy of pancreatic cancer. Finally, we present results of studies of cyclin D1 inhibition. Suppression of cyclin D1 by cyclin D1 antisense mRNA expression was associated with growth inhibition and an increase in chemosensitivity to fluoropyrimidines and platinum compounds. Because human pancreatic cancers are relatively chemoresistant and material for chemosensitivity testing with the human tumor colony-forming assay (HTCA) is in most cases difficult to obtain, future investigations should aim at the development of methods requiring only very small samples to analyzemarkers of chemosensitivity. Our results further suggest that chemotherapy in combination with strategies to increase chemosensitivity may be a reasonable regimen for the treatment of human pancreatic cancer in the future.