[Frontiers in Bioscience 3, d1148-1160, November 15, 1998]
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CAVEAT LECTOR




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MOLECULAR PATHOBIOLOGY OF PANCREATIC ADENOCARCINOMA

Shamlal Mangray and Thomas C King

Department of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, RI

Received 8/24/98 Accepted 9/4/98

7. THERAPEUTIC IMPLICATIONS

Molecular genetic alterations that disturb cell cycle regulation in tumor cells can affect their response to chemotherapeutic agents and radiation. Many of the genes which regulate the critical cell cycle checkpoint at G1/S are altered pancreatic adenocarcinoma. Knowledge of these genetic alterations in individual tumors may allow selection of optimal therapeutic strategy for individual patients. Phase II studies are currently ongoing to assess the potential role of p53 and p16INK4a alterations in determining response to Taxol chemoradiation (2). Furthermore, the availability of biologic therapies which target specific oncogenes such as farnesyl transferase inhibitors of K-ras and HerceptinTM for HER2/neu require knowledge of a tumor's genetic composition to permit rational therapeutic decisions.

Gene therapy protocols for pancreatic adenocarcinoma are beginning and offer promise for the future. Strategies include tumor suppressor gene replacement and the use of antisense RNA to prevent the expression of oncogenes (74). Wild type p53 can potentially be introduced into tumors to promote apoptosis and chemosensitivity as has been accomplished in nonsmall cell lung cancer. Similar strategies are planned for p16INK4a replacement. Liposome mediated antisense K-ras constructs have been successfully employed to inhibit dissemination of pancreatic adenocarcinoma in the murine peritoneal cavity. The development of appropriate and effective vectors and transfection strategies which can target tumor cells is currently a major limiting factor in developing clinically useful gene therapy protocols.

Adoptive immunotherapy is another form of gene therapy that is being explored as a possible treatment for pancreatic adenocarcinoma. McCarty et al. recently reported the use of high affinity human p53-specific cytotoxic T-lymphocytes (CTLs) from transgenic mice to suppress the growth of p53-over expressing human tumors in severe combined immunodeficient mice (75). The p53-specific CTLs lysed p53-overexpressing pancreatic carcinoma cell lines and inhibited the growth of established human tumor xenografts. Undoubtedly, additional novel strategies will be developed as well.