ABSTRACT
The use of prodrug-activated ("suicide") gene therapy has been shown to be effective in inducing tumor regression when only a small proportion of tumor cells contains the suicide gene. These experiments were designed to test whether additional therapeutic benefit may be obtained by stimulating the immune response. Murine MC26 colon carcinoma cells, either untransduced or transduced with genes for herpes simplex virus-1 thymidine kinase (HSV1-TK) or human GM-CSF, were injected subcutaneously into syngeneic BALB/c mice in various combinations. Inoculation of equal numbers of untransduced and HSV1-TK-containing cells followed by ganciclovir (GCV) treatment resulted in almost complete tumor regression, but by 7 weeks, tumors had recurred in all mice. A similar initial regression was obtained using equal numbers of cells containing HSV1-TK and GM-CSF genes, but >80% of these mice remained tumor-free after 3 months. Groups of tumor-free mice that had received GM-CSF-containing cells were left for different periods of time and rechallenged with unmodified MC26 cells on the opposite flank. Of the mice rechallenged 14, 28, and 108 days later, 100%, 88%, and 57%, respectively, showed complete resistance to unmodified tumor cells. In mice that showed tumor regrowth, tumor volume was much less than in control mice. Adoptive transfer of spleen cells from resistant mice to naïve syngeneic mice resulted in partial resistance to challenge with unmodified tumor cells. Specific cytotoxicity against MC26 cells was only demonstrable in mice receiving GM-CSF- and HSV1-TK-containing tumor cells. These experiments show that the presence of cells secreting GM-CSF in HSV1-TK-containing, regressing tumor is able to induce complete or partial resistance to tumor rechallenge. This indicates the potential usefulness of GM-CSF in enhancing other antitumor therapies.
Subject(s)
Colonic Neoplasms/immunology , Genetic Therapy , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Herpesvirus 1, Human/genetics , Immunity, Cellular/physiology , Animals , Colonic Neoplasms/mortality , Colonic Neoplasms/therapy , Combined Modality Therapy , Female , Ganciclovir/pharmacology , Herpesvirus 1, Human/drug effects , Herpesvirus 1, Human/enzymology , Immunization , Mice , Mice, Inbred BALB C , Neoplasm Recurrence, Local , Neoplasm Transplantation , Spleen/metabolism , Survival Rate , T-Lymphocytes/immunology , Thymidine Kinase/metabolismSubject(s)
Cell Death/genetics , Genetic Therapy/methods , Neoplasms/therapy , Animals , Antimetabolites/therapeutic use , Combined Modality Therapy , Cytokines/therapeutic use , Ganciclovir/therapeutic use , Genes, Viral/physiology , Genetic Vectors/therapeutic use , Mice , Neoplasms/immunology , Neoplasms/pathology , Prodrugs/therapeutic use , Rats , Simplexvirus/genetics , Thymidine Kinase/genetics , Thymidine Kinase/therapeutic useABSTRACT
Gallstones are commonly found within the main bile duct (MBD) of patients undergoing cholecystectomy. Retained MBD stones are a common cause of obstructive symptoms and complications. Endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy (ES) is the recommended modality for both the detection of such stones and their extraction. Recent trials of ERCP in conjunction with laparoscopic cholecystectomy suggest that it should be reserved for use post-operatively. Gallstones within the MBD are the most common single cause of acute pancreatitis. Initial treatment is supportive, although new agents designed to suppress the systemic inflammatory response are under development and have proved beneficial in clinical trials. Severe cases should be treated with systemic antibiotics and early removal of the obstructing stones by ERCP and ES. Prophylactic cholecystectomy is recommended to prevent further attacks of gallstone pancreatitis.
