Development of systemic immunologic responses against hepatic metastases during gene therapy for peritoneal carcinomatosis with retroviral HS-tk and ganciclovir

J Gastrointest Surg. 1997 Nov-Dec;1(6):527-33. doi: 10.1016/s1091-255x(97)80069-8.


Gene therapy with retroviral mediated gene transfer of the herpes simplex thymidine kinase (HS-tk) gene into a tumor mass confers sensitivity of the tumor cells to ganciclovir (GCV). Tumor-specific immunologic responses may develop following treatment of the primary tumor with retroviral HS-tk and GCV. In the present study we assessed whether GCV treatment of HS-tk transduced colon cancer (TK+) implanted in the peritoneal cavity induced a systemic antitumor response that would inhibit growth of a second wild-type (TK-) tumor implanted in the liver. DHDK12 rat colon cancer cells were transduced in vitro with the retroviral HS-tk vector and established as a permanent cell line (TK+ cells). TK+ or TK- DHDK12 cells (6x10(6) cells) were injected intraperitoneally on day 0 into BD-IX rats. On day 10, TK- cells (3x10(6) cells) were injected into the liver in all the groups. The animals were then treated with GCV (150 mg/kg) for 13 days. TK+ peritoneal tumors underwent significant regression during therapy with GCV (0.05+/-0.004 g; n=7) compared to wild-type (TK-) tumors (2.2+/-0.7g; n=6) (P<0.05). The volume of TK- tumors in the liver was significantly lower in GCV-treated rats with TK+ peritoneal tumors (12.5+/-8.3 mm3) compared to rats with TK- peritoneal tumors (96.7+/-18.1 mm3) (P<0.05). Histology of the liver tumors in the TK+ groups showed a dense monocytic infiltrate with fibrosis and only occasional viable tumor cells. Gene therapy with retroviral HS-tk vectors may provide a novel approach to treatment of gastrointestinal cancer by both direct cytotoxicity and an indirect mechanism that may include enhanced immuno logic responses against disseminated disease.

MeSH terms

  • Animals
  • Carcinoma / pathology*
  • Carcinoma / therapy*
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Ganciclovir / therapeutic use*
  • Genetic Therapy / methods*
  • Herpes Simplex / enzymology*
  • Herpes Simplex / genetics*
  • Liver Neoplasms / prevention & control*
  • Liver Neoplasms / secondary*
  • Male
  • Peritoneal Neoplasms / pathology*
  • Peritoneal Neoplasms / therapy*
  • Rats
  • Thymidine Kinase / genetics*


  • Thymidine Kinase
  • Ganciclovir