Intraperitoneal administration of pMP6/liposome complexes inhibits the growth of co-localized colon-26 adenocarcinoma cells by inducing a tumor-specific immune response.

BACKGROUND: In our previous study, we found complexes of the non-coding pMP6 plasmid and cationic liposomes which exerted antitumor activity in the C26 model. We now sought to unravel the underlying protective effector mechanism(s). MATERIALS AND METHODS: C26 recipients (i.p.; day 0) were injected once (day -2) or twice (days -2 and 2) with pMP6/liposome complexes. Thus treated mice were evaluated for tumor growth and the occurrence of innate and specific immune responses. RESULTS: A single pMP6/liposome injection prolonged the survival of the animals as compared to non-treated C26 recipients (median survival 28 vs. 19 days). Two injections not only prolonged the survival time (median survival 55 days) but completely prevented tumor development in 50% of C26 recipients. I.p. administration of pMP6/liposome complexes resulted in the expression of the proinflammatory cytokines IL-6, IFN-gamma and TNF-alpha. This was followed by the appearance of activated NK cells within the peritoneal cavity and, somewhat later, by the induction of C26-specific CTLs. T cell depletion studies demonstrated the latter to be critical for the protective effect to occur. CONCLUSION: Our data suggests that co-application of tumor cells and immunostimulatory pDNA/liposome complexes induces a protective and tumor-specific T cell response. Therefore these complexes may be considered promising agents in the immunological gene therapy of cancer.

In vivo gene transfer of murine interleukin-4 inhibits colon-26-mediated cancer cachexia in mice.

Cancer cachexia has been suggested to be mediated by various cytokines derived either from tumor or host tissue. In the murine colon-26 (C-26) adenocarcinoma model IL-1, secreted by tumor-infiltrating mononuclear phagocytes, has an important role in induction of cancer cachexia. In order to suppress production of IL-1 in peritoneal macrophages we have used liposome-mediated gene transfer of the anti-inflammatory cytokine mIL-4, known as a potent inhibitor of IL-1 production. Balb/c mice were transfected by intraperitoneal inoculation of C-26 tumor cells. The mIL-4 transfected animals showed increased survival rate, delayed symptoms of cachexia and reduced anorexia in comparison with tumor-bearing control groups. However, tumor growth inhibition was not seen in mIL-4-transfected animals. Peritoneal macrophages from surviving mIL-4-transfected mice, when stimulated with LPS ex vivo, showed decreased IL-1 alpha production, 1672 +/- 202 pg/2 x 10(6) cells in contrast to tumor-bearing control animals, 3975 +/- 89 pg/2 x 10(6) cells, mock-transfected tumor-bearing animals 4004 +/- 174 pg/2 x 10(6) cells and tumor-free animals, 3142 +/- 60 pg/2 x 10(6) cells (p < 0.004). The present study demonstrates that in vivo gene transfer of an anti-inflammatory cytokine reduces cancer-associated cachexia by inhibition of IL-1 alpha production of tumor surrounding peritoneal macrophages, without a significant effect on tumor growth.

Gene therapy in surgery: Part II: Application to septic shock and to organ transplantation.

BACKGROUND: With the increasing body of knowledge in molecular biology, gene transfer respectively gene therapy becomes more and more a valid therapeutic option. METHODS: This is a critical review of gene therapy protocols for treatment of different types of cancer. Furthermore, the pathophysiological mechanism, therapeutically strategies as well as experimental approaches toward gene transfer in septic shock and organ transplantation are critically elucidated. RESULTS: Gene transfer as a therapeutic option was first successfully applied in children with severe combined immunodeficiency (SCID) in 1990. The majority of gene marking or gene therapy protocols approved for human clinical trials to date are related to the treatment of cancer. Besides viral vectors for brain tumors, non-viral vectors, liposomes particularly, with almost no side effects are increasingly used. CONCLUSIONS: Different approaches of gene transfer in cancer patients are under investigation. Experimental data of septic shock treatment and rejection therapy of the allograft in organ recipients with gene transfer are encouraging for future applications in clinical trials.