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Suprarenal IVC reconstruction is justified in selected cases, with good functional results. When the renal confluence is resected along with the IVC, renal vein reconstruction may be needed to avoid acute renal failure. The oncologic results of such extensive resections are poor. Adjuvant therapy should be evaluated.

Taken together, these results suggest the potential use of suicide gene-modified tumor cells as therapeutic vaccines against liver metastasis from colon carcinoma.

A significant bacterial translocation in the MLNs occurs after portal triad clamping and liver resection, although not clinically relevant.

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In addition, we observed an increased glyceraldehyde-3-phosphate dehydrogenase expression, which has been shown to be sufficient to trigger an autophagic process. Autophagy is a self-digestion pathway whereby cytoplasmic material is sequestered by a structure termed the autophagosome for subsequent degradation and recycling. As bacteria are known to trigger autophagy, we assessed whether bacterial CpG motifs might induce autophagy in TLR9-positive tumor cells. We showed that CpG-ODN can induce autophagy in rodent and human tumor cell lines and was TLR9-dependent. In addition, an increase in the number of autophagosomes can also be observed in vivo after CpG motif intratumoral injection. Our findings bring new insights on the effect of bacterial CpG motifs in tumor cells and may be relevant for cancer treatment and more generally for gene therapy ap-

Background: Suicide gene therapy consists of the transfer into tumour cells of a "suicide" gene that can convert a non-toxic compound into a lethal drug. Expression of the cytosine deaminase gene leads to the conversion of the non-toxic compound 5-fluorocytosine to 5-fluorouracil. We have recently shown that "suicide cell based vaccination" consisting of intrahepatic injection of cytosine deaminase expressing colon cancer cells followed by 5-fluorocytosine treatment induces regression of a distant wild-type liver tumour in rats. Aims: This study was conducted to test if (i) a distant bystander effect on a liver tumour can be induced after subcutaneous suicide cell based vaccination and (ii) suicide cell based vaccination is efficient in limiting tumour dissemination to extrahepatic compartments. Methods: An aggressive variant of rat colon carcinoma cells was selected after successive passages in vitro. Rats carrying an experimental liver "metastasis" generated by injection of these cells were vaccinated by subcapsular or subcutaneous injection of cytosine deaminase expressing cells followed by 5-fluorocytosine treatment. Results: Subcutaneous and subcapsular vaccination induced 70% regression in the median volume of the pre-established liver tumour (p=0.001) and abolished tumour dissemination compared with control animals. Conclusions: This study has compared for the first time the efficiency of subcutaneous and intrahepatic suicide cell based vaccination in a metastatic colorectal carcinoma model in rats. The results indicate that both modes of vaccination are equally efficient in inducing a systemic antitumour response, suggesting that this strategy is a powerful approach against the development and dissemination of metastatic colon carcinoma.

The cytosine deaminase (CD) gene converts the nontoxic prodrug, 5-fluorocytosine (5-FC), into 5-fluorouracil (5-FU). We previously showed that injection of CD-bearing cancer cells followed by 5-FC treatment can act as an autologous tumor vaccine in a syngenic liver metastasis model in rats. In the present work, we analyzed the antitumor efficiency of a direct intratumoral injection of a CD-expressing plasmid. In rats bearing microscopic or macroscopic metastases in right and left liver lobes, an injection of a CD-expressing plasmid was performed in the left lobe tumor, followed by 5-FC treatment of the animals. A significant regression of the DNA-injected tumor was observed in 5-FC-treated rats, both in microscopic (P ‫؍‬ .007) or advanced (P < .0001) tumor models. Moreover, this treatment also induced a potent distant bystander effect on untreated controlateral liver tumors and extrahepatic metastases, resulting in an increased survival compared with control animals in both tumor models (P < .05). In conclusion, these data suggest that direct intratumoral injection of a CD-expressing plasmid, associated to 5-FC administration, can constitute a powerful and innocuous alternative treatment for unresectable liver metastases from colon carcinoma. C olon carcinoma represents one of the most frequent cancers in Westernized countries and is associated with a high mortality, as a result of the appearance of metastases preferentially located in the liver. Resection of liver metastases constitutes the only curative treatment. Because resection is applicable in only 10% to 20% of patients, many efforts are dedicated to the development of alternative treatments. Suicide-gene therapy consists of the transfer into tumor cells of a "killer gene" that converts a systemically administered nontoxic compound into a lethal drug. This strategy has proven to be effective in several tumor models in rodents. 1 The bacterial cytosine deaminase (CD) gene encodes an enzyme capable of converting cytosine into uracil. Mammalian cells possess no endogenous CD gene. When the bacterial CD gene is expressed in mammalian cells, the enzyme transforms the nontoxic antifungal agent, 5-fluorocytosine (5-FC), into 5-fluorouracil (5-FU), a widely used chemotherapeutic drug. Consequently, expression of the CD gene within cancer cells results in a specific tumortargeted chemotherapy. Although bypassing the toxic side effects of a systemic chemotherapy is, by itself, an interesting point, the key effects of this strategy rely on the existence of two associated "bystander effects." The first one, termed « local bystander effect, » is known to induce complete tumor regression even if only a small proportion of cells in a tumor express the suicide gene. 2,3 The second effect, or « distant bystander effect, » results in the regression of distant, unmodified tumors, and is mediated by the triggering of an immune reaction following destruction of the tumor expressing the suicide gene. [4][5][6][7][8][9][10][11] Previously, we developed a vaccination strategy ...