Subcutaneous or intrahepatic injection of suicide gene modified tumour cells induces a systemic antitumour response in a metastatic model of colon carcinoma in rats

Abstract

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.

Phase I Study of MetXia-P450 Gene Therapy and Oral Cyclophosphamide for Patients with Advanced Breast Cancer or Melanoma

“…This may be due to the actions of cyclophosphamide associated with tumor necrosis but may also be partially attributed to the potential increased cell kill and release of tumor-associated antigens at the site of MetXia-P450 injection. This phenomenon of antitumor immune bystander effects, following gene-directed enzyme prodrug therapy, has previously only been reported in animal studies (12,13,15) and requires further evaluation in clinical trials. A further possible mechanism for antitumor activity may relate to the possibility of antiangiogenic activity of low-dose cyclophosphamide.…”

Efficient electrogene therapy for pancreatic adenocarcinoma treatment using the bacterial purine nucleoside phosphorylase suicide gene with fludarabine

“…Thus, the efficiency of ePNP electrogene therapy in such a situation is clearly linked to the high bystander effect of the ePNP/fludarabine system, already described in several in vivo studies (5,40,(44)(45)(46)(47). Suicide gene systems are also able to induce a systemic anti-tumor response, called 'vaccination based on cellular suicide' (53). So, electrogene therapy with ePNP can be efficient against tumor spreading and metastases development by the addition of this immune stimulation with the concomitant so-called bystander effect.…”

Adenovirus-mediated prodrug-enzyme therapy for CEA-producing colorectal cancer cells

“…We will develop this promising gene therapy against CEA-producing colorectal cancers by improving the vector construct and developing an efficient enhancerpromoter region (Nyati et al 2002b), which refers to the Cre/loxp system (Goto et al 2001;Ueda et al 2001). We intend to clinically apply this VEDPT by using vectors controlled by cancer specific promoters for multimodality treatment against recurrent colorectal cancer (Humphreys et al 2001;Pierrefite-Carle et al 2002;Sangro et al 2002).…”