Total vascular exclusion of the liver enhances the efficacy of retroviral-mediated associated thymidine kinase and interleukin-2 genes transfer against multiple hepatic tumors in rats

Alvès, Arnaud; Charre, Lionel; Cardoso, Jorge; Fabrè, Monique; Brisson, E.; Houssin, D; Soubrane, Olivier; Klatzmann, David

doi:10.1067/msy.2003.152

Cited by 11 publications

(14 citation statements)

References 32 publications

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“…5 Rats were treated at Day 10, a time at which they all showed disseminated LM, the great majority of which developed superficially under Glisson's capsule and had diameters ranging between 1 and 2 mm. They received IPV injection of various retroviral vector-producing cells under TVE, a treatment that we previously showed to be efficient when using suicide gene therapy.…”

Section: Resultsmentioning

confidence: 99%

“…5 Our choice of using IL-12 is due to its central role in the immune system; IL-12 appears as one of the most potent cytokines for stimulating antitumor immunity, 22,23 acting by the: (i) induction of a TH1 immune response, (ii) activation of natural killer cells and cytotoxic T lymphocytes, (iii) enhanced expression of adhesion molecules of endothelial cells, thus facilitating the traffic of lymphocytes to the tumor, and (iv) induction of a potent antiangiogenic effect. Strong antitumoral activity of IL-12 has been demonstrated in several tumor models, including liver tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Aggressive nonresectable MLM were induced by direct intraportal vein (IPV) injection of 2 Â 10 7 DHDK12 cells. 5 At Day 10, rats were randomized into four groups. IPV injection and TVE of the liver have been previously reported.…”

Section: In Vivo Experimental Protocolsmentioning

confidence: 99%

“…IPV injection and TVE of the liver have been previously reported. 5 In control group (n ¼ 12), rats were given IPV injections of saline under TVE; in HSV1-TK group (n ¼ 12), rats were given IPV injections of 5 Â 10 6 M11 cells under TVE; in IL-12 group (n ¼ 12), rats were given IPV injections of 5 Â 10 6 PA317mIL12 cells under TVE; in HSV1-TK and IL-12 group (n ¼ 12), rats were given IPV injections of 5 Â 10 6 M11 cells and 5 Â 10 6 PA317mIL12 cells under TVE.…”

Section: In Vivo Experimental Protocolsmentioning

confidence: 99%

“…4 Furthermore, we have recently observed that both HSV1-TK, followed by GCV administration, and interleukin-2 (IL-2) retrovirus-mediated gene transfer to the liver through the portal vein under TVE led to a significant antitumoral effect against aggressive macroscopic multiple liver metastases (MLM). 5 In addition, despite complete curative liver resection, recurrent disease develops in nearly two-thirds of patients, most often in the liver remnant. To date, only one study, combining hepatic arterial infusion and systemic chemotherapy, has suggested that adjuvant chemotherapy after liver resection could be helpful for reducing tumor recurrences and increasing survival.…”

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confidence: 99%

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Adjuvant interleukin-12 gene therapy for the management of colorectal liver metastases

et al. 2004

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In humans, no efficient treatment exists not only against multifocal liver metastases (LM) but also against recurrent microscopic liver metastases within the liver remnant following curative liver resection. Furthermore, in nonmultifocal LM, partial liver resection could be performed, but in more than 50% of the patients, tumor recurrence within liver remnant is observed, partly due to the growth of dormant cancer cells in the setting of postoperative host immune dysfunction. We investigated the therapeutic potential of interleukin-12 (IL-12) immuno-gene therapies in these experimental models under total vascular exclusion (TVE) of the liver. In rats with multiple LM of DHDK12 colon cancer cells, we observed a significant reduction in tumor volume after retroviral-mediated gene transfer of either herpes simplex virus thymidine kinase (HSV1-TK) and ganciclovir (GCV) administration, or IL-12. Combined treatment with HSV1-TK/GCV and IL-12 resulted in improved tumor volume reduction and even survival. In rats with recurrent microscopic DHDK12 LM established after partial liver resection, we observed significantly decreased recurrent tumor volumes and increased survival after retroviral-mediated IL-12 gene transfer. In both settings, immunohistological analysis revealed that IL-12 immuno-gene therapy was accompanied by an infiltration of CD8 þ T lymphocytes within the tumors. Altogether, our results suggest that IL-12 adjuvant gene therapy could improve the management of patients with either resectable or unresectable LM.

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Section: Resultsmentioning

confidence: 99%