Replication-deficient rSV40 mediate pancreatic gene transfer and long-term inhibition of tumor growth

Abstract

Pancreatic cancer is one of the most aggressive and devastating human malignancies. There is an urgent need for more effective therapy for patients with advanced disease. In this context, genetic therapy potentially represents a rational new approach to treating pancreatic cancer, which could provide an adjunct to conventional options. Because of the promise of recombinant SV40 vectors, we tested their ability to deliver a transgene, and to target a transcript, so as to inhibit pancreatic tumors growth in vivo. BxPC3 and Capan-1 cells were efficiently transduced using SV40 vectors without selection, as compared to synthetic vectors PEI. SV40 vectors were as efficient as adenoviral vectors, and provided long-term transgene expression. Next, we devised a SV40-derived, targeted gene therapy approach of pancreatic cancer, by combining hTR tumor-specific promoter with sst2 somatostatin receptor tumor-suppressor gene. In vitro cell proliferation was strongly impaired following administration of SV(hTR-sst2). SV40-derived sst2-mediated antiproliferative effect was dependent on the local production of somatostatin. In vivo, intratumoral gene transfer of sst2 using rSV40 vectors resulted in a marked inhibition of Capan-1 tumor progression, and proliferation. These results represent the initial steps toward a novel approach to the gene therapy of pancreatic cancer using SV40 as a vector.

Adult Stromal Cells Derived from Human Adipose Tissue Provoke Pancreatic Cancer Cell Death both In Vitro and In Vivo

“…Thus, human PDAC tumors were established in athymic mice following the subcutaneous injection of Capan-1 cells as a very aggressive model of PDAC [42], [43]. Fourteen to seventeen days following tumor engraftment, a single dose of ADSCs, corresponding to 10 3 ADSCs/mm 3 of tumor was transferred in vivo into growing tumors.…”

Using lentiviral vectors for efficient pancreatic cancer gene therapy

“…[29][30][31] Other gene delivery systems, such as complexed DNA (PEI), adenovirus and SV40-derived vectors showed poor efficiencies or transient expression of the transgene, respectively. 8,9 Lentiviral vectors were developed to overcome these limitations. The lentiviral vector-mediated gene therapy has great promise in cancer treatment, because of its long-term expression and high efficiency in transducing dividing and nondividing cells, including the chemoresistant population located in the hypoxic cores of tumors.…”

“…In this study, lentiviral-based vectors surpass nonviral vectors (PEI), adenoviral or SV40-based vectors in their ability to transduce PC-derived cells. 8,9 Understanding the molecular basis of PC has provided a wide range of potential intracellular targets for gene therapy approaches. 36 Targeting PC by molecular abnormality remains elusive because of the accumulation of multiple genetic changes during its multistep carcinogenesis.…”

“…[4][5][6][7] We have experimented with nonviral vectors, adenoviral and SV40-based vectors, which showed gene delivery to PC cells, and provided evidence of therapeutic efficacy. [8][9][10][11] However, the current low transduction efficiency of the synthetic nonviral vector and the transient gene expression using both viral vectors present major disadvantages in the cost of clinical application. An alternative approach is the development of more competitive expression vectors for PC gene delivery.…”

Initial Characterization of Integrase-Defective Lentiviral Vectors for Pancreatic Cancer Gene Therapy

“…Indeed, we have experimented synthetic (polyethylenimine, PEI) and viral-based (adenovirus, SV40) vectors, which demonstrated gene delivery to PDAC cells and evidence of therapeutic efficacy, both in vitro and in vivo. [5][6][7] However, the low efficacy of gene transfer using PEI, 5,7 the inherent immunogenic-ity of adenovirus, 8 and the manufacturing hurdles of SV40 vectors 9 challenge the use of these delivery vehicles in clinical trials. On the other hand, we recently found that lentiviral vectors (LVs) demonstrated the highest efficacy and reliability to inhibit PDAC cell proliferation both in vitro and in vivo, [10][11][12][13] and elected LVs as promising gene delivery vectors for PDAC gene therapy.…”