Treatment of Chemotherapy-Resistant Human Ovarian Cancer Xenografts in C.B-17/SCID Mice by Intraperitoneal Administration of <i>Clostridium perfringens</i> Enterotoxin

Santin, Alessandro D.; Canè, Stefania; Bellone, Stefania; Palmieri, Michela; Siegel, Eric R.; Thomas, Maria; Román, Juan José Mora; Burnett, Alexander; Cannon, Martin J.; Pecorelli, Sërgio

doi:10.1158/0008-5472.can-04-3472

Cited by 100 publications

(115 citation statements)

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“…Other in vivo studies of external therapeutic application of recombinant CPE also reported strong necrosis in the tumor tissues. 33,[35][36][37] In conclusion, we report the successful tumor-targeted CPE gene therapy in vitro and in vivo. This approach efficiently eradicates tumor cells, and provides an attractive therapeutic option for the potential local treatment of refractory solid tumors (including unresectable tumor lesions, residual tumors or recurrences), originating from colon, mammary, pancreas or prostate cancer, which overexpress claudin-3 or -4.…”

Section: Discussionmentioning

confidence: 68%

“…Application of recombinant CPE protein leads to the dose-dependent rapid eradication of claudin-4-or claudin-3-overexpressing pancreas, breast or colon cancer cells in vitro and in vivo. 17,18,[33][34][35][36][37] The intratumoral in vivo application of recombinant CPE did not induce toxinassociated side effects, supporting its great therapeutic potential. However, these approaches require repeated, almost continuous regional or loco-regional application of recombinant CPE at doses ranging from 0.5 to 1.0 mg CPE per application to achieve therapeutic effects.…”

Section: Introductionmentioning

confidence: 76%

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Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

et al. 2011

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Bacterial toxins are known to be effective for cancer therapy. Clostridium perfringens enterotoxin (CPE) is produced by the bacterial Clostridium type A strain. The transmembrane proteins claudin-3 and -4, often overexpressed in numerous human epithelial tumors (for example, colon, breast, pancreas, prostate and ovarian), are the targeted receptors for CPE. CPE binding to them triggers formation of membrane pore complexes leading to rapid cell death. In this study, we aimed at selective tumor cell killing by CPE gene transfer. We generated expression vectors bearing the bacterial wild-type CPE cDNA (wtCPE) or translationoptimized CPE (optCPE) cDNA for in vitro and in vivo gene therapy of claudin-3-and -4-overexpressing tumors. The CPE expression analysis at messenger RNA and protein level revealed more efficient expression of optCPE compared with wtCPE. Expression of optCPE showed rapid cytotoxic activity, hightened by CPE release as bystander effect. Cytotoxicity of up to 100% was observed 72 h after gene transfer and is restricted to claudin-3-and -4-expressing tumor lines. MCF-7 and HCT116 cells with high claudin-4 expression showed dramatic sensitivity toward CPE toxicity. The claudin-negative melanoma line SKMel-5, however, was insensitive toward CPE gene transfer. The non-viral intratumoral in vivo gene transfer of optCPE led to reduced tumor growth in MCF-7 and HCT116 tumor-bearing mice compared with the vector-transfected control groups. This novel approach demonstrates that CPE gene transfer can be employed for a targeted suicide gene therapy of claudin-3-and -4-overexpressing tumors, leading to the rapid and efficient tumor cell killing in vitro and in vivo.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 76%

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

et al. 2011

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“…There have been previous reports to indicate that claudin-4 is upregulated in primary breast (Kominsky et al, 2004;Tokes et al, 2005), ovarian (Rangel et al, 2003;Agarwal et al, 2005;Santin et al, 2005), prostate (Long et al, 2001;Sheehan et al, 2007) squamous cell carcinoma (Morita et al, 2004) and pancreatic cancers (Michl et al, 2001(Michl et al, , 2003Nichols et al, 2004;Sato et al, 2004) but is downregulated in gastric cancer (Lee et al, 2005). In this study, the increasing prominence of claudin-4 compared with other candidate genes evaluated at both RNA and protein levels was confirmed with highest levels in PCa metastatic cells.…”

Section: Discussionmentioning

confidence: 97%

Identification of claudin-4 as a marker highly overexpressed in both primary and metastatic prostate cancer

Landers¹,

Samaratunga²,

Teng³

et al. 2008

Br J Cancer

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In the quest for markers of expression and progression for prostate cancer (PCa), the majority of studies have focussed on molecular data exclusively from primary tumours. Although expression in metastases is inferred, a lack of correlation with secondary tumours potentially limits their applicability diagnostically and therapeutically. Molecular targets were identified by examining expression profiles of prostate cell lines using cDNA microarrays. Those genes identified were verified on PCa cell lines and tumour samples from both primary and secondary tumours using real-time RT -PCR, western blotting and immunohistochemistry. Claudin-4, coding for an integral membrane cell-junction protein, was the most significantly (Po0.00001) upregulated marker in both primary and metastatic tumour specimens compared with benign prostatic hyperplasia at both RNA and protein levels. In primary tumours, claudin-4 was more highly expressed in lower grade (Gleason 6) lesions than in higher grade (Gleason X7) cancers. Expression was prominent throughout metastases from a variety of secondary sites in fresh-frozen and formalin-fixed specimens from both androgen-intact and androgen-suppressed patients. As a result of its prominent expression in both primary and secondary PCas, together with its established role as a receptor for Clostridium perfringens enterotoxin, claudin-4 may be useful as a potential marker and therapeutic target for PCa metastases.

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“…18 A recent report using an ovarian cancer mouse model has shown that intra-abdominal administration caused significant inhibition of tumor growth and extended survival in xenografted C.B-17/SCID mice. 19 In addition, another claudin family member, claudin-7, has also been found elevated in ovarian cancer and may represent another target for detection and/or therapy. 7 Although the importance of CLDN3 in cancer biology is becoming clear, the mechanisms of regulation of CLDN3 in ovarian and other cancers are still unclear.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the CLDN3 gene in ovarian cancer cells

Honda¹,

Pazin²,

D’Souza³

et al. 2007

Cancer Biology & Therapy

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AcKnowleDgeMenTSWe thank Dr. Ashani Weeraratna and the members of our laboratory for useful comments on the manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. Research PaperRegulation of the CLDN3 Gene in Ovarian Cancer Cells AbSTrAcTThe claudin (CLDN) genes encode a family of proteins involved in the formation and function of tight junctions. CLDN gene expression is frequently altered in several human cancers, and in particular, CLDN3 and CLDN4 are commonly overexpressed in ovarian cancer. However, the mechanisms leading to the deregulation of these genes in cancer remain unclear. In the present study, we have examined the CLDN3 promoter and have identified a minimal region containing an Sp1 site crucial for its activity. In addition, we find that the CLDN3 promoter is regulated through epigenetic processes. Cells that express high levels of CLDN3 exhibit low DNA methylation and high histone H3 acetylation of the critical CLDN3 promoter region, and the reverse is observed in cells that do not express this gene. CLDN3-negative cells can be induced to express CLDN3 through treatment with DNA methyltransferase or histone deacetylase inhibitors. Interestingly, in vitro binding experiments, as well as chip assays show that Sp1 binds the unmethylated promoter much more efficiently, providing a mechanism for CLDN3 silencing in non-expressing cells. Finally, siRNA-mediated knockdown of Sp1 led to a significant decrease of CLDN3 expression at both the mRNA and protein levels, demonstrating a crucial role for this transcription factor in the regulation of CLDN3. Our data provide a basis for CLDN3 expression in ovarian cancer cells, as well as a mechanism for the silencing of this promoter in tumors lacking expression of claudin-3.

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Treatment of Chemotherapy-Resistant Human Ovarian Cancer Xenografts in C.B-17/SCID Mice by Intraperitoneal Administration of Clostridium perfringens Enterotoxin

Abstract: Ovarian cancer remains the most lethal gynecologic malig-

Cited by 100 publications

References 25 publications

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

Identification of claudin-4 as a marker highly overexpressed in both primary and metastatic prostate cancer

Regulation of the CLDN3 gene in ovarian cancer cells

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