Regression of prostate cancer xenografts by a lentiviral vector specifically expressing diphtheria toxin A

Abstract

We have constructed a prostate-specific lentiviral vector based on the promoter of the prostate-specific antigen (PSA). The PSA promoter-based lentiviral vector has been used to deliver the diphtheria toxin A (DTA) gene into prostate cancer cells, and has shown promising tissue-specific eradication of prostate cancer cells in cell culture. To evaluate the efficacy of eradicating human prostate cancer cells in vivo, we used human LNCaP prostate xenografts in nude mice as an animal model and found that with a single injection of the DTA lentiviral vector into LNCaP prostate tumors, approximately 75% of the tumors (from three experiments; conducted 9/11, 11/15 and 3/4) in the animals were completely eradicated. The DTA vector has also shown the ability to cause tumor regression in recurrent prostate tumors. Intravenous injection of the DTA lentiviral vector into nude mice elicited no pathogenic effects, suggesting that this prostate tissue-specific vector is safe for eradicating prostate cancer cells in vivo.

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

“…[5][6][7][8]10 Apart from diphteria toxin and Pseudomonas exotoxin, other toxins such as streptolysin O and CPE came into focus. The two latter toxins are both pore-forming proteins, of which streptolysin O is rather unspecific, whereas CPE possesses specificity in action.…”

“…4 Particularly for the treatment of refractory tumors, use of these toxins represents an applicable option and was tested in vitro and in vivo to treat various cancers, and have also been efficiently used in gene therapeutic applications. [5][6][7][8] The most extensively used toxins are diphteria toxin (Corynebacterium diphteriae) and Pseudomonas exotoxin A (Pseudomonas aeruginosa), which both inhibit protein synthesis by specific ribosylation of elongation factor-2. 4,9 The two toxins were used for the treatment of prostate, pancreatic, ovarian, lung carcinoma and glioblastoma with promising therapeutic efficacies, and exerted also therapeutic efficacy in gene therapy approaches.…”

“…4,9 The two toxins were used for the treatment of prostate, pancreatic, ovarian, lung carcinoma and glioblastoma with promising therapeutic efficacies, and exerted also therapeutic efficacy in gene therapy approaches. [5][6][7][8][10][11][12][13][14] Alternatively, the pore-forming bacterial toxins streptolysin O (Streptococcus pyrogenes) and Clostridium perfringens enterotoxin (CPE) came into focus as promising cancer therapeutics. [15][16][17][18] CPE is produced by the anaerobic gram-positive Clostridium perfringens type A strain, known to cause food poisoning.…”

Lentiviral vectors: optimization of packaging, transduction and gene expression

“…A patient-derived PSA promoter inserted into an HIV-1-based vector has driven efficient transgenic activity in prostate cells with satisfactory efficacy and specificity in in vitro as well as in vivo experiments [132]. More recently, a PSA promoter-based HIV-1 vector has been used to deliver the diphtheria toxin A gene into prostate cancer cells, and has shown promising tissuespecific eradication of prostate cancer cells in cell culture and in a mouse tumor model [133].…”

Neutral endopeptidase inhibits prostate cancer tumorigenesis by reducing FGF-2-mediated angiogenesis

“…12 Recent studies have begun to examine their utility in cancer gene therapy. Pellinen et al 14 reported a 50-95% lentiviral gene transfer efficiency in studies of 42 tumor cell lines from 10 different human tumor types, and lentiviralmediated inhibition of cell growth and/or tumor formation in athymic mice have been demonstrated in prostate cancer, [15][16][17][18] liver cancer, 19 oral squamous cancer, 20 cervical cancer 21 and melanoma. 19,22 We chose to evaluate the effect of lentiviral vector-mediated NEP transfer in NEP-deficient DU145 cells.…”