Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences

Abstract

BackgroundOvarian cancer ascites fluid (OCAF), contains malignant cells, is usually present in women with an advanced stage disease and currently has no effective therapy. Hence, we developed a new therapy strategy to target the expression of diphtheria toxin gene under the control of H19 regulatory sequences in ovarian tumor cells. H19 RNA is present at high levels in human cancer tissues (including ovarian cancer), while existing at a nearly undetectable level in the surrounding normal tissue.MethodsH19 gene expression was tested in cells from OCAF by the in-situ hybridization technique (ISH) using an H19 RNA probe. The therapeutic potential of the toxin vector DTA-H19 was tested in ovarian carcinoma cell lines and in a heterotopic animal model for ovarian cancer.ResultsH19 RNA was detected in 90% of patients with OCAF as determined by ISH. Intratumoral injection of DTA-H19 into ectopically developed tumors caused 40% inhibition of tumor growth.ConclusionThese observations may be the first step towards a major breakthrough in the treatment of human OCAF, while the effect in solid tumors required further investigation. It should enable us to identify likely non-responders in advance, and to treat patients who are resistant to all known therapies, thereby avoiding treatment failure.

Long Non-coding RNA GAS5 Functions as a Tumor Suppressor in Renal Cell Carcinoma

“…Intratumoral injections of BC-819 (DTA-H19) plasmid, which carries the gene for the A subunit of diphtheria toxin under the regulation of the H19 promoter, induce the expression of high levels of diphtheria toxin specifically in the tumor resulting in a reduction of tumor size in human trials. Recent studies have yielded encouraging results in a wide range of carcinomas including NSCLC, colon, bladder, pancreatic and ovarian cancers (Amit and Hochberg;Hasenpusch et al;Smaldone and Davies;Sidi et al, 2008;Mizrahi et al, 2009). The successful trial undoubtedly gives us a faith and good method for the treatment of RCC through manipulating the expression of GAS5 in vivo.…”

Introducing PeptoPlexes: Polylysine‐block‐Polysarcosine Based Polyplexes for Transfection of HEK 293T Cells

“…This screening gave a quantitative overview over the transfection efficiencies of the PLys-block-PSar systems compared to jetPEI (linear PEI, mean molecular weight of 22 kDa; [60] see Figure 6). In general, there are two important requirements for good transfection efficiency: [15,61] First, the reagent should provide stable complexation of pDNA to prohibit degradation and facilitate cellular uptake while allowing endosomal translocation and intracellular release.…”

The Role of Long Non-Coding RNAs in Ovarian Cancer

“…Besides, H19 RNA has been detected in the majority of patients with ovarian cancer ascites fluid. The intratumoral injection of diphtheria toxin A chain-H19 into ectopically developed tumors has led to a significant inhibition of tumor growth [43] .…”