Abstract
IntroductionOvarian cancer ascitic fluid, which contains malignant cells, is usually present in women with an advanced stage disease. There are currently no effective therapies for the treatment of ovarian cancer ascitic fluid. We developed a new therapeutic strategy to target expression of the diphtheria toxin fragment A gene in ovarian tumor cells under the control of H19 regulatory sequences.Case presentationA 64-year-old Caucasian woman was diagnosed with a stage IIIc epithelial ovarian cancer. She suffered from progressive disease, accumulation of malignant ascites that needed to be drained weekly, abdominal pain, vomiting, anorexia and severe weakness. Infusion of the diphtheria toxin A chain-H19 plasmid into the peritoneum of our patient resulted in complete resolution of the ascites with minimum adverse events.ConclusionOn the basis of this preliminary experience, we are currently conducting an extensive Phase I study on a larger number of patients in order to assess the safety and preliminary efficacy of this novel patient-oriented treatment approach.
Highlights
Ovarian cancer ascitic fluid, which contains malignant cells, is usually present in women with an advanced stage disease
Our patient was treated with the DTA-H19 plasmid administered intraperitoneally after demonstrating high levels of H19 RNA in the ascites cells by in situ hybridization analyses (ISH) and RT-polymerase chain reaction (PCR) analysis (Figure 1)
The graph pattern shows two peaks of plasmid DNA in different time lines after infusion (Figure 2). This can be explained by the fact that some of the plasmid is transferred to the blood stream from the peritoneum which might be indicated by the first peak, and it is transferred through the lymphatic system into the venous blood stream [13] which might be represented by the later second peak in the graph (Figure 2)
Summary
H19 is a paternally imprinted, maternally expressed, oncofetal gene that has no protein product [1]. Based on the results from our pre-clinical studies [5], we applied a tailored transcriptional regulatory sequence selection approach as a patient oriented DNA-based therapy This approach to gene therapy of human cancer exploits the genetic and epigenetic alterations in cancer for targeting the expression of toxic genes. Due to stable disease after six courses of treatment she further received topotecan for eight courses followed by gemcitabine, doxil and etoposide Despite this aggressive therapy, the woman suffered from progressive disease, accumulation of malignant ascites that needed to be drained weekly, abdominal pain, vomiting, anorexia and severe weakness. CT and PET-CT scans were performed at six weeks and 3.5 months after the first treatment, respectively Both scans showed that there were still multiple intra-peritoneal areas of 2-Deoxy-2-[18F]fluoro-DGlucose (FDG) uptake indicating the presence of cellular activity of the tumor, an arrest in disease progression and disappearance of ascites were noticed
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