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Use of H19 Gene Regulatory Sequences in DNA-Based Therapy for Pancreatic Cancer.

Scaiewicz V, Sorin V, Fellig Y, Birman T, Mizrahi A, Galula J, Abu-Lail R, Shneider T, Ohana P, Buscail L, Hochberg A, Czerniak A - J Oncol (2010)

Bottom Line: In vitro experiments showed that the vector was effective in reducing Luciferase protein activity on pancreatic carcinoma cell lines.In addition, no visible metastases were found in the treated group of the orthotopic model.These results indicate that the treatment with the vector DTA-H19 might be a viable new therapeutic option for patients with unresectable pancreatic cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram, Jerusalem 91904, Israel.

ABSTRACT
Pancreatic cancer is the eighth most common cause of death from cancer in the world, for which palliative treatments are not effective and frequently accompanied by severe side effects. We propose a DNA-based therapy for pancreatic cancer using a nonviral vector, expressing the diphtheria toxin A chain under the control of the H19 gene regulatory sequences. The H19 gene is an oncofetal RNA expressed during embryo development and in several types of cancer. We tested the expression of H19 gene in patients, and found that 65% of human pancreatic tumors analyzed showed moderated to strong expression of the gene. In vitro experiments showed that the vector was effective in reducing Luciferase protein activity on pancreatic carcinoma cell lines. In vivo experiment results revealed tumor growth arrest in different animal models for pancreatic cancer. Differences in tumor size between control and treated groups reached a 75% in the heterotopic model (P = .037) and 50% in the orthotopic model (P = .007). In addition, no visible metastases were found in the treated group of the orthotopic model. These results indicate that the treatment with the vector DTA-H19 might be a viable new therapeutic option for patients with unresectable pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus

Heterotopic model for pancreatic cancer. (a) Average tumor volume of Luc-H19 group (n = 8) and DTA-H19 group (n = 7) during the experiment using CRL-1469 cells. Treatments were administrated on days 0, 3, and 6 by direct intratumoral injection after subcutaneous implantation of human pancreatic carcinoma cells in the back of nude mice. Three days after the last treatment, the animals were sacrificed. (b) Average of ex vivo tumor volume at the end of the experiment, tumors generated using CRL-1469 cells. (c) Tumor Growth Progression of Luc-H19 (n = 5) and DTA-H19 (n = 5) groups, in experiment using CRL-2547 cell line.
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fig4: Heterotopic model for pancreatic cancer. (a) Average tumor volume of Luc-H19 group (n = 8) and DTA-H19 group (n = 7) during the experiment using CRL-1469 cells. Treatments were administrated on days 0, 3, and 6 by direct intratumoral injection after subcutaneous implantation of human pancreatic carcinoma cells in the back of nude mice. Three days after the last treatment, the animals were sacrificed. (b) Average of ex vivo tumor volume at the end of the experiment, tumors generated using CRL-1469 cells. (c) Tumor Growth Progression of Luc-H19 (n = 5) and DTA-H19 (n = 5) groups, in experiment using CRL-2547 cell line.

Mentions: Tumors were generated into athymic nude mice back by subcutaneous injection of CRL-1469 cells and then treated with DTA-H19 (n = 7) or Luc-H19 (n = 8, control group) plasmid by direct injection into the tumor. Results showed that treatment with DTA-H19 resulted in an arrest of tumor growth, leading to a relative maintenance of tumor volume (Figure 4(a)). A significant difference in tumor growth progression between the two groups was found, indicating that the growth of the DTA-H19 treated group was arrested (P-value =  .036). This observation was confirmed by the final ex vivo tumor volume, which showed to be significantly smaller for the DTA-H19 group as compared to the control group (P-value =  .038) (Figure 4(b)).


Use of H19 Gene Regulatory Sequences in DNA-Based Therapy for Pancreatic Cancer.

Scaiewicz V, Sorin V, Fellig Y, Birman T, Mizrahi A, Galula J, Abu-Lail R, Shneider T, Ohana P, Buscail L, Hochberg A, Czerniak A - J Oncol (2010)

Heterotopic model for pancreatic cancer. (a) Average tumor volume of Luc-H19 group (n = 8) and DTA-H19 group (n = 7) during the experiment using CRL-1469 cells. Treatments were administrated on days 0, 3, and 6 by direct intratumoral injection after subcutaneous implantation of human pancreatic carcinoma cells in the back of nude mice. Three days after the last treatment, the animals were sacrificed. (b) Average of ex vivo tumor volume at the end of the experiment, tumors generated using CRL-1469 cells. (c) Tumor Growth Progression of Luc-H19 (n = 5) and DTA-H19 (n = 5) groups, in experiment using CRL-2547 cell line.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2967839&req=5

fig4: Heterotopic model for pancreatic cancer. (a) Average tumor volume of Luc-H19 group (n = 8) and DTA-H19 group (n = 7) during the experiment using CRL-1469 cells. Treatments were administrated on days 0, 3, and 6 by direct intratumoral injection after subcutaneous implantation of human pancreatic carcinoma cells in the back of nude mice. Three days after the last treatment, the animals were sacrificed. (b) Average of ex vivo tumor volume at the end of the experiment, tumors generated using CRL-1469 cells. (c) Tumor Growth Progression of Luc-H19 (n = 5) and DTA-H19 (n = 5) groups, in experiment using CRL-2547 cell line.
Mentions: Tumors were generated into athymic nude mice back by subcutaneous injection of CRL-1469 cells and then treated with DTA-H19 (n = 7) or Luc-H19 (n = 8, control group) plasmid by direct injection into the tumor. Results showed that treatment with DTA-H19 resulted in an arrest of tumor growth, leading to a relative maintenance of tumor volume (Figure 4(a)). A significant difference in tumor growth progression between the two groups was found, indicating that the growth of the DTA-H19 treated group was arrested (P-value =  .036). This observation was confirmed by the final ex vivo tumor volume, which showed to be significantly smaller for the DTA-H19 group as compared to the control group (P-value =  .038) (Figure 4(b)).

Bottom Line: In vitro experiments showed that the vector was effective in reducing Luciferase protein activity on pancreatic carcinoma cell lines.In addition, no visible metastases were found in the treated group of the orthotopic model.These results indicate that the treatment with the vector DTA-H19 might be a viable new therapeutic option for patients with unresectable pancreatic cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram, Jerusalem 91904, Israel.

ABSTRACT
Pancreatic cancer is the eighth most common cause of death from cancer in the world, for which palliative treatments are not effective and frequently accompanied by severe side effects. We propose a DNA-based therapy for pancreatic cancer using a nonviral vector, expressing the diphtheria toxin A chain under the control of the H19 gene regulatory sequences. The H19 gene is an oncofetal RNA expressed during embryo development and in several types of cancer. We tested the expression of H19 gene in patients, and found that 65% of human pancreatic tumors analyzed showed moderated to strong expression of the gene. In vitro experiments showed that the vector was effective in reducing Luciferase protein activity on pancreatic carcinoma cell lines. In vivo experiment results revealed tumor growth arrest in different animal models for pancreatic cancer. Differences in tumor size between control and treated groups reached a 75% in the heterotopic model (P = .037) and 50% in the orthotopic model (P = .007). In addition, no visible metastases were found in the treated group of the orthotopic model. These results indicate that the treatment with the vector DTA-H19 might be a viable new therapeutic option for patients with unresectable pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus