Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo

J. M. DiMaio, B. M. Clary, D. F. Via, E. Covency, T. N. Pappas, H. K. Lyerly, R. D. Beauchamp, A. Shaked, J. A. Norton

Research output: Contribution to journalArticle

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Abstract

Background. Directed enzyme pro-drug therapy incorporates the delivery of a gene to a cancer cell that will be specifically expressed and will confer sensitivity to a therapeutic agent. Tumor-specific gene expression can be achieved by coupling the promoter for the carcinoembryonic antigen (CEA) to a gene such as herpes simplex virus thymidine kinase (HSV-tk), which phosphorylates ganciclovir to a potent DNA synthesis inhibitor. Methods. Retroviral vectors were constructed to contain the CEA promoter coupled to HSV-tk (LN-CEA-TK) and were used to transduce the CEA-expressing pancreatic carcinoma cell line BXPC3. Recombinant pancreatic carcinoma cell lines expressing HSV-tk (BXPC3(CEA-TK)) were then tested for sensitivity to the toxic effects on ganciclovir after engraftment into severe combined immunodeficient mice. Tumors were generated by subcutaneous inoculation of 20 x 106 tumor cells consisting of BXPC3 and/or BXPC3(CEA-TK) cells in ratios of 100:0, 90:10, 50:50, 10:90, and 0:100. After 3 days mice received daily ganciclovir (0.1 mg/kg) or phosphate-buffered saline solution by intraperitoneal injection and were monitored for tumor growth. Results. All severe combined immunodeficient mice inoculated with BXPC3 or BXPC3(CEA-TK) cells in any proportion developed large pancreatic tumors. As expected, a significant reduction in tumor size was seen in the BXPC3(CEA-TK) engrafted mice receiving ganciclovir compared with mice receiving phosphate-buffered saline solution or mice engrafted with only BXPC3. In addition, all animals with any fraction of cells expressing HSV-tk exhibited a significant reduction in tumor growth, including animals with only 10% of cells expressing HSV-tk. Conclusions. These results suggest the potential utility of directed enzyme pro-drug therapy in patients with CEA-expressing pancreatic carcinoma.

Original languageEnglish (US)
Pages (from-to)205-213
Number of pages9
JournalSurgery
Volume116
Issue number2
StatePublished - 1994

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Carcinoembryonic Antigen
Prodrugs
Pancreatic Neoplasms
Genetic Therapy
Thymidine Kinase
Drug Therapy
Simplexvirus
Ganciclovir
Enzymes
Neoplasms
SCID Mice
Sodium Chloride
Phosphates
Nucleic Acid Synthesis Inhibitors
Cell Line
Poisons
Growth
Intraperitoneal Injections
Genes
Gene Expression

ASJC Scopus subject areas

  • Surgery

Cite this

DiMaio, J. M., Clary, B. M., Via, D. F., Covency, E., Pappas, T. N., Lyerly, H. K., ... Norton, J. A. (1994). Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo. Surgery, 116(2), 205-213.

Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo. / DiMaio, J. M.; Clary, B. M.; Via, D. F.; Covency, E.; Pappas, T. N.; Lyerly, H. K.; Beauchamp, R. D.; Shaked, A.; Norton, J. A.

In: Surgery, Vol. 116, No. 2, 1994, p. 205-213.

Research output: Contribution to journalArticle

DiMaio, JM, Clary, BM, Via, DF, Covency, E, Pappas, TN, Lyerly, HK, Beauchamp, RD, Shaked, A & Norton, JA 1994, 'Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo', Surgery, vol. 116, no. 2, pp. 205-213.
DiMaio JM, Clary BM, Via DF, Covency E, Pappas TN, Lyerly HK et al. Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo. Surgery. 1994;116(2):205-213.
DiMaio, J. M. ; Clary, B. M. ; Via, D. F. ; Covency, E. ; Pappas, T. N. ; Lyerly, H. K. ; Beauchamp, R. D. ; Shaked, A. ; Norton, J. A. / Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo. In: Surgery. 1994 ; Vol. 116, No. 2. pp. 205-213.
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abstract = "Background. Directed enzyme pro-drug therapy incorporates the delivery of a gene to a cancer cell that will be specifically expressed and will confer sensitivity to a therapeutic agent. Tumor-specific gene expression can be achieved by coupling the promoter for the carcinoembryonic antigen (CEA) to a gene such as herpes simplex virus thymidine kinase (HSV-tk), which phosphorylates ganciclovir to a potent DNA synthesis inhibitor. Methods. Retroviral vectors were constructed to contain the CEA promoter coupled to HSV-tk (LN-CEA-TK) and were used to transduce the CEA-expressing pancreatic carcinoma cell line BXPC3. Recombinant pancreatic carcinoma cell lines expressing HSV-tk (BXPC3(CEA-TK)) were then tested for sensitivity to the toxic effects on ganciclovir after engraftment into severe combined immunodeficient mice. Tumors were generated by subcutaneous inoculation of 20 x 106 tumor cells consisting of BXPC3 and/or BXPC3(CEA-TK) cells in ratios of 100:0, 90:10, 50:50, 10:90, and 0:100. After 3 days mice received daily ganciclovir (0.1 mg/kg) or phosphate-buffered saline solution by intraperitoneal injection and were monitored for tumor growth. Results. All severe combined immunodeficient mice inoculated with BXPC3 or BXPC3(CEA-TK) cells in any proportion developed large pancreatic tumors. As expected, a significant reduction in tumor size was seen in the BXPC3(CEA-TK) engrafted mice receiving ganciclovir compared with mice receiving phosphate-buffered saline solution or mice engrafted with only BXPC3. In addition, all animals with any fraction of cells expressing HSV-tk exhibited a significant reduction in tumor growth, including animals with only 10{\%} of cells expressing HSV-tk. Conclusions. These results suggest the potential utility of directed enzyme pro-drug therapy in patients with CEA-expressing pancreatic carcinoma.",
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AU - DiMaio, J. M.

AU - Clary, B. M.

AU - Via, D. F.

AU - Covency, E.

AU - Pappas, T. N.

AU - Lyerly, H. K.

AU - Beauchamp, R. D.

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AU - Norton, J. A.

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N2 - Background. Directed enzyme pro-drug therapy incorporates the delivery of a gene to a cancer cell that will be specifically expressed and will confer sensitivity to a therapeutic agent. Tumor-specific gene expression can be achieved by coupling the promoter for the carcinoembryonic antigen (CEA) to a gene such as herpes simplex virus thymidine kinase (HSV-tk), which phosphorylates ganciclovir to a potent DNA synthesis inhibitor. Methods. Retroviral vectors were constructed to contain the CEA promoter coupled to HSV-tk (LN-CEA-TK) and were used to transduce the CEA-expressing pancreatic carcinoma cell line BXPC3. Recombinant pancreatic carcinoma cell lines expressing HSV-tk (BXPC3(CEA-TK)) were then tested for sensitivity to the toxic effects on ganciclovir after engraftment into severe combined immunodeficient mice. Tumors were generated by subcutaneous inoculation of 20 x 106 tumor cells consisting of BXPC3 and/or BXPC3(CEA-TK) cells in ratios of 100:0, 90:10, 50:50, 10:90, and 0:100. After 3 days mice received daily ganciclovir (0.1 mg/kg) or phosphate-buffered saline solution by intraperitoneal injection and were monitored for tumor growth. Results. All severe combined immunodeficient mice inoculated with BXPC3 or BXPC3(CEA-TK) cells in any proportion developed large pancreatic tumors. As expected, a significant reduction in tumor size was seen in the BXPC3(CEA-TK) engrafted mice receiving ganciclovir compared with mice receiving phosphate-buffered saline solution or mice engrafted with only BXPC3. In addition, all animals with any fraction of cells expressing HSV-tk exhibited a significant reduction in tumor growth, including animals with only 10% of cells expressing HSV-tk. Conclusions. These results suggest the potential utility of directed enzyme pro-drug therapy in patients with CEA-expressing pancreatic carcinoma.

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