Intratumoral activation of cyclophosphamide by retroviral transfer of the cytochrome P45O 2B1 in a pancreatic tumor model. Combination with the HSVtk/GCV system

Meritxell Carrió, Joana Visa, Anna Cascante, Xavier P. Estivill, Cristina Fillat

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: Pancreatic cancer is one of the most aggressive human tumors and the development of new therapeutic approaches is particularly urgent since current therapies are not effective. The use of pro-drug-activating genes is a possible approach for cancer gene therapy. Methods: The present study evaluated the efficiency of the cytochrome P450 2B1 (CYP2B1) suicide gene that encodes the enzyme responsible for activating the pro-drug cyclophosphamide (CPA), in pancreatic tumor cells in vitro and in vivo. The effects on tumor growth of the combination of two suicide systems, CYP2B1/CPA and herpes simplex virus thymidine kinase gene/ganciclovir (HSVtk/GCV), were also studied. Results: Retroviral CYP2B1 transfer followed by CPA treatment highly sensitized pancreatic tumor cells NP-9, NP-18, and NP-31, and led to stabilization of tumor growth in a pancreatic tumor model. Differences in tumor volume at the end of the treatment were statistically significant when compared with animals injected with CPA alone. The combination of both suicide systems CYP2B1/CPA and HSVtk/GCV in vitro resulted in a potentiation of the killing effect. However, no potentiation was achieved in vivo, although retardation in tumor growth was evident. Conclusions: The results show that in situ transduction of pancreatic tumor cells with the CYP2B1 gene by retroviral vectors clearly increases the sensitivity to CPA. Moreover, they suggest that in order to achieve a potentiation on cell killing when the two suicide systems HSVtk/GCV and CYP2B1/CPA are combined, co-expression of both genes in the same tumor cell would be necessary.

Original languageEnglish
Pages (from-to)141-149
Number of pages9
JournalJournal of Gene Medicine
Volume4
Issue number2
DOIs
Publication statusPublished - Mar 2002
Externally publishedYes

Fingerprint

Ganciclovir
Thymidine Kinase
Simplexvirus
Cytochromes
Cytochrome P-450 CYP2B1
Cyclophosphamide
Genes
Neoplasms
Suicide
Prodrugs
Growth
Neoplasm Genes
Human Development
Therapeutics
Tumor Burden
Pancreatic Neoplasms
Genetic Therapy
Gene Expression

Keywords

  • Cytochrome P450 2B1
  • Gene therapy
  • Pancreatic cancer
  • Retrovirus
  • Thymidine kinase

ASJC Scopus subject areas

  • Genetics

Cite this

Intratumoral activation of cyclophosphamide by retroviral transfer of the cytochrome P45O 2B1 in a pancreatic tumor model. Combination with the HSVtk/GCV system. / Carrió, Meritxell; Visa, Joana; Cascante, Anna; Estivill, Xavier P.; Fillat, Cristina.

In: Journal of Gene Medicine, Vol. 4, No. 2, 03.2002, p. 141-149.

Research output: Contribution to journalArticle

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abstract = "Background: Pancreatic cancer is one of the most aggressive human tumors and the development of new therapeutic approaches is particularly urgent since current therapies are not effective. The use of pro-drug-activating genes is a possible approach for cancer gene therapy. Methods: The present study evaluated the efficiency of the cytochrome P450 2B1 (CYP2B1) suicide gene that encodes the enzyme responsible for activating the pro-drug cyclophosphamide (CPA), in pancreatic tumor cells in vitro and in vivo. The effects on tumor growth of the combination of two suicide systems, CYP2B1/CPA and herpes simplex virus thymidine kinase gene/ganciclovir (HSVtk/GCV), were also studied. Results: Retroviral CYP2B1 transfer followed by CPA treatment highly sensitized pancreatic tumor cells NP-9, NP-18, and NP-31, and led to stabilization of tumor growth in a pancreatic tumor model. Differences in tumor volume at the end of the treatment were statistically significant when compared with animals injected with CPA alone. The combination of both suicide systems CYP2B1/CPA and HSVtk/GCV in vitro resulted in a potentiation of the killing effect. However, no potentiation was achieved in vivo, although retardation in tumor growth was evident. Conclusions: The results show that in situ transduction of pancreatic tumor cells with the CYP2B1 gene by retroviral vectors clearly increases the sensitivity to CPA. Moreover, they suggest that in order to achieve a potentiation on cell killing when the two suicide systems HSVtk/GCV and CYP2B1/CPA are combined, co-expression of both genes in the same tumor cell would be necessary.",
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