Intratumoral activation of cyclophosphamide by retroviral transfer of the cytochrome P450 2B1 in a pancreatic tumor model. Combination with the HSVtk/GCV system.
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 P4502B1 (CYP2B1) suicide gene that encodes the enzyme responsible for activating the pro-drug cyclophosphamide (CPA), in pancreatic tumor cells invitro 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.
Carrió
Meritxell
M
Centre de Genètica Mèdica i Molecular, Institut de Recerca Oncològica (IRO), Barcelona, Spain.
Visa
Joana
J
Cascante
Anna
A
Estivill
Xavier
X
Fillat
Cristina
C
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D002454:Cell Differentiation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology*; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs; D012190:Retroviridae / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics; D013997:Time Factors; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D000998:Antiviral Agents; D017077:Culture Media, Conditioned; D011355:Prodrugs; D003520:Cyclophosphamide; D019362:Cytochrome P-450 CYP2B1; D013937:Thymidine Kinase; D015774:Ganciclovir