Background: Our aim was to ascertain whether gene therapy with the suicide gene thymidine kinase (TK) of the HSV and with the immunostimulatory cytokine IL-2, may exert a beneficial effect for pancreatic cancer (PC) treatment ‘in vivo’. Methods: The retroviral transduction of MIA PaCa 2, CAPAN- 1 and PANC-1 lines was made using a vector coexpressing IL-2 and TK. Three TK, 3 TK lines and 60 SCID mice 6 weeks old, were used. All mice received 5 million cells i.p. Ganciclovir (GCV) (100 mg/kg/day) or saline were i.p. daily injected from day 7 to day 21. The mice were then followed up and sacrificed at day 31. For each line four groups, five mice each, were identified: 1. TK and saline; 2. TK and GCV; 3. TK and saline; 4. TK and GCV. No evident, small (60mm3) or large (60mm3) tumor masses (TM) were found. The presence or absence of liver, pancreas, lung, kidney and spleen metastases was verified by microscopy. Results: No mice had lung or kidney metastases. In TK injected mice treated with saline, the lines PANC-1 and MIA PaCa 2 gave more frequent liver (100% and 63.6%) and spleen (37.5% and 90.9%) metastases than CAPAN-1 (12.5% and 25%) (X2 12.8, p 0.01 and X2 9.6, p 0.01). In mice injected with TKor TK PANC-1 lines after saline, no difference was found for any parameter. In TK MIA PaCa 2 injected and saline treated mice, TM were absent (60%) or 60mm3 (40%) and no liver metastases were found (100%), differently from TK MIA PaCa 2 (TM 60mm3 in all cases and liver metastases in 66.6%) (X2 11.0, p 0.01 and Fisher’s exact test: p 0.05). In TK CAPAN-1 injected and saline treated mice, TM were 60mm3 (100%), differently from TK CAPAN-1 (X2 8.0, p 0.05). GCV treatment did not modify any histological parameter when considering mice injected with TK cell lines. Conclusion: The suicide gene TK does not modify the pattern of PC ‘in vivo’; the presence of the immunostimulatory cytokine IL-2 may exert beneficial or adverse effects depending on the biological characteristics of the PC derived tumors.
Suicide gene therapy with HSV-TK in pancreatic cancer: no “in vivo” effect
FOGAR, PAOLA;CECCHETTO, ATTILIO;GRECO, ELIANA;BASSO, DANIELA;ZAMBON, CARLO-FEDERICO;PLEBANI, MARIO;PEDRAZZOLI, SERGIO
2002
Abstract
Background: Our aim was to ascertain whether gene therapy with the suicide gene thymidine kinase (TK) of the HSV and with the immunostimulatory cytokine IL-2, may exert a beneficial effect for pancreatic cancer (PC) treatment ‘in vivo’. Methods: The retroviral transduction of MIA PaCa 2, CAPAN- 1 and PANC-1 lines was made using a vector coexpressing IL-2 and TK. Three TK, 3 TK lines and 60 SCID mice 6 weeks old, were used. All mice received 5 million cells i.p. Ganciclovir (GCV) (100 mg/kg/day) or saline were i.p. daily injected from day 7 to day 21. The mice were then followed up and sacrificed at day 31. For each line four groups, five mice each, were identified: 1. TK and saline; 2. TK and GCV; 3. TK and saline; 4. TK and GCV. No evident, small (60mm3) or large (60mm3) tumor masses (TM) were found. The presence or absence of liver, pancreas, lung, kidney and spleen metastases was verified by microscopy. Results: No mice had lung or kidney metastases. In TK injected mice treated with saline, the lines PANC-1 and MIA PaCa 2 gave more frequent liver (100% and 63.6%) and spleen (37.5% and 90.9%) metastases than CAPAN-1 (12.5% and 25%) (X2 12.8, p 0.01 and X2 9.6, p 0.01). In mice injected with TKor TK PANC-1 lines after saline, no difference was found for any parameter. In TK MIA PaCa 2 injected and saline treated mice, TM were absent (60%) or 60mm3 (40%) and no liver metastases were found (100%), differently from TK MIA PaCa 2 (TM 60mm3 in all cases and liver metastases in 66.6%) (X2 11.0, p 0.01 and Fisher’s exact test: p 0.05). In TK CAPAN-1 injected and saline treated mice, TM were 60mm3 (100%), differently from TK CAPAN-1 (X2 8.0, p 0.05). GCV treatment did not modify any histological parameter when considering mice injected with TK cell lines. Conclusion: The suicide gene TK does not modify the pattern of PC ‘in vivo’; the presence of the immunostimulatory cytokine IL-2 may exert beneficial or adverse effects depending on the biological characteristics of the PC derived tumors.
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