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3 Acta Biochimica Polonica

3 2004

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Antitumour activity of Salmonella typhimurium VNP20047 in B16(F10) murine melanoma model.

100%

Jazowiecka-Rakus J. , Szala S.

Acta Biochimica Polonica

2004

tom 51

nr 3

851-856

A tumour therapy is proposed based on attenuated Salmonella typhimurium VNP20047 expressing the Escherichia coli cytosine deaminase gene. VNP20047 was administered intravenously to B16(F10) melanoma-bearing C57BL/6 mice. VNP20047 proliferated within tumours and livers regardless of the initial inoculum dose. After 10 days the number of bacteria increased in livers up to 4.2 × 106 cfu/g and decreased in tumours down to 5.9 × 106 cfu/g. VNP20047 at 1 × 105 cfu/mouse, when combined with 5-fluorocytosine, inhibited tumour growth by 85% without prolonging animal survival. Histology studies revealed severe lesions in tumours and livers. These data suggest that S. typhimurium VNP20047 induced inflammatory responses, even though the strain was attenuated.

CEA-negative glioblastoma and melanoma cells are sensitive to cytosine deaminase-5-fluorocytosine therapy directed by the carcinoembryonic antigen promoter

75%

Dabrowska A. , Szary J. , Kowalczuk M. , Szala S. , Ugorski M.

Acta Biochimica Polonica

2004

tom 51

nr 3

Recent studies have suggested that carcinoembryonic antigen (CEA)-promoter sequences are active only in CEA-positive cells, filing in the criteria for tumor specific targeting of suicide genes. However, the present study on gene therapy of colon cancer and cell-specificity of CEA promoter, provide evidence that CEA-positive and CEA-negative cells transfected with E. coli cytosine deaminase (CD) gene under the control of CEA promotor sequence are sensitive to enzyme/pro-drug therapy with 5-fluorocytosine (5-FC). Individual clones derived from the CEA-negative cell lines: melanoma Hs294T and glioblastoma T98G after transfection with CD differed profoundly in their sensitivity to 5-FC. The IC50 values for several clones of the CEA-neg- ative cells were almost the same as for CEA-positive colon cancer cells. Such 5-FC-sensitive clones derived from the population of CEA-negative cells, present even in small number, because of the very effective bystender effect of this enzyme/pro-drug system can cause severe problems during therapy by efficiently killing surrounding normal cells. Safety is the major issue in gene therapy. Our data suggest that the safety of gene-directed enzyme pro-drug therapy (GDEPT) with CEA promoter driven expression of therapeutic genes is not so obvious as it has originally been claimed.

Antitumour activity of Salmonella typhimurium VNP20047 in B16[F10] murine melanoma model

63%

Jazowiecka-Rakus J. , Szala S.

Acta Biochimica Polonica

2004

tom 51

nr 3

A tumour therapy is proposed based on attenuated Salmonella typhimurium VNP20047 expressing the Escherichia coli cytosine deaminase gene. VNP20047 was administered intravenously to B16(F10) melanoma-bearing C57BL/6 mice. VNP20047 proliferated within tumours and livers regardless of the initial inoculum dose. After 10 days the number of bacteria increased in livers up to 4.2 x 106 cfu/g and decreased in tumours down to 5.9 x 106 cfu/g. VNP20047 at 1 x 105 cfu/mouse, when combined with 5-fluorocytosine, inhibited tumour growth by 85% without prolonging animal survival. Histology studies revealed severe lesions in tumours and livers. These data suggest that S. typhimurium VNP20047 induced inflammatory responses, even though the strain was attenuated.