tailieunhanh - Báo cáo khoa học: The in vitro effects of CRE-decoy oligonucleotides in combination with conventional chemotherapy in colorectal cancer cell lines

The cAMP response element consensus sequence directs the transcription of a wide range of genes. A 24-mer single-stranded cAMP response element decoy oligonucleotide (CDO) has been shown to compete with these sequences for binding transcription factors and therefore interferes with cAMP-induced gene transcription. We have examined the effect of this CDOalone and in combinationwith a range of common chemotherapeutic agents in colorectal cancer cell lines. | Eur. J. Biochem. 271 2773-2781 2004 FEBS 2004 doi The in vitro effects of CRE-decoy oligonucleotides in combination with conventional chemotherapy in colorectal cancer cell lines Wai M. Liu Katherine A. Scott Sipra Shahin and David J. Propper New Drug Study Group Barry Reed Oncology Laboratory St. Bartholomew s Hospital London UK The cAMP response element consensus sequence directs the transcription of a wide range of genes. A 24-mer singlestranded cAMP response element decoy oligonucleotide CDO has been shown to compete with these sequences for binding transcription factors and therefore interferes with cAMP-induced gene transcription. We have examined the effect of this CDO alone and in comhinaiion with a range of common chemotherapeutic agents in colorectal cancer cell lines. CDOhad a potent anti-proliferative effect in colorectal cell lines yet a similar enhancement of cell death was not observed. Simple drug-drug interaction studies showed that combining CDOwith chemotherapy resulted in an enhancement of the antiproliferative effects. Furthermore this cytostatic effect was protracted and associated with an increase in senescence-associated b-galactosidase activity at pH 6. There is a possible role for p21waf1 in mediating this effect as the enhancement of cell growth inhibition was not observed in cells lacking the ability to correctly upregulate this protein. Additionally significant decreases in cyclin-dependent kinase CDK 1 and CDK 4 function were seen in the responsive cells. These data provide a possible model of drug interaction in colorectal cell lines which involves the complex interplay of the molecules regulating the cell cycle. Clinically the cytostatic ability of CDOcould improve and enhance the antiproliferative effects of conventional cytotoxic agents. Keywords cAMP response element colorectal cancer oligonucleotide decoy factors synergy. The regulation of transcription by using short sequence oligonucleotides has