Abstract:
PURPOSE:We investigated whether a 5-fluorouracil (5-FU)-resistant tumor could regain chemosensitivity after the administration of 5-aza-2'-deoxycytidine (DAC) as a demethylating agent. METHODS:Human colorectal cancer cells (SW48) are characterized by the hypermethylation of proapoptotic genes. They were transplanted into 20 athymic BALB/c nu/nu mice which were randomly placed into 4 groups (1 = control; 2 = 5-FU alone; 3 = DAC alone; 4 = DAC followed by 5-FU). We evaluated the synergistic effect of DAC and 5-FU on the growth of these xenografts. Reactivation of proapoptotic genes in these cells was analyzed by methylation-specific PCR. Gene expression was determined by a quantitative reverse-transcription PCR assay. RESULTS:Compared with the control group, relative tumor volumes were statistically significantly decreased only in group 4 mice (p = 0.006). In groups 3 and 4, p14, p16 and death-associated protein kinase (DAPK) promoter regions were demethylated and p14 gene expression was gradually increased after DAC administration. CONCLUSION:DAC could be a useful medicine that breaks the silencing of various genes and recovers some expressions. By pretreating with DAC at a nontoxic level, we confirmed the restoration of 5-FU chemosensitivity and apoptosis induction. The combination of demethylating agents and several cytotoxic drugs has potential in clinical practice.
journal_name
Oncologyjournal_title
Oncologyauthors
Morita S,Iida S,Kato K,Takagi Y,Uetake H,Sugihara Kdoi
10.1159/000107110subject
Has Abstractpub_date
2006-01-01 00:00:00pages
437-45issue
5-6eissn
0030-2414issn
1423-0232pii
000107110journal_volume
71pub_type
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