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Growth inhibition of pancreatic tumor cells by modified antisense oligodeoxynucleotides
A Fiedler1, C Knorre, Y Franke
1Research Unit for Molecular Oncology, Clinic for General and Thoracic Surgery, Christian-Albrechts-University, Kiel, Germany.
Introduction:
Pancreatic adenocarcinomas are largely resistant to apoptosis. More than 50% of pancreatic tumors reveal mutations in the p53 tumor suppressor gene.
Methods:
We investigated the growth of pancreatic tumor cells after downregulation of p53 protein expression by antisense oligodeoxynucleotides.
Results:
Proliferation and p53 expression of PancTu-I cells overexpressing mutant p53 protein were inhibited by antisense oligodeoxynucleotide treatment. When analyzed, two of three other pancreatic tumor cell lines with mutated p53 were also inhibited in their growth. Two of two wild-type (wt) p53 pancreatic tumor cells were not significantly influenced by p53 expression and were, only to a lesser extent, affected in their proliferation. K562 cells (lacking p53 mRNA) and normal human skin fibroblasts used as a target mismatch control showed no changes in proliferation rates with treatment. The different biological effects in the various cells were not caused by differences in the uptake of the oligodeoxynucleotides as monitored by confocal laser-scanning microscopy.
Conclusions:
Truncation and 5'- and 3'-lipophilic modifications of the oligodeoxynucleotides drastically enhanced the growth inhibition of PancTu-I cells, which were resistant to apoptosis-inducing agents. Furthermore, a higher sequence-specificity of the observed effects was achieved with these compounds.
Insights
Downregulating p53 protein expression using antisense oligodeoxynucleotides inhibited pancreatic tumor cell growth, particularly in cells with mutated p53. Modified oligodeoxynucleotides enhanced this effect.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Pancreatic adenocarcinomas exhibit significant resistance to apoptosis.
- Over 50% of pancreatic tumors harbor mutations in the p53 tumor suppressor gene.
Purpose of the Study:
- To investigate the impact of p53 protein downregulation on pancreatic tumor cell growth.
- To evaluate the efficacy of antisense oligodeoxynucleotides in targeting p53 in pancreatic cancer.
Main Methods:
- Utilized antisense oligodeoxynucleotides to downregulate p53 protein expression in pancreatic tumor cell lines.
- Assessed cell proliferation and p53 expression levels.
- Employed confocal laser-scanning microscopy to monitor oligodeoxynucleotide uptake.
Main Results:
- Antisense oligodeoxynucleotide treatment inhibited proliferation and p53 expression in PancTu-I cells with mutant p53.
- Growth inhibition was observed in two of three other pancreatic tumor cell lines with mutated p53.
- Wild-type p53 pancreatic tumor cells showed less significant effects on proliferation.
- Control cells (K562, fibroblasts) exhibited no changes in proliferation.
Conclusions:
- Modified oligodeoxynucleotides (truncated, lipophilic) significantly enhanced growth inhibition in PancTu-I cells resistant to apoptosis.
- These modifications also improved the sequence-specificity of the observed anti-cancer effects.