GROWTH-INHIBITION OF PANCREATIC TUMOR-CELLS BY MODIFIED ANTISENSE OLIGODEOXYNUCLEOTIDES

Introduction: Pancreatic adenocarcinomas are largely resistant to apop tosis. More than 50% of pancreatic tumors reveal mutations in the p53 tumor suppressor gene. Methods: We investigated the growth of pancreat ic tumor cells after downregulation of p53 protein expression by antis ense 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 d ifferences in the uptake of the oligodeoxynucleotides as monitored by confocal laser-scanning microscopy. Conclusions: Truncation and 5'- an d 3'-lipophilic modifications of the oligodeoxynucleotides drastically enhanced the growth inhibition of PancTu-I cells, which were resistan t to apoptosis-inducing agents. Furthermore, a higher sequence-specifi city of the observed effects was achieved with these compounds.