Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RI alpha subunit of protein kinase A after oraladministration

Overexpression of the RI alpha subunit of cAMP-dependent protein kinase (PK A) has been demonstrated in various human cancers. PKA has been suggested a s a potential target for cancer therapy. The goal of the present study was to evaluate an anti-PKA antisense oligonucleotide (mixed-backbone oligonucl eotide) as a therapeutic approach to human cancer treatment. The identified oligonucleotide inhibited the growth of cell lines of human colon cancer ( LS174T. DLD-1). leukemia (HL-60), breast cancer (MCF-7. MDA-MB-468), and lu ng cancer (A549) in a time-, concentration-, and sequence-dependent manner. in a dose-dependent manner, the oligonucleotide displayed in vivo antitumo r activity in severe combined immunodeficient and nude mice bearing xenogra fts of human cancers of the colon (LS174T). breast (MDA-MB-468), and lung ( A549). The routes of drug administration were intraperitoneal and oral. Syn ergistic effects were found when the antisense oligonucleotide was used in combination with the cancer chemotherapeutic agent cisplatin. The pharmacok inetics of the oligonucleotide after oral administration of S-35-labeled ol igonucleotide into tumor-bearing mice indicated an accumulation and retenti on of the oligonucleotide in tumor tissue. This study further provides a ba sis for clinical studies of the antisense oligonucleotide targeted to the R I alpha subunit of PKA (GEM 231) as a cancer therapeutic agent used alone o r in combination with conventional chemotherapy.