Antisense oligonucleotide targeted to RIalpha subunit of cAMP-dependent protein kinase (GEM231) enhances therapeutic effectiveness of cancer chemotherapeutic agent irinotecan in nude mice bearing human cancer xenografts: in vivo synergistic activity, pharmacokinetics and host toxicity.

Abstract

The RIalpha-subunit of cAMP-dependent protein kinase (PKA) is overexpressed in various human cancers and PKA has been suggested to be a potential target for cancer therapy. We have shown an antisense oligonucleotide with advanced chemistry (mixed-backbone oligonucleotide) targeted to PKA RIalpha-subunit (GEM231) to have anti-tumor activity in vitro and in vivo. In the present study, we demonstrated synergistic effects between the anti-PKA antisense oligonucleotide and the clinically used anticancer agent irinotecan, using nude mouse models of human cancers of colon (LS174T and DLD-1), breast (MCF-7), prostate (DU-145 and PC-3) and lung (H1299). To elucidate the underlying mechanisms, in vivo pharmacokinetics of irinotecan was determined following pre-treatment of oligo GEM 231 in CD-1 mice and nude mice bearing LS174T xenografts. GEM 231 increased tissue uptake of irinotecan. However, no significant change in host toxicity was observed following combination treatment of irinotecan and GEM231 compared with irinotecan alone. These results suggest that GEM231 have a role in irinotecan metabolism and its antitumor activity, providing a basis for future development of this oligonucleotide as a chemosensitizer for irinotecan-based therapy.

• Authors: Hui Wang, Jie Hang, Zhenqi Shi, Mao Li, Dong Yu, Ekambar R Kandimalla, Sudhir Agrawal, Ruiwen Zhang
• Journal: International journal of oncology (Int J Oncol) Vol. 21 Issue 1 Pg. 73-80 (Jul 2002) ISSN: 1019-6439 [Print] Greece
• PMID: 12063552 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• GEM231
• Oligonucleotides
• Oligonucleotides, Antisense
• Irinotecan
• Cyclic AMP-Dependent Protein Kinases
• Camptothecin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, therapeutic use, toxicity)
• Body Weight (drug effects)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Camptothecin (administration & dosage, analogs & derivatives)
• Colonic Neoplasms (drug therapy, genetics, metabolism)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, genetics)
• Dose-Response Relationship, Drug
• Drug Synergism
• Female
• Humans
• Irinotecan
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy, genetics, metabolism)
• Oligonucleotides (administration & dosage)
• Oligonucleotides, Antisense (therapeutic use)
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• Survival Rate
• Tissue Distribution
• Treatment Outcome