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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / toxicity*
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Body Weight / drug effects
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Camptothecin / administration & dosage
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Camptothecin / analogs & derivatives*
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / genetics
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Dose-Response Relationship, Drug
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Drug Synergism
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Female
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Humans
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Irinotecan
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Male
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism*
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Oligonucleotides / administration & dosage
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Oligonucleotides, Antisense / therapeutic use*
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Survival Rate
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Tissue Distribution
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Treatment Outcome
Substances
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GEM231
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Oligonucleotides
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Oligonucleotides, Antisense
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Irinotecan
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Cyclic AMP-Dependent Protein Kinases
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Camptothecin