title: 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.affiliation: Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Hang
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Shi
authors.forename: Mao
authors.initials: M
authors.lastname: Li
authors.forename: Dong
authors.initials: D
authors.lastname: Yu
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.forename: Sudhir
authors.initials: S
authors.lastname: Agrawal
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000008:administration & dosage; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: C425328:GEM231; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D000077146:Irinotecan; D017868:Cyclic AMP-Dependent Protein Kinases; D002166:Camptothecin