Antisense anti-MDM2 mixed-backbone oligonucleotides enhance therapeutic efficacy of topoisomerase I inhibitor irinotecan in nude mice bearing human cancer xenografts: In vivo activity and mechanisms.
Antisense oligonucleotides have been investigated as anticancer agents administered alone or in combination with conventional chemotherapeutics. In the present study, we demonstrated synergistic effects between anti-MDM2 antisense oligonucleotides and the clinically used anticancer agent irinotecan, using nude mouse models of human colon cancers (LS174T and DLD-1). Surprisingly, a 5-base mismatch oligonucleotide also showed similar effects. To elucidate the underlying mechanisms, in vitro and in vivo pharmacokinetic and pharmacodynamic studies were performed. In LS174T cells, the antisense oligonucleotide, but not the mismatch oligonucleotide, specifically inhibited MDM2 expression, resulting in a significant increase in irinotecan-associated p53 activation and p21 induction. In DLD-1 cells, the antisense oligonucleotide specifically inhibited MDM2 expression, resulting in a significant increase in irinotecan-associated p21 induction although mutant p53 levels remained unchanged. Both oligonucleotides increased tissue uptake of irinotecan and the conversion of irinotecan to its active metabolite SN-38. These results suggest that oligonucleotides have a role in irinotecan metabolism and action, providing a basis for future development of antisense oligonucleotides as a sensitizer for irinotecan-based therapy.
Wang
Hui
H
Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Wang
Shuyi
S
Nan
Li
L
Yu
Dong
D
Agrawal
Sudhir
S
Zhang
Ruiwen
R
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D002166:Camptothecin