title: GTI-2040, an antisense agent targeting the small subunit component (R2) of human ribonucleotide reductase, shows potent antitumor activity against a variety of tumors.
abstract: GTI-2040 is a 20-mer oligonucleotide that is complementary to a coding region in the mRNA of the R2 small subunit component of human ribonucleotide reductase. In vitro studies using a number of human tumor cell lines have demonstrated that GTI-2040 decreases mRNA and protein levels of R2 in a sequence- and target-specific manner. In vivo studies have shown that GTI-2040 significantly inhibits growth of human colon tumors (adenocarcinoma), pancreatic tumors (adenocarcinoma), liver tumors, lung tumors, breast tumors (adenocarcinoma), renal tumors, ovarian tumors (adenocarcinoma), melanoma, brain glioblastoma-astrocytoma, prostatic tumors, and cervical tumors in nude and/or severe combined immunodeficient mice. Antitumor effects were not observed with an oligonucleotide containing four mismatches to the R2 sequence or with a scrambled sequence containing the same base content but not complementary to R2. This suggests that an antisense mechanism is responsible for the in vivo observations. In addition to tumor growth assays, GTI-2040 was tested in a murine model of human lymphoma. Treatment of severe combined immunodeficient mice bearing Burkitt's lymphoma with GTI-2040, but not control oligonucleotides, greatly extended the survival of mice, and survival extended well beyond the treatment period. Finally, GTI-2040 specifically inhibits metastasis of human melanoma cells to the lungs in nude mice. Taken together, the results of these studies indicate that GTI-2040 can act as a selective and specific anticancer agent against a broad range of human tumors.
authors.affiliation: Lorus Therapeutics Inc, Toronto, Ontario, M9W 4Z7 Canada.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Lee
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Vassilakos
authors.forename: Ningping
authors.initials: N
authors.lastname: Feng
authors.forename: Viengthong
authors.initials: V
authors.lastname: Lam
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Xie
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.forename: Hongnan
authors.initials: H
authors.lastname: Jin
authors.forename: Keyong
authors.initials: K
authors.lastname: Xiong
authors.forename: Chenyi
authors.initials: C
authors.lastname: Liu
authors.forename: Jim
authors.initials: J
authors.lastname: Wright
authors.forename: Aiping
authors.initials: A
authors.lastname: Young
mesh_terms: D000818:Animals; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D018899:CpG Islands / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C464617:GTI2040; D012264:Ribonucleotide Reductases; C108427:ribonucleotide reductase R2 subunit