title: GTI-2501, an antisense agent targeting R1, the large subunit of human ribonucleotide reductase, shows potent anti-tumor activity against a variety of tumors.
abstract: GTI-2501 is a 20-mer oligonucleotide that is complementary to a coding region in the mRNA of R1, the large subunit of ribonucleotide reductase (RNR). In vitro studies, have demonstrated that GTI-2501 decreases mRNA and protein levels of R1 in a sequence-specific and dose-dependent manner. Furthermore, GTI-2501 inhibits the growth of human lung, liver, ovary, brain, melanoma, breast and pancreatic tumor cells in colony forming assays. In vivo studies have shown that GTI-2501 significantly inhibits growth of human colon, pancreas, lung, breast, renal, ovarian, melanoma, brain glioblastoma-astrocytoma, and prostatic tumors in CD-1 nude, Balb/c nude and/or SCID mice. GTI-2501 treatment caused total regression of human breast and renal tumor xenografts in mice. These effects are not observed with a scrambled control oligonucleotide containing the same base content but not complementary to R1. GTI-2501 specifically inhibits metastasis of human melanoma cells to the lungs in CD-1 athymic nude mice and prolongs the survival of mice bearing human lymphoma. Taken together these results suggest that an antisense mechanism of action is responsible for growth inhibition in vitro and in vivo and that GTI-2501 can act as a selective and specific anti-tumor agent.
authors.affiliation: Lorus Therapeutics Inc., Ontario, M9W 4Z7, Canada. ylee@lorusthera.com
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: Hongnan
authors.initials: H
authors.lastname: Jin
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.forename: Keyong
authors.initials: K
authors.lastname: Xiong
authors.forename: Jim
authors.initials: J
authors.lastname: Wright
authors.forename: Aiping
authors.initials: A
authors.lastname: Young
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C464618:GTI2501; D012264:Ribonucleotide Reductases