GEM-231 (Hybridon).
GEM-231 is an 18-mer hybrid oligonucleotide under development by Hybridon for the potential treatment of cancer. This compound was initially developed for colon cancer [256660], and progressed to phase II trials in October 1998 [301009]. Hybridon initiated a phase I dose-escalation study enrolling up to 25 patients with refractory solid tumors, in January 1998 at the Lombardi Cancer Center, Georgetown University Medical Center [275860]. GEM-231 was well tolerated in multiple, escalating doses, and that high plasma levels could be safely achieved [301009]. In addition to antitumor effects, when used as a single agent in animal tumor models, GEM-231 has also demonstrated potentiation of the effects of certain conventional cytotoxic chemotherapy drugs [230699]. Hybridon is conducting studies of the DNA methyltransferase gene and has identified specific sequences on mRNA as targets for chemically-modified antisense oligonucleotides. Hybridon has synthesized compounds that alter methylation of cultured human cancer cells and inhibit their ability to grow in cell culture and inhibit tumor formation in mice [191303]. The work is being carried out in collaboration with McGill University in Montreal and as part of a joint venture called MethylGene, set up by Hybridon and private investors. GEM-231 and other oligonucleotides were claimed in WO- 09515378. Hybridon has been issued with two US patents, US- 05652355 and US-05562356, claiming chemically advanced, mixed-backbone oligonucleotides. The first claims mixed backbone 'hybrid' oligonucleotides, which are second generation chemistries, comprising an internal segment of modified DNA flanked by segments of modified RNA (2'-O-methyl substituted). The other claims mixed backbone 'inverted hybrid' oligonucleotides, which comprises an internal segment of naturally-linked, 2'-O-substituted RNA flanked by modified DNA segments [257135].
Blay
J
J
Dalhousie University, Department of Pharmacology, Faculty of Medicine, Sir Charles Tupper Building, Halifax, Nova Scotia, B3H 4H7, Canada. jblay@is.dal.ca