title: Phase 1, randomized, double-blind trial of 7-allyl-8-oxoguanosine (loxoribine) in advanced cancer.
abstract: Guanine ribonucleosides substituted at the 8 position of the guanine ring are a unique class of immunomodulators, the lead compound of which is 7-allyl-8-oxoguanosine (loxoribine). We conducted a double-blind randomized phase I study to evaluate the safety, pharmacokinetics, and immunologic effects of single ascending doses of loxoribine in patients with advanced cancer. Twenty-four patients were treated in three dose tiers of 8 patients each, utilizing a unique statistical design, so that within each group, patients were randomized in blocks of 4 to receive loxoribine initially and then placebo 4 weeks later--a sequence that was reversed in the remaining 4 patients. In 23 courses of loxoribine and 20 courses of placebo, toxicity was mild and infrequent at all dose tiers (1 mg/kg, 5 mg/kg and 10 mg/kg. Both antibody-dependent cellular cytotoxicity and lymphokine-activated killer cytotoxicity were transiently depressed following loxoribine administration at all doses. Loxoribine is safe at doses up to 10 mg/kg in patients with advanced cancer, and produces modest immunologic effects. Further testing, particularly in conjunction with other immunologic agents, is warranted.
authors.affiliation: University of Pittsburgh Cancer Institute, PA, USA. Agarwala@msx.upmc.edu
authors.forename: S S
authors.initials: SS
authors.lastname: Agarwala
authors.forename: J M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: J
authors.initials: J
authors.lastname: Bryant
mesh_terms: D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D006151:Guanosine; C068562:loxoribine