Dose and regimen effects of poly ICLC, an interferon inducer, in a multi-dose bleomycin model of interstitial pulmonary fibrosis.
The antifibrotic effects of an interferon inducer, polyinosinic-polycytidylic acid complexed with poly-L-lysine (poly ICLC), was evaluated in a bleomycin-hamster model of pulmonary fibrosis. Hamsters received three consecutive intratracheal doses of bleomycin (2.5, 2.0, and 1.5 U/kg/5 ml) or saline at weekly intervals. Poly ICLC at three doses (0.5, 1.0, and 1.5 mg/kg body weight) or saline was injected intraperitoneally by daily and semiweekly regimens for four weeks, and animals were sacrificed at five weeks. In both the daily and semiweekly poly ICLC regimens, hamsters receiving bleomycin plus poly ICLC demonstrated increased mortality and decreased weight gain compared to the vehicle and bleomycin control groups. The groups receiving bleomycin plus daily poly ICLC demonstrated poly ICLC-dose related effects for weight changes, lung hydroxyproline and lung prolyl hydroxylase activity. Depending on the poly ICLC dose, bleomycin plus daily poly ICLC produced significantly decreased hydroxyproline or significantly increased hydroxyproline and prolyl hydroxylase activity compared to the bleomycin control group. In contrast, the groups receiving bleomycin plus semiweekly poly ICLC did not demonstrate poly ICLC-dose related effects or significant differences from the bleomycin control group for any of the biochemical assays performed. The results of this study indicate that, depending on dose and regimen, poly ICLC can reduce collagen accumulation or produce a synergistic toxicity when administered with multiple doses of bleomycin. The toxic effects may restrict the therapeutic potential of poly ICLC in combination with bleomycin for anticancer therapy.
Wild
J S
JS
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis 95616.
Hyde
D M
DM
Giri
S N
SN
D000818:Animals; D001761:Bleomycin; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006909:Hydroxyproline / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007369:Interferon Inducers / Q000008:administration & dosage / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology*; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000378:metabolism; D015430:Weight Gain
D007369:Interferon Inducers; D001761:Bleomycin; D011107:Polylysine; C019531:poly ICLC; D011393:Procollagen-Proline Dioxygenase; D013482:Superoxide Dismutase; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C; D006909:Hydroxyproline