title: Enhanced antitumor efficacy of cisplatin by tirapazamine-transferrin conjugate.
abstract: Combination of tirapazamine (TPZ) with cisplatin has been studied extensively in clinical trial for tumor therapy. However, in phase III clinical trial, the combination therapy did not show overall survival improvement in patients. To decrease the side effects and increase the efficacy of the combination therapy, TPZ was conjugated with transferrin (Tf-G-TPZ) for targeted delivery and co-administered with cisplatin. In vitro toxicity study showed that the combination of Tf-G-TPZ with cisplatin induced substantially higher cytotoxicity of tumor cells than the combination of TPZ and cisplatin. After Tf-G-TPZ was intravenously injected into tumor-bearing mice, its total accumulation in tumor was 2.3 fold higher than that of the unmodified TPZ, suggesting transferrin-mediated target delivery of TPZ into the tumor tissue. With the increased accumulation of Tf-G-TPZ in tumor, the synergistic anti-tumor effects of Tf-G-TPZ and cisplatin were also enhanced as showed by the 53% tumor inhibition rate. Meanwhile, the side effects such as body weight lost were not significantly increased. Therefore, Tf-G-TPZ holds great promise to a better substitute for TPZ in the combination therapy with cisplatin.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Tang
authors.forename: Yanan
authors.initials: Y
authors.lastname: Du
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077704:Tirapazamine; D014168:Transferrin / Q000008:administration & dosage / Q000737:chemistry; D014227:Triazines / Q000008:administration & dosage / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D014168:Transferrin; D014227:Triazines; D000077704:Tirapazamine; D002945:Cisplatin