title: Enhanced therapeutic efficacy of a novel liposome-based formulation of SN-38 against human tumor models in SCID mice.
abstract: SN-38 is an active metabolite of CPT-11. The poor solubility of SN-38 in any pharmaceutically acceptable solvent and pH-dependent activity has limited its clinical use. Our objective was to evaluate an easy-to-use liposome-based formulation of SN-38 (LE-SN38) and compare the antitumor activity with its pro-drug CPT-11 against cancer cell lines and human xenograft tumor models. The cytotoxicity of LE-SN38 and CPT-11 was determined in four human cancer cell lines using the sulforhodamine B assay. The therapeutic efficacy was tested against human colon (HT-29) and breast (MX-1) xenograft tumor models in SCID mice. LE-SN38 with greater than 95% drug entrapment was found to be highly cytotoxic against four different cell lines with GI50 values of less than 0.1 microM. In the HT-29 tumor model, LE-SN38 (q x d5) at 2, 4 or 8 mg/kg resulted in 33, 81 and 91% tumor growth inhibition, respectively, compared to the drug-free liposome group. In contrast, similar dose levels of CPT-11 treatment led to only 2, 36 and 46% growth inhibition. For the MX-1 model, LE-SN38 (q x d5) regressed tumor growth by 44 and 88% at 4 and 8 mg/kg dose, respectively, whereas no regression was observed in the CPT-11-treated group. We conclude that LE-SN38 is a novel liposome-based formulation with enhanced therapeutic efficacy against human tumor models.
authors.affiliation: Research and Development, NeoPharm Inc., Waukegan, IL 60085, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lei
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chien
authors.forename: Saifuddin
authors.initials: S
authors.lastname: Sheikh
authors.forename: Allen
authors.initials: A
authors.lastname: Zhang
authors.forename: Shahid
authors.initials: S
authors.lastname: Ali
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D024803:Biomedical Enhancement / Q000379:methods*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D003110:Colonic Neoplasms / Q000188:drug therapy; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007275:Injections, Intravenous; D000077146:Irinotecan; D008081:Liposomes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D016513:Mice, SCID; D013678:Technology, Pharmaceutical / Q000639:trends; D014183:Transplantation, Heterologous / Q000379:methods; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D000077146:Irinotecan; D002166:Camptothecin