title: In vitro and in vivo characterization of a combination chemotherapy formulation consisting of vinorelbine and phosphatidylserine.
abstract: The purpose of these studies was to design an intravenous drug formulation consisting of two active agents having synergistic in vitro activity. Specifically, we describe a novel drug combination consisting of a cytotoxic agent (vinorelbine) with an apoptosis-inducing lipid (phosphatidylserine, PS). In vitro cytotoxicity screening of PS and vinorelbine, alone and in combination, against human MDA435/LCC6 breast cancer and H460 lung cancer cells was used to identify the molar ratio of these two agents required for synergistic activity. PS and vinorelbine were co-formulated in a lipid-based system at the synergistic molar ratio and the pharmacokinetic and antitumor characteristics of the combination assessed in mice bearing H460 tumors. The cytotoxicity of the lipid, and the synergy between the lipid and vinorelbine, were specific to PS; these effects were not observed using control lipids. A novel formulation of PS, incorporated as a membrane component in liposomes, and encapsulating vinorelbine using a pH gradient based loading method was developed. The PS to vinorelbine ratio in this formulation was 1/1, a ratio that produced synergistic in vitro cytotoxicity over a broad concentration range. The vinorelbine and PS dual-agent treatment significantly delayed the growth of subcutaneous human H460 xenograft tumors in Rag2M mice compared to the same dose of free vinorelbine given alone or given as a cocktail of the free vinorelbine simultaneously with empty PS-containing liposomes. These studies demonstrate the potential to develop clinically relevant drug combinations identified using in vitro drug-drug interactions combined with lipid-based delivery systems to co-formulate drugs at their synergistic ratios.
authors.affiliation: Celator Pharmaceuticals Inc., Vancouver, BC, Canada. mwebb@bccrc.ca
authors.forename: Murray S
authors.initials: MS
authors.lastname: Webb
authors.forename: Sharon
authors.initials: S
authors.lastname: Johnstone
authors.forename: Tara J
authors.initials: TJ
authors.lastname: Morris
authors.forename: Allison
authors.initials: A
authors.lastname: Kennedy
authors.forename: Ryan
authors.initials: R
authors.lastname: Gallagher
authors.forename: Natashia
authors.initials: N
authors.lastname: Harasym
authors.forename: Troy
authors.initials: T
authors.lastname: Harasym
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Shew
authors.forename: Paul
authors.initials: P
authors.lastname: Tardi
authors.forename: Wieslawa H
authors.initials: WH
authors.lastname: Dragowska
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Mayer
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D015195:Drug Design; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010718:Phosphatidylserines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D013678:Technology, Pharmaceutical; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D010718:Phosphatidylserines; D014747:Vinblastine; D000077235:Vinorelbine