title: The use of Tris-lipidation to modify drug cytotoxicity in multidrug resistant cells expressing P-glycoprotein or MRP1.
abstract: 1. Increasing the lipophilicity is a strategy often used to improve a compound's cellular uptake and retention but this may also convert it into a substrate for an ATP-dependent transporter such as P-glycoprotein or the multidrug resistance-associated protein (MRP1), which are involved in cellular efflux of drugs. Tris-Lipidation of compounds is a convenient way of modifying drug lipophilicity and generating an array of derivatives with diverse properties. 2. To determine the effect of Tris-Lipidation on a drug's cytoxicity in multidrug resistant cells, various glycyl-Tris-mono- (GTP1), di- (GTP2) and tri-palmitate (GTP3) derivatives were prepared of the cancer chemotherapeutic drugs chlorambucil and methotrexate, and of the anti-HIV drug AZT. The cytotoxicity of these derivatives and their parent compounds was determined in the CEM/VLB(100) cells with increased P-glycoprotein expression, the CEM/E1000 cells that overexpress MRP1 and the parent, drug-sensitive CCRF-CEM cells. 3. Increasing the lipophilicity of AZT increased its cytotoxicity in the sensitive CCRF-CEM parental cell line while decreased cytotoxicity was observed for the methotrexate derivatives. For the chlorambucil derivatives, both increased (GTP1) and decreased (GTP2) cytotoxicity occurred in the CCRF-CEM cells. With the exception of AZT-GTP1, all GTP1 and GTP2 derivatives of chlorambucil, methotrexate and AZT had decreased cytotoxicity in the P-glycoprotein-expressing CEM/VLB(100) cells while chlorambucil-GTP1, methotrexate-GTP2 and methotrexate-GTP3 were the only compounds with decreased cytotoxicity in the MRP1-overexpressing CEM/E1000 cells. 4. The number of palmitate residues, the position of derivatisation and the type of linkage all may affect the P-glycoprotein and MRP1 substrate properties. 5. Tris-Lipidation may therefore provide a useful way of manipulating the pharmacokinetic properties of drugs.
authors.affiliation: Bill Walsh Cancer Research Laboratories, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. rdavey@med.usyd.edu.au
authors.forename: Ross A
authors.initials: RA
authors.lastname: Davey
authors.forename: Mary W
authors.initials: MW
authors.lastname: Davey
authors.forename: Karen V
authors.initials: KV
authors.lastname: Cullen
authors.forename: Xanthe E
authors.initials: XE
authors.lastname: Wells
authors.forename: Craig L
authors.initials: CL
authors.lastname: Francis
authors.forename: Hua-Ming
authors.initials: HM
authors.lastname: Williams
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Minoo J
authors.initials: MJ
authors.lastname: Moghaddam
authors.forename: Fred
authors.initials: F
authors.lastname: Widmer
authors.forename: Robert G
authors.initials: RG
authors.lastname: Whittaker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002021:Buffers; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000502:physiology*; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis*; D014325:Tromethamine / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002021:Buffers; D008055:Lipids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014325:Tromethamine; C421109:multidrug resistance-associated protein 1