title: Paclitaxel sensitivity in relation to ABCB1 expression, efflux and single nucleotide polymorphisms in ovarian cancer.
abstract: ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells.
authors.affiliation: 1] Department of Gynaecological Oncology, Westmead Hospital [2] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia.
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Russell
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beesley
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Xiao Qing
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Sue
authors.initials: S
authors.lastname: Healey
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Henderson
authors.affiliation: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Wong
authors.affiliation: 1] Department of Gynaecological Oncology, Westmead Hospital [2] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Emmanuel
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Galletta
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Johnatty
authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Australia [2] Sir Peter MacCallum Department of Oncology [3] Department of Pathology, University of Melbourne, Melbourne, Australia [4] Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Bowtell
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Murray
authors.initials: M
authors.lastname: Norris
authors.affiliation: 1] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia [2] Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Harnett
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: 1] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia [2] Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia [3] Pathology West ICPMR Westmead, Sydney, Australia [4].
authors.forename: Rosemary L
authors.initials: RL
authors.lastname: Balleine
authors.affiliation: 1] Department of Gynaecological Oncology, Westmead Hospital [2] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia [3] Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia [4].
authors.forename: Anna
authors.initials: A
authors.lastname: deFazio
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D005838:Genotype; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D017239:Paclitaxel