title: Peloruside A Inhibits Growth of Human Lung and Breast Tumor Xenografts in an Athymic nu/nu Mouse Model.
abstract: Peloruside A is a microtubule-stabilizing agent isolated from a New Zealand marine sponge. Peloruside prevents growth of a panel of cancer cell lines at low nanomolar concentrations, including cell lines that are resistant to paclitaxel. Three xenograft studies in athymic nu/nu mice were performed to assess the efficacy of peloruside compared with standard anticancer agents such as paclitaxel, docetaxel, and doxorubicin. The first study examined the effect of 5 and 10 mg/kg peloruside (QD×5) on the growth of H460 non-small cell lung cancer xenografts. Peloruside caused tumor growth inhibition (%TGI) of 84% and 95%, respectively, whereas standard treatments with paclitaxel (8 mg/kg, QD×5) and docetaxel (6.3 mg/kg, Q2D×3) were much less effective (%TGI of 50% and 18%, respectively). In a second xenograft study using A549 lung cancer cells and varied schedules of dosing, activity of peloruside was again superior compared with the taxanes with inhibitions ranging from 51% to 74%, compared with 44% and 50% for the two taxanes. A third xenograft study in a P-glycoprotein-overexpressing NCI/ADR-RES breast tumor model showed that peloruside was better tolerated than either doxorubicin or paclitaxel. We conclude that peloruside is highly effective in preventing the growth of lung and P-glycoprotein-overexpressing breast tumors in vivo and that further therapeutic development is warranted. Mol Cancer Ther; 14(8); 1816-23. ©2015 AACR.
authors.affiliation: Reata Pharmaceuticals, Inc., Irving, Texas.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
authors.affiliation: Reata Pharmaceuticals, Inc., Irving, Texas.
authors.forename: Melissa
authors.initials: M
authors.lastname: Krauth
authors.affiliation: CTRC Institute for Drug Development, San Antonio, Texas.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wick
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Ginelle
authors.initials: G
authors.lastname: Gellert
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jef K
authors.initials: JK
authors.lastname: De Brabander
authors.affiliation: School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Northcote
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand. john.h.miller@vuw.ac.nz.
authors.forename: John H
authors.initials: JH
authors.lastname: Miller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007783:Lactones; D043823:Taxoids; C414085:peloruside A; D000077143:Docetaxel; D017239:Paclitaxel