title: TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells.
abstract: Brain metastases of breast and other cancers remain resistant to chemotherapeutic regimens that are effective systemically, in part due to the blood-brain barrier. We report that TPI-287, a new microtubule-stabilizing agent, displays in vitro cytotoxic activity similar to taxanes and epothilones. Unlike the taxanes, TPI-287 is permeable through the blood-brain barrier. Brain-to-plasma ratios of TPI-287 after a single injection typically exceeded one and were as high as 63.8 in the rat and 14.1 in the mouse. A brain-tropic derivative of the MDA-MB-231 triple-negative breast cancer cell line, 231-BR, was used to test whether TPI-287 may be efficacious at preventing or treating brain metastases. TPI-287 had growth inhibitory effects comparable with paclitaxel when 231-BR tumor cells were injected into the mammary fat pad. Brain metastatic colonization was determined by intracardiac injection of 231-BR cells, with treatment beginning on day 3 to 4 postinjection, culminating in a histologic count of brain metastases in brains necropsied days 25 to 28 postinjection. In this assay, paclitaxel, ixabepilone, and nab paclitaxel did not have significant inhibitory activity. TPI-287 was ineffective in the same assay using a 6 mg/kg every week schedule; however an 18 mg/kg dose delivered on days 3, 7, and 11 significantly reduced the outgrowth of brain metastases (55% reduction, P = 0.028) and reduced proliferation in brain metastases (16% reduction, P = 0.008). When TPI-287 treatment was delayed until days 18, 22, and 26 postinjection, efficacy was reduced (17% reduction, not significant). These data suggest that TPI-287 may have efficacy when administered early in the course of the disease.
authors.affiliation: Women's Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Fitzgerald
authors.forename: David L
authors.initials: DL
authors.lastname: Emerson
authors.forename: Yongzhen
authors.initials: Y
authors.lastname: Qian
authors.forename: Talha
authors.initials: T
authors.lastname: Anwar
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Sandra
authors.initials: S
authors.lastname: Silberman
authors.forename: Diane
authors.initials: D
authors.lastname: Palmieri
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D051381:Rats; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014018:Tissue Distribution; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C578069:TPI-287; D043823:Taxoids; D050257:Tubulin Modulators