639 POSTER RTA 301 (peloruside): a novel microtubule stabilizer with potent in vivo activity against lung cancer and resistant breast cancer

Meyer, Craig S.; Ferguson, Donald J.; Krauth, Melissa; Wick, M.J.; Northcote, Peter T.

doi:10.1016/s1359-6349(06)70644-9

Cited by 16 publications

(13 citation statements)

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“…This was seen in an in vivo study using a mouse model of multiple sclerosis in which significant mortality was seen with Ptx but not with Pel [26]. Also, in an unpublished study in mice that compared anti-tumour action of Pel and Ptx at their maximum tolerated dose, Pel was better tolerated than Ptx or docetaxel [27].…”

Section: Unique Proteomic Changes In Response To Pel Compared To Ptxmentioning

confidence: 92%

Paclitaxel effects on the proteome of HL-60 promyelocytic leukemic cells: comparison to peloruside A

et al. 2010

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Paclitaxel (Taxol®), a drug used to treat solid tumors of the breast, ovary and lung, stabilizes microtubules and arrests cells in G(2)/M of the cell cycle. Using two-dimensional differential in-gel electrophoresis (DIGE), we examined the proteomic response of a human HL-60 promyeloid leukemic cell line to paclitaxel. Our intention was to compare the effects of paclitaxel to those of a new-generation microtubule-stabilizing agent, peloruside A, investigated in an earlier study. In response to 100 nM paclitaxel treatment for 24 h, 21 identified proteins changed in abundance, with 13 increases and 8 decreases. In addition, 21 other unidentified proteins were also changed by treatment with paclitaxel. Using Western blotting, the transcription factor c-Myc was shown to be reduced in abundance by both drugs. Our results showed both differences and similarities at the single protein level between paclitaxel and peloruside A, although the same general classes of proteins: cytoskeletal, nucleic acid binding, stress, and apoptotic proteins, changed following exposure. The proteomic response to paclitaxel was more extensive than the response to an equipotent dose of peloruside A.

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Section: Unique Proteomic Changes In Response To Pel Compared To Ptxmentioning

confidence: 92%

Paclitaxel effects on the proteome of HL-60 promyelocytic leukemic cells: comparison to peloruside A

et al. 2010

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“…The tolerability and in vivo efficacy of peloruside A in xenograft models of non-small cell lung cancer and Pgp-expressing breast cancer was presented at the Molecular Targets meeting in 2004 97. Reata Pharmaceuticals licensed the rights to peloruside A (RTA 301) in 2005 as a member of their preclinical development program 98.…”

Section: Microtubule Stabilizersmentioning

confidence: 99%

Microtubule dynamics as a target in oncology

Risinger

Giles

Mooberry

2009

Cancer Treatment Reviews

222

197

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Drugs that affect microtubule dynamics, including the taxanes and vinca alkaloids, have been a mainstay in the treatment of leukemias and solid tumors for decades. New, more effective microtubule-targeting agents continue to enter into clinical trials and some, including the epothilone ixapebilone, have been approved for use. In contrast, several other drugs of this class with promising preclinical data were later shown to be ineffective or intolerable in animal models or clinical trials. In this review we discuss the molecular mechanisms as well as preclinical and clinical results for a variety of microtubule-targeting agents in various stages of development. We also offer a frank discussion of which microtubule-targeting agents are amenable to further development based on their availability, efficacy and toxic profile.

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“…PelA is also less sensitive to multi‐drug resistance than paclitaxel (Gaitanos et al. , 2004) and is better tolerated by mice than paclitaxel at high doses (Meyer et al. , 2006; Crume et al.…”

Section: Introductionmentioning

confidence: 99%

Microtubule stabilization by peloruside A and paclitaxel rescues degenerating neurons from okadaic acid‐induced tau phosphorylation

Das

Miller

2012

Eur J of Neuroscience

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Many cellular organelles must travel long distances in neurons to perform their specific functions, and this transport is highly dependent on the microtubule network within the axon. Hyperphosphorylation of microtubule-associated tau protein destabilizes microtubules and leads to neuronal cell death. This destabilization can be corrected in part by treatment with microtubule-stabilizing drugs such as paclitaxel and epothilone. The phosphatase inhibitor okadaic acid inhibits the outgrowth of neurites in neuronal cell cultures by hyperphosphorylating tau protein. In this study using neuronal cultures derived from the cerebral cortex of early postnatal Sprague-Dawley rats, we examined whether stabilization of microtubules by peloruside A, a microtubule-stabilizing agent that binds to a different site on β-tubulin from paclitaxel, could counter the deleterious effects of 8 h exposure to 15 nm okadaic acid. Peloruside A reversed the decrease in axonal outgrowth and branching seen in neuronal cultures treated with okadaic acid and rescued neurons from growth cone collapse. Although peloruside A had no effect on the hyperphosphorylation of tau caused by okadaic acid, it restored the levels of acetylated tubulin, a marker of stable microtubules, and reversed the okadaic acid-induced depression of growth-associated protein-43, an axonal growth regulator. Thus, microtubule-stabilizing drugs show promise as new therapeutic agents for treating damaged microtubule networks characteristic of neurodegenerative disease.

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639 POSTER RTA 301 (peloruside): a novel microtubule stabilizer with potent in vivo activity against lung cancer and resistant breast cancer

Cited by 16 publications

References 0 publications

Paclitaxel effects on the proteome of HL-60 promyelocytic leukemic cells: comparison to peloruside A

Paclitaxel effects on the proteome of HL-60 promyelocytic leukemic cells: comparison to peloruside A

Microtubule dynamics as a target in oncology

Microtubule stabilization by peloruside A and paclitaxel rescues degenerating neurons from okadaic acid‐induced tau phosphorylation

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