Past and future of the mitotic spindle as an oncology target.

Tubulin poisons were first discovered decades ago, but the recent clinical and commercial success of Taxol has led to a renaissance in the search for novel mitotic spindle poisons to treat cancer. Many tubulin poisons have been identified, but few have demonstrated clinical utility. Recent studies have begun to identify the factors that differentiate the efficacy of these agents. In addition, promising alternative approaches to targeting the mitotic spindle have been identified from detailed studies of mitotic regulation and mechanics.

[1]  C. L. Blackburn,et al.  A marine natural product inhibitor of kinesin motors. , 1998, Science.

[2]  R. Benezra,et al.  Mitotic checkpoints: from yeast to cancer. , 2001, Current opinion in genetics & development.

[3]  T. Fojo,et al.  Paclitaxel-resistant Human Ovarian Cancer Cells Have Mutant β-Tubulins That Exhibit Impaired Paclitaxel-driven Polymerization* , 1997, The Journal of Biological Chemistry.

[4]  Xuebiao Yao,et al.  The Microtubule-dependent Motor Centromere–associated Protein E (CENP-E) Is an Integral Component of Kinetochore Corona Fibers That Link Centromeres to Spindle Microtubules , 1997, The Journal of cell biology.

[5]  T. Halazonetis,et al.  Chfr defines a mitotic stress checkpoint that delays entry into metaphase , 2000, Nature.

[6]  P. Schiff,et al.  Promotion of microtubule assembly in vitro by taxol , 1979, Nature.

[7]  D. Brady,et al.  Complex formation between Mad1p, Bub1p and Bub3p is crucial for spindle checkpoint function , 2000, Current Biology.

[8]  R. Flavell,et al.  Double knockout of the MRP gene leads to increased drug sensitivity in vitro. , 1996, Cancer research.

[9]  M. Kirschner,et al.  Dynamic instability of microtubule growth , 1984, Nature.

[10]  David O. Morgan,et al.  Regulation of the APC and the exit from mitosis , 1999, Nature Cell Biology.

[11]  B. Schaar,et al.  CENP-E Function at Kinetochores Is Essential for Chromosome Alignment , 1997, The Journal of cell biology.

[12]  K. Kinzler,et al.  Characterization of MAD2B and other mitotic spindle checkpoint genes. , 1999, Genomics.

[13]  J. McIntosh,et al.  CENP-meta, an Essential Kinetochore Kinesin Required for the Maintenance of Metaphase Chromosome Alignment in Drosophila , 2000, The Journal of cell biology.

[14]  J. Pietenpol,et al.  Defective G1-S cell cycle checkpoint function sensitizes cells to microtubule inhibitor-induced apoptosis. , 1999, Cancer research.

[15]  E. Eisenhauer,et al.  Phase I dose-finding study of a new taxane, RPR 109881A, administered as a one-hour intravenous infusion days 1 and 8 to patients with advanced solid tumors. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  G. Wahl,et al.  DNA rereplication in the presence of mitotic spindle inhibitors in human and mouse fibroblasts lacking either p53 or pRb function. , 1997, Cancer research.

[17]  Y. Sánchez,et al.  Incomplete cytokinesis and induction of apoptosis by overexpression of the mammalian polo-like kinase, Plk3. , 2000, Cancer research.

[18]  R. Medema,et al.  Polo-like kinase-1 is a target of the DNA damage checkpoint , 2000, Nature Cell Biology.

[19]  H. McLeod,et al.  Genomic instability at the BUB1 locus in colorectal cancer, but not in non-small cell lung cancer. , 2000, Cancer research.

[20]  K. Gelmon,et al.  Phase I study of liposomal vincristine. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  A. Murray,et al.  The Xenopus Chromokinesin Xkid Is Essential for Metaphase Chromosome Alignment and Must Be Degraded to Allow Anaphase Chromosome Movement , 2000, Cell.

[22]  A. Riva,et al.  A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts. , 1999, Cancer research.

[23]  M. Zucchetti,et al.  Oral efficacy and bioavailability of a novel taxane. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  S. Nomoto,et al.  Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers. , 2001, Cancer letters.

[25]  P. Schiff,et al.  Taxol stabilizes microtubules in mouse fibroblast cells. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[26]  T. Jacks,et al.  Characterization of the p53-Dependent Postmitotic Checkpoint following Spindle Disruption , 1998, Molecular and Cellular Biology.

[27]  F. Townsley,et al.  Cdc20 associates with the kinase aurora2/Aik. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[28]  S. Barlow,et al.  Elimination of permeability mutants from selections for drug resistance in mammalian cells , 1989, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  G. C. Rogers,et al.  Microtubule motors in mitosis , 2000, Nature.

[30]  G. M. Wilson,et al.  Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. , 1994, Cancer research.

[31]  R J Fletterick,et al.  The design plan of kinesin motors. , 1997, Annual review of cell and developmental biology.

[32]  K. Nicolaou,et al.  The coral-derived natural products eleutherobin and sarcodictyins A and B: effects on the assembly of purified tubulin with and without microtubule-associated proteins and binding at the polymer taxoid site. , 1999, Biochemistry.

[33]  K. Altmann,et al.  Epothilones and related structures--a new class of microtubule inhibitors with potent in vivo antitumor activity. , 2000, Biochimica et biophysica acta.

[34]  T. Mitchison,et al.  Microtubule polymerization dynamics. , 1997, Annual review of cell and developmental biology.

[35]  R. Donehower,et al.  Neurotoxicity of Taxol. , 1993, Journal of the National Cancer Institute. Monographs.

[36]  Xiao-tao Chen,et al.  Structure-activity profiles of eleutherobin analogs and their cross-resistance in Taxol-resistant cell lines , 1999, Cancer Chemotherapy and Pharmacology.

[37]  B. Goldspiel.  Clinical Overview of the Taxanes , 1997, Pharmacotherapy.

[38]  I D Kuntz,et al.  Inhibitors of kinesin activity from structure-based computer screening. , 2000, Biochemistry.

[39]  D. Glover,et al.  Polo-like kinases: a team that plays throughout mitosis. , 1998, Genes & development.

[40]  Yun Zheng,et al.  CENP-E forms a link between attachment of spindle microtubules to kinetochores and the mitotic checkpoint , 2000, Nature Cell Biology.

[41]  F. Barr,et al.  The Rab6‐binding kinesin, Rab6‐KIFL, is required for cytokinesis , 2000, The EMBO journal.

[42]  S. Haggarty,et al.  Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. , 1999, Science.

[43]  M. Kavallaris,et al.  Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. , 1997, The Journal of clinical investigation.

[44]  D. Budman.  Vinorelbine (Navelbine): a third-generation vinca alkaloid. , 1997, Cancer investigation.

[45]  G L Rosner,et al.  Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen: a cancer and leukemia group B study. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[46]  H. Lane,et al.  Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo , 1995, Cell.

[47]  E. Lazarides,et al.  Taxol-Induced Mitotic Block Triggers Rapid Onset of a p53-Independent Apoptotic Pathway , 1995, Molecular medicine.

[48]  B. Schaar,et al.  Characterization of the Kinetochore Binding Domain of CENP-E Reveals Interactions with the Kinetochore Proteins CENP-F and hBUBR1 , 1998, The Journal of cell biology.

[49]  Timothy J. Mitchison,et al.  Probing Spindle Assembly Mechanisms with Monastrol, a Small Molecule Inhibitor of the Mitotic Kinesin, Eg5 , 2000, The Journal of cell biology.

[50]  Carissa A. Sanchez,et al.  A p53-dependent mouse spindle checkpoint , 1995, Science.

[51]  W. B. Derry,et al.  Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. , 1996, Cancer research.

[52]  R. Coulson,et al.  Cyclin-like accumulation and loss of the putative kinetochore motor CENP-E results from coupling continuous synthesis with specific degradation at the end of mitosis , 1994, The Journal of cell biology.

[53]  Bert Vogelstein,et al.  Mutations of mitotic checkpoint genes in human cancers , 1998, Nature.

[54]  K. Wood,et al.  CENP-E as an Essential Component of the Mitotic Checkpoint In Vitro , 2000, Cell.

[55]  G. Cavaletti,et al.  Effect on the peripheral nervous system of the short-term intravenous administration of paclitaxel in the rat. , 1997, Neurotoxicology.

[56]  C. Thompson,et al.  Expression of Bcl-xL and loss of p53 can cooperate to overcome a cell cycle checkpoint induced by mitotic spindle damage. , 1996, Genes & development.

[57]  M. Jordan,et al.  Effects of vinblastine, podophyllotoxin and nocodazole on mitotic spindles. Implications for the role of microtubule dynamics in mitosis. , 1992, Journal of cell science.

[58]  J. Sloan,et al.  Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[59]  Roger Cooke,et al.  A structural change in the kinesin motor protein that drives motility , 1999, Nature.

[60]  J. Bisi,et al.  Dominant-negative polo-like kinase 1 induces mitotic catastrophe independent of cdc25C function. , 2000, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[61]  I. S. Johnson,et al.  The action of vincaleukoblastine on mitosis in vitro , 1960 .

[62]  F. Cabanillas,et al.  Clinical and Preclinical Pharmacology of Liposomal Vincristine , 2000 .

[63]  G. Wahl,et al.  p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest. , 1998, Cancer research.