laulimalide and Neoplasms

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.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bridged Bicyclo Compounds, Heterocyclic; Cell Division; Clinical Trials as Topic; Colchicine; Drug Delivery Systems; Drug Screening Assays, Antitumor; Epothilones; Humans; Lactones; Macrolides; Microtubules; Neoplasms; Steroids; Taxoids; Tubulin Modulators; Vinca Alkaloids

Microtubule stabilization by chemotherapy is a powerful weapon in the war against cancer. Disruption of the mitotic spindle activates a number of signaling pathways, with consequences that may protect the cell or lead to its death via apoptosis. Taxol, the first microtubule stabilizing drug to be identified, has been utilized successfully in the treatment of solid tumors for two decades. Several features, however, make this drug less than ideal, and the search for next generation stabilizing drugs with increased efficacy has been intense and fruitful. Microtubule stabilizing agents (MSAs), including the taxanes, the epothilones, discodermolide, laulimalide, and eleutherobin, form an important and expanding family of chemotherapeutic agents. A strong understanding of their molecular signaling consequences is essential to their value, particularly in regard to their potential for combinatorial chemotherapy - the use of multiple agents to enhance the efficacy of cancer treatment. Here we present a critical review of research on the signaling mechanisms induced by MSAs, their relevance to apoptosis, and their potential for exploitation by combinatorial therapy.

Topics: Alkanes; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cyclooxygenase 2; Diterpenes; Epothilones; Humans; Inhibitor of Apoptosis Proteins; Interleukin-1; Interleukin-8; Lactones; Macrolides; MAP Kinase Kinase 1; MAP Kinase Signaling System; Maturation-Promoting Factor; Microtubule-Associated Proteins; Microtubules; Neoplasm Proteins; Neoplasms; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrones; Signal Transduction; Survivin; Taxoids; Tumor Suppressor Protein p53