Abstract
Malignancies are a major cause of morbidity and mortality worldwide. Cancer is a cell disease, characterized by a deviation of the control mechanisms of proliferation and differentiation of cells. Among the treatments available, chemotherapy is often the first choice. Epothilones are a new class of anticancer drugs that act by interacting with cellular microtubules interrupting the proliferation of cancer cells. Many synthetic and semi-synthetic analogues of epothilones have been prepared aiming improvement in effectiveness and tolerability, based on QSAR studies. These analogues have been effective for treatment of tumors resistant to first-line treatments. Six new epothilones are being subjected to clinical trials. Ixabepilone (Ixempra®) was approved by FDA in 2007, patupilone is in phase III clinical trial for ovarian and peritoneum cancer. Sagopilone, desoxiepothilone and KOS-1584 are in phase II clinical trials, for the treatment of recurrent glioblastoma and advanced metastatic breast cancer, metastasic breast cancer and metastatic pulmonary cancer, respectively. Desoxiepothilone reached only phase II trials and BMS-310705 reached phase III/IV trials, but were not approved for clinical use due to adverse effects such as neurotoxicity and severe diarrhea, which were dose-limiting. Furthermore, the low t1/2 (40h) in comparison with other class analogues, does not recommend the clinical use of this derivative. Some other synthetized epothilones presented antineoplastic activity in vitro, but are not yet submitted to clinical studies. Neuropathies and diarrhea are adverse effects presented by some substances of this class of anticancer drugs.
Keywords: Anticancer agents, chemotherapy, ixabepilone, patupilone, sagopilone, structure-activity relationship, semi-syntetic analogs.
Anti-Cancer Agents in Medicinal Chemistry
Title:From Bacteria to Antineoplastic: Epothilones A Successful History
Volume: 13 Issue: 7
Author(s): Samuel Kaiser, Joseane John Muller, Pedro Eduardo Froehlich, Simone Cristina Baggio Gnoatto and Ana Maria Bergold
Affiliation:
Keywords: Anticancer agents, chemotherapy, ixabepilone, patupilone, sagopilone, structure-activity relationship, semi-syntetic analogs.
Abstract: Malignancies are a major cause of morbidity and mortality worldwide. Cancer is a cell disease, characterized by a deviation of the control mechanisms of proliferation and differentiation of cells. Among the treatments available, chemotherapy is often the first choice. Epothilones are a new class of anticancer drugs that act by interacting with cellular microtubules interrupting the proliferation of cancer cells. Many synthetic and semi-synthetic analogues of epothilones have been prepared aiming improvement in effectiveness and tolerability, based on QSAR studies. These analogues have been effective for treatment of tumors resistant to first-line treatments. Six new epothilones are being subjected to clinical trials. Ixabepilone (Ixempra®) was approved by FDA in 2007, patupilone is in phase III clinical trial for ovarian and peritoneum cancer. Sagopilone, desoxiepothilone and KOS-1584 are in phase II clinical trials, for the treatment of recurrent glioblastoma and advanced metastatic breast cancer, metastasic breast cancer and metastatic pulmonary cancer, respectively. Desoxiepothilone reached only phase II trials and BMS-310705 reached phase III/IV trials, but were not approved for clinical use due to adverse effects such as neurotoxicity and severe diarrhea, which were dose-limiting. Furthermore, the low t1/2 (40h) in comparison with other class analogues, does not recommend the clinical use of this derivative. Some other synthetized epothilones presented antineoplastic activity in vitro, but are not yet submitted to clinical studies. Neuropathies and diarrhea are adverse effects presented by some substances of this class of anticancer drugs.
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Kaiser Samuel, Muller John Joseane, Froehlich Eduardo Pedro, Baggio Gnoatto Cristina Simone and Bergold Maria Ana, From Bacteria to Antineoplastic: Epothilones A Successful History, Anti-Cancer Agents in Medicinal Chemistry 2013; 13 (7) . https://dx.doi.org/10.2174/18715206113139990133
DOI https://dx.doi.org/10.2174/18715206113139990133 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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