IXABEPILONE Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
Ixabepilone, a semisynthetic analog of epothilone B, was launched for the treatment of metastatic or locally advanced breast cancer. It is indicated
for use in combination with capecitabine in patients who have previously failed
treatment with an anthracycline such as doxorubicin and a taxane such as
paclitaxel. It is also approved as monotherapy for the treatment of metastatic or
locally advanced breast cancer in patients whose tumors are resistant or
refractory to anthracyclines, taxanes, and capecitabine. Ixabepilone is the first
member of the epothilone family of anticancer agents to be approved.
Epothilones are novel cytotoxic macrolides derived from bacterial fermentation.
Like the taxanes, their mechanism of action involves binding to and stabilizing microtubules, which results in mitotic arrest and apoptosis.
The most common adverse reactions (X20%) associated with ixabelipone as monotherapy or in combination with capecitabine were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/ mucositis, diarrhea, and musculoskeletal pain. The most common hematologic abnormalities (W 40%) include neutropenia, leukopenia, anemia, and thrombocytopenia. Ixabelipone in combination with capecitabine is contraindicated in patients with AST or ALT W2.5 ULN (upper limit of normal) or bilirubin W1 ULN due to increased risk of toxicity and neutropenia-related death.
Verwenden
Ixabepilone is an anti-tumor agent used in the treatment of patients suffering from solid tumors, such as metastatic breast cancer.
Definition
ChEBI: A macrocycle that is a lactam analogue of epothilone B. Binds directly to beta-tubulin subunits on microtubules, leading to suppression of microtubule dynamics.
Allgemeine Beschreibung
The epothilones are macrocyclic lactones that have a mechanismof action similar to that of the taxanes but offer severaladvantages.Ixabepilone is the semisyntheticamide analog of epothilone B that is isolated from themyxobacterium Sorangium cellulosum. The epothilonesshowed potent in vitro activity but greatly decreased activityin vivo caused by metabolic instability via hydrolysis ofthe macrocyclic lactone. Conversion to the lactam increasedstability and maintained in vivo activity. Ixabepilone hasbeen recently (2007) approved for the treatment of metastaticbreast cancer that is resistant to the taxanes. The agent isbelieved to bind to the same site occupied by the taxanes.Molecular modeling studies have been utilized to identifya common pharmacophore between the taxanes andepothilones.Like the taxanes, ixabepilone binds to β-tubulin and stabilizesmicrotubules resulting in cell death.The agent is usefulin cancers that have become resistant to the taxanes, becauseit is not removed by Pgp and is still capable of binding to altered beta tubulin to which the taxanes no longer bind.Increased water solubility also allows the agent to be administeredwithout the need for Cremophor EL, reducing thechance of hypersensitivity reactions. The current indicationsfor the agent are in metastatic breast cancer in combinationwith capecitabine after the failure of an anthracycline and ataxane and as monotherapy in metastatic breast cancer afterfailure of an anthracycline, a taxane, and capecitabine. Theagent is extensively metabolized in the liver primarily byCYP3A4 to give over 30 different metabolites. Eliminationoccurs primarily in the feces (65%) with a smaller amount(21%) occurring in the urine. The terminal elimination halflifeis 52 hours. Major toxicities associated with the useof ixabepilone have included peripheral neuropathy andmyelosuppression occurring as neutropenia. Occurring lessfrequently are alopecia, nausea, vomiting, mucositis, diarrhea,and muscle pain.
IXABEPILONE Upstream-Materialien And Downstream Produkte
Upstream-Materialien
2-Oxiraneundecanoic acid, 3-[(2S,3E)-2-amino-3-methyl-4-(2-methyl-4-thiazolyl)-3-buten-1-yl]-β,ζ-dihydroxy-γ,γ,ε,η,2-pentamethyl-δ-oxo-, (βS,εR,ζS,ηS,2R,3S)-
Azacyclohexadec-13-ene-2,6-dione, 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-, (4S,7R,8S,9S,13Z,16S)-
2-Oxiraneundecanoic acid, 3-[(2S,3E)-2-azido-3-methyl-4-(2-methyl-4-thiazolyl)-3-buten-1-yl]-β,ζ-dihydroxy-γ,γ,ε,η,2-pentamethyl-δ-oxo-, (βS,εR,ζS,ηS,2R,3S)-
277749-43-6
224580-49-8
277749-45-8
Epothilone B
277749-36-7
Downstream Produkte
