ixabepilone
Regulatory sources consulted
Approved indications
- Resistant or refractory locally advanced or metastatic breast cancer, alone or with capecitabine according to label criteria.
Contraindications
Absolute
- Hypersensitivity to ixabepilone or Cremophor EL diluent; ANC <1,500/mm³ or platelets <100,000/mm³; with capecitabine, AST/ALT >2.5×ULN or bilirubin >1×ULN.
Clinical warnings
- Monitor blood counts before each cycle and through the nadir. Do not administer outside a specialist oncology protocol; myelosuppression may cause fatal infection or bleeding. — DailyMed, set_id 241f0b1e-8b95-470d-876f-bf1804daaf18
- It may cause severe peripheral neuropathy, hypersensitivity, and neutropenic death, especially with hepatic impairment. Monitor for extravasation. — DailyMed, set_id 241f0b1e-8b95-470d-876f-bf1804daaf18
Drug interactions
- HighStrong CYP3A4 inhibitors or inducers
Mechanism: They may substantially alter exposure.
Recommendation: Avoid both. If a strong inhibitor is unavoidable, reduce to 20 mg/m²; do not increase for inducers except under the exact label scheme.
DailyMed, set_id 241f0b1e-8b95-470d-876f-bf1804daaf18
Pregnancy and lactation
It may cause fetal harm. Verify pregnancy before treatment; women use contraception during and for 7 months afterward, men during and for 4 months afterward. Do not breastfeed during treatment or for 2 weeks afterward. It may impair fertility.
Recent literature (PubMed)
Breast cancer is the most commonly diagnosed malignancy and the fifth leading cause of cancer deaths worldwide. Surgery and radiation therapy are localized therapies for early-stage and metastatic breast cancer. The management of breast cancer is determined in large part by the HER2 (human epidermal growth factor receptor 2), HR (hormone receptor), ER (estrogen receptor), and PR (progesterone receptor) status. Our views of breast cancer are evolving as its molecular hallmarks are examined, which now include immunohistochemical markers (ER, PR, HER2, and proliferation marker protein Ki-67), genomic markers (BRCA1/2 and PIK3CA), and immunomarkers (tumor-infiltrating lymphocytes and PDL1). About two-thirds of malignancies of the breast are HR-positive/HER2-negative; accordingly, endocrine-based therapy is a major treatment option for these patients. Hormonal or endocrine therapy includes selective estrogen receptor modulators (SERMs) such as raloxifene, tamoxifen and toremifene, selective estrogen-receptor degraders (SERDs) including elacestrant and fulvestrant, and aromatase inhibitors such as anastrozole, letrozole, and exemestane. A variety of cytotoxic chemotherapeutic agents are used to treat HR-negative breast cancer patients. These agents include taxanes (docetaxel, nab-paclitaxel, and paclitaxel), anthracyclines (doxorubicin, epirubicin), anti-metabolites (capecitabine, gemcitabine, fluorouracil, methotrexate), alkylating agents (carboplatin, cisplatin, and cyclophosphamide), and drugs that target microtubules (eribulin, ixabepilone, ado-trastuzumab emtansine). Patients with ER-positive tumors are treated with 5-10 years of endocrine therapy and chemotherapy. For patients with metastatic breast cancer, standard first-line and follow-up therapy options include targeted approaches such as CDK4/6 inhibitors, PI3K inhibitors, PARP inhibitors, and anti-PDL1 immunotherapy, depending on the tumor type and molecular profile.
Aim: A systematic review and network meta-analysis (NMA) was performed to evaluate the efficacy of first-line treatments for locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) patients.Materials & methods: Databases were searched for randomized controlled trials evaluating first-line treatments for locally recurrent unresectable or metastatic TNBC patients. NMA was performed to estimate relative treatment effects on overall and progression-free survival between pembrolizumab + chemotherapy and other interventions.Results: NMA including eight trials showed that the relative efficacy of pembrolizumab + chemotherapy was statistically superior to that of other immunotherapy- or chemotherapy-based treatment regimens.Conclusion: Pembrolizumab + chemotherapy confers benefits in survival outcomes versus alternative interventions for the first-line treatment of locally recurrent unresectable or metastatic TNBC patients. Clinical value of initial treatments for patients with advanced triple-negative breast cancerWhat is this article about? Around 15% of breast cancer patients have the triple-negative breast cancer (TNBC) subtype, which has the worst prognosis. Treatments targeting the immune system, such as pembrolizumab, were recently found to improve the outcomes of patients with cancer that is at an advanced stage or resistant to standard therapies. However, clinical trials evaluating the efficacy of cancer treatments typically compare only two alternative treatments. Therefore, we conducted this study to understand the relative efficacy of several commonly used initial treatments for advanced TNBC by indirectly comparing the results of all available clinical trials that were sufficiently similar. We identified trials by systematically searching the medical literature and analyzed the results of several clinical trials together to estimate the efficacy of pembrolizumab + chemotherapy compared with several other initial treatment regimens for
Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium Sorangium cellulosum. This review summarizes results in the study of epothilones against cancer with preclinical results and clinical studies from 2010-2022. Epothilone have mechanisms of action similar to paclitaxel by inducing tubulin polymerization and apoptosis with low susceptibility to tumor resistance mechanisms. It is active against refractory tumors, being superior to paclitaxel in many respects. Since the discovery of epothilones, several derivatives have been synthesized, and most of them have failed in Phases II and III in clinical trials; however, ixabepilone and utidelone are currently used in clinical practice. There is robust evidence that triple-negative breast cancer (TNBC) treatment improves using ixabepilone plus capecitabine or utidelone in combination with capecitabine. In recent years innovative synthetic strategies resulted in the synthesis of new epothilone derivatives with improved activity against refractory tumors with better activities when compared to ixabepilone or taxol. These compounds together with specific delivery mechanisms could be developed in anti-cancer drugs.
Microtubules are dynamic polymers composed of α- and β-tubulin heterodimers. Microtubules are universally conserved among eukaryotes and participate in nearly every cellular process, including intracellular trafficking, replication, polarity, cytoskeletal shape, and motility. Due to their fundamental role in mitosis, they represent a classic target of anti-cancer therapy. Microtubule-stabilizing agents currently constitute a component of the most effective regimens for ovarian cancer therapy in both primary and recurrent settings. Unfortunately, the development of resistance continues to present a therapeutic challenge. An understanding of the underlying mechanisms of resistance to microtubule-active agents may facilitate the development of novel and improved approaches to this disease.
Microtubules are appealing as intracellular targets for anticancer activity due to their importance in cell division. Three important binding sites are present on the tubulin protein: taxane, vinca, and colchicine binding sites (CBS). Many USFDA-approved drugs such as paclitaxel, ixabepilone, vinblastine, and combretastatin act by altering the dynamics of the microtubules. Additionally, a large number of compounds have been synthesized by medicinal chemists around the globe that target different tubulin binding sites. Although CBS inhibitors have proved their cytotoxic potential, no CBS-targeting drug had been able to reach the market. Several studies have reported design, synthesis, and biological evaluation of indole derivatives as potential anticancer agents. These compounds have been shown to inhibit cancer cell proliferation, induce apoptosis, and disrupt microtubule formation. Moreover, the binding affinity of these compounds to the CBS has been demonstrated using molecular docking studies and competitive binding assays. The present work has reviewed indole derivatives as potential colchicine-binding site inhibitors. The structure-activity relationship studies have revealed the crucial pharmacophoric features required for the potent and selective binding of indole derivatives to the CBS. The development of these compounds with improved efficacy and reduced toxicity could potentially lead to the development of novel and effective cancer therapies.