1.Mechanism of action of ixabepilone and its interactions with the βIII‑tubulin isotype
Manu Lopus • Greg Smiyun • Herb Miller • Emin Oroudjev • Leslie Wilson • Mary Ann Jordan. Cancer Chemother Pharmacol (2015) 76:1013–1024
Here we examined ixabepilone’s binding to microtubules and its effects on microtubule assembly in vitro and on the parameters of microtubule dynamic instability both in vitro with microtubules assembled from puriied tubulin and with microtubules in MCF7 breast cancer cells. We found that ixabepilone binds to microtubules with a variable stoichiometry of 1–2 molecules of drug for every tubulin molecule in microtubules. The absence or reduction of βIII-tubulin makes microtubules more susceptible to the suppressive effects of ixabepilone on dynamic instability in vitro and in cells and enhances mitotic arrest. Our results indicate that βIII-tubulin reduces the effects of ixabepilone on microtubule dynamics and on mitotic arrest, and thus increased βIII-tubulin expression may contribute to ixabepilone resistance in tumors.
2.Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks, in metastatic breast cancer
Neelima Denduluri • James J. Lee • Janice Walshe • Arlene W. Berman • Ujala Vatas • Catherine K. Chow. Invest New Drugs (2006) 25:63–67
Finally, this trial was designed to rule out a 5% response rate in favor of a 20%response rate using a two stage design. With only 12 patients enrolled and no responses, there is a 90% chance that the true response rate is 17.5% or less. Given the number of other positive trials with this agent, it is possible that the current trial has produced a false negative result, although it is unlikely that the true response ratewould be 20% or higher. Unlike previous trials with efﬁcacy of ixabepilone in breast cancer with different dosing schedules, our trial suggests that the 8–10 mg/m2 daily for 3 days regimen may not be an effective therapy in this heavily pretreated population. Current Phase III trials with ixabepilone should give us more deﬁnitive conclusions about the therapeutic efﬁcacy of different dose schedules of ixabepilone in metastatic breast cancer.
3.Weekly ixabepilone administration in heavily pretreated metastatic breast cancer patients
Ellen B. Kossoff • Nuttapong Ngamphaiboon • Thomas J. Laudico • Tracey L. O’Connor. Med Oncol (2011) 28:S115–S120
Weekly paclitaxel is regarded as a standard of care in metastatic breast cancer due to improvements in efﬁcacy and tolerability seen with this schedule. The Cancer and Leukemia Group B (CALGB 9840) demonstrated that weekly paclitaxel was superior to every 3-week paclitaxel as treatment of metastatic breast cancer with improvements seen in RR (42%vs. 29%) and TTP (median, 9 vs. 5 months) with this schedule. Because ixabepilone is pharmacologically similar to the taxanes, weekly administration of ixabepilone may offer similar beneﬁts to those of weekly paclitaxel. The available clinical data,while limited, suggest that weekly ixabepilone is a reasonable option for breast cancer patients.
4.Silencing A7-nAChR levels increases the sensitivity of gastric cancer cells to ixabepilone treatment
Chao-Chiang Tu & Chien-Yu Huang & Wan-Li Cheng & Chin-Sheng Hung. Tumor Biol.
Taxanes are potent antimicrotubule agents that are used in the treatment of advanced gastric cancer as first- and second-line therapies and that have response rates of approximately 15∼24%. However, the majority of patients with advanced gastric cancer eventually develop progressive diseases after initially responding to taxane-based treatment. Ixabepilone, a semisynthetic analog of epothilone B, promotes tumor cell death by stabilizing microtubules and inducing apoptosis similar to taxanes. In fact, ixabepilone structurally differs from taxanes and is less susceptible to tumor resistance mechanisms, including P-glycoprotein overexpression and beta-tubulin mutations, the two most common mechanisms of resistance to paclitaxel. In addition, ixabepilone is more potent than paclitaxel in promoting beta-tubulin polymerization in both paclitaxel-sensitive and paclitaxel-resistant cell lines. Accumulating clinical trials have proven the efficacy of ixabepilone in a broad variety of tumor types, including metastatic or treatment-resistant breast cancer, advanced prostate cancer, pancreatic cancer, non-small cell lung cancer, endometrial carcinoma, ovarian cancer, and renal cell carcinoma. The US Food and Drug Administration has approved ixabepilone for the treatment of locally advanced breast cancer since 2007. Trials examining ixabepilone as a monotherapy or in combination with other classical cytotoxics are currently in progress, and further roles for ixabepilone in the treatment of cancer are hoped for