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The full text of this article hosted at iucr. Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. A method for the analysis of disaccharides by mass spectrometry is described. Disaccharides and disaccharide alditols were subjected to periodate oxidation and reduction and the products were analysed by electron ionization and fast atom bombardment mass spectrometry as peracetylated and permethylated derivatives. The compounds gave simple mass spectra with intense and characteristic ions from which glycosidic linkage positions and ring size could be determined. Volume 21 , Issue 4.
The potency was comparable to the parental epothilones and significantly higher than that observed for paclitaxel.
Focus issue: BMS asymptotic symmetries - Classical and Quantum Gravity - IOPscience
Moreover, the agent was found to affect both tubulin polymerization and cell cycle progression. These in vitro studies established that ixabepilone retained the microtubule-targeting activity of parental epothilones, and that it had significant activity against taxane-resistant cell-lines.
The authors further used a wide panel of in vivo xenograft mice models to examine the anti-cancer efficacy of ixabepilone. In these studies, Lee et al. As compared to other epothilones, which did not have any in vivo activity, these results clearly showed that ixabepilone was active in vivo.
More importantly, the authors used three resistant, patient-derived xenograft models ovarian, breast and pancreatic cancer and showed very impressive anti-cancer activity of ixabepilone. In an interesting conclusion, the authors also evaluated the anti-cancer effects of ixabepilone after oral administration. Using a paclitaxel-resistant and -sensitive xenograft model, it was shown that ixabepilone had remarkable anti-cancer activity after oral administration.
Overall, these studies suggested that, as compared to taxanes, ixabepilone had activity against resistant tumors and could possibly be delivered by oral administration, two potentially significant improvements over other microtubule-targeting chemotherapeutics.
The study by Lee and colleagues 4 provided the incentive for a large-scale clinical development program of ixabepilone involving a variety of schedules, infusion durations, and combinations.
In Phase I trials, responses were observed in a wide range of tumors, and the main toxicities reported were neutropenia, peripheral sensory neuropathy, and hypersensitivity reactions 5. The main clinical benefits and subsequent development of ixabepilone has been in metastatic breast cancer. In several Phase II trials, single-agent ixabepilone was found to be active in patients with metastatic breast cancer as first line treatment, and in those resistant to an anthracycline and taxane 6.
The combination of ixabepilone and capecitabine was also extensively explored in Phase I and II trials and found to be both safe and active in women with metastatic breast cancer previously treated with an anthracycline and a taxane.
This combination was subsequently compared with single-agent capecitabine in the same disease setting in two large, randomized Phase III trials. On the basis of these studies, the US FDA approved the use of ixabepilone in combination with capecitabine in metastatic or locally-advanced breast cancer resistant to treatment with an anthracycline and a taxane, and as monotherapy in tumors that are also resistant to capecitabine 7. Pooled subset analyses of the two Phase III studies have suggested that ixabepilone plus capecitabine shows superior overall survival compared with capecitabine alone in patients with Karnofsky performance status 70—80 8.
It is of note that the European Medicines Agency did not approve ixabepilone based on the consideration that its therapeutic benefits do not outweigh the risk of significant toxicities, in particular neuropathy, despite post-hoc support for a positive benefit-risk ratio based on Q-TWiST analysis 9. In the context of observed side effect profiles, it is of interest to point out that the poor aqueous solubility of ixabepilone resulted in a formulation strategy similar to that used earlier for paclitaxel, that uses a vehicle containing large amounts of polyoxyethylated castor oil Kolliphor EL; previously Cremophor EL and ethanol.
This formulation requires the use of relatively prolonged infusion times, and has been associated with acute hypersensitivity reactions that require premedication with antihistamines. In addition, this formulation may limit drug penetration in tumor cells, can act as a perpetrator in pharmacokinetic drug interactions, and could directly or indirectly contribute to treatment-related peripheral neuropathy This latter possibility would be consistent with available clinical data on the comparative side effect profiles of the two FDA-approved paclitaxel formulations, which suggest that, at equimolar doses, the formulation containing Cremophor EL is substantially more neurotoxic.
Since the original FDA approval of ixabepilone, significant effort has been focused on the identification of potentially useful pharmacodynamic markers to monitor drug effects on tumors and normal tissue, as well as on the development of predictive markers to allow more tailored therapy for patients Unfortunately, efforts to validate the predictive value of such putative biomarkers for ixabepilone have not yet been successful.
An area of research that has remained unexplored for ixabepilone relates to the study of population pharmacokinetics in order to individualize dose and schedule of administration. This discipline seeks to identify the measurable patho physiologic factors that cause changes in the dose-concentration relationship and the extent of these alterations so that, if these are associated with clinically significant shifts in the therapeutic index, dosage can be appropriately modified in an individual patient.
It is obvious that a careful collection of data during the development of drugs and subsequent analyses could be helpful to collect some essential information on the drug. Unfortunately, important information is often lost by failing to analyze this data or due to the fact that the relevant samples or data were never collected, as in the case of ixabepilone.
Another currently unexplored opportunity for therapy refinement with ixabepilone is to evaluate the contribution of germline variants in genes with a confirmed or suspected role in the highly unpredictable pharmacokinetic profile of ixabepilone. Identification of genetic and environmental factors associated with interindividual variability in the disposition of highly metabolized drugs such as ixabepilone is potentially vital to predicting or eventually adapting appropriate, individualized doses.
The broad clinical development program of ixabepilone has also involved exploration of single-agent use across the spectrum of breast cancer stages as well as combinations with other cytotoxic regimens, including carboplatin, liposomal doxorubicin, and epirubicin, and with molecularly-targeted agents such as bevacizumab, cetuximab, sorafenib, dasatinib, and trastuzumab. These studies have demonstrated that the potential benefits of ixabepilone in patients with breast cancer are maintained across the conventional molecular subgroups, including in women with triple-negative disease.
Moreover, other, structurally-distinct epothilones have been developed in recent years and are being evaluated in a variety of advanced solid tumors beyond breast cancer as monotherapies and in combination with other agents. These studies indicate that, despite their relative minor structural differences, the individual epothilones show distinct safety and efficacy profiles across a range of malignant diseases and may ultimately have non-oncologic indications as well The original report published by Lee and colleagues 4 in Clinical Cancer Research serves as an example where preclinical efficacy data were predictive of future clinical success, and it has provided the basis for subsequent development of multiple cytotoxic agents targeting microtubules.
Indeed, the FDA approval of ixabepilone for use in the treatment of breast cancer shows that an important role remains for the development of cytotoxic drugs in cancer therapy, especially for patients with advanced disease 5. Disclosure of Potential Conflicts of interest. Pabla, A. National Center for Biotechnology Information , U. Clin Cancer Res. Author manuscript; available in PMC Mar Navjotsingh Pabla and Alex Sparreboom.
Author information Copyright and License information Disclaimer.
Department of Pharmaceutical Sciences, St. Corresponding Author: Copyright notice.
The publisher's final edited version of this article is available free at Clin Cancer Res. Volume 21 , Issue 4.
Focus issue: BMS asymptotic symmetries
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Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Abstract A method for the analysis of disaccharides by mass spectrometry is described. Citing Literature Number of times cited according to CrossRef: El-Feky, Gamal M. Zayed, Yaseen A. Elshaier and Fahd M.
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