6549 POSTER Treatment of recurrent or progressive brain metastases with patupilone in patients with non-small cell lung cancer (NSCLC): results of a multicenter, open-label phase II study

Abrey, L.; Johri, A.; Wen, P.Y.; Govindan, Ramaswamy; Reimers, Hans; Robins, H. I.; Bedout, Sabine De; Hennan, L.; Ko, Jung-Keun; Rigas, James R.

doi:10.1016/s1359-6349(07)71377-0

“…It is currently in clinical trials for a number of different solid tumors, including brain metastases in breast and ovarian cancer, melanoma and other solid tumors (Dumontet & Jordan, 2010) . It has shown promising effects in a phase II study in refractory brain metastases in non-small cell lung cancer (Abrey et al, 2007). Compared to PTX, patupilone is up to 20 times more potent and is effective in taxane-resistant cells.…”

Section: The Epothilonesmentioning

confidence: 99%

Characterisation of Zampanolide as a Microtubule-Stabilizing Agent

Field¹

0

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<p>Microtubule-stabilizing agents (MSAs) are extremely important chemotherapeutic drugs since microtubules (MTs) are one of the most successful cancer drug targets. Currently there are four MSAs that are clinically used for the treatment of cancer. Cancer cells, however, can develop resistance towards these drugs, the most common being over-expression of the P-glycoprotein drug efflux pump. Zampanolide (ZMP), a novel secondary metabolite isolated from a marine sponge consists of a 20-membered macrolide ring with an unusual N-acyl-hemiaminal side chain. It is a potent MSA with similar cellular effects to the clinically relevant MSAs, Taxol®, Taxotere® and Ixempra®. ZMP has a small number of stereogenic centers and therefore is relatively easier to synthesize than other macrolide natural products. Using established cancer cell lines and isolated bovine brain tubulin ZMP in the present study was further characterized as a potential anti-cancer compound and was shown to have significant advantages over currently used MSAs. These studies provided insight into how this important drug class induces MT assembly, suggesting strategies for the development of new generation MSAs for use in the clinic. ZMP and its less active analog dactylolide competed with paclitaxel for binding to MTs and represented a novel MSA chemotype. Unlike traditional taxoid site ligands, ZMP remained significantly more cytotoxic in cell lines with mutations in the taxoid binding site, and behaved in an unusual manner in vitro. This was later found to be due to its mechanism of binding which involved covalent modification of two amino acids in the taxoid binding site, histidine 229 as the major product and asparagine 228 as the minor product. Alkylation of both these luminal site residues was also detected in unassembled tubulin, providing the first direct evidence that the taxoid binding site exists in unassembled tubulin and suggesting that the induction of MT nucleation by MSAs may proceed through an allosteric mechanism. X-ray crystallography data confirmed the presence of this binding site in unassembled tubulin and indicated that covalent modification occurs at C9 of ZMP with the NE2 of the histidine side chain. The potent stabilization of MTs observed with ZMP occurred due to its side chain interaction with the stabilizing M-loop of β-tubulin. In unassembled tubulin the M-loop is unordered. Upon ZMP binding, it is restructured into a short, well-defined helix. It is this restructuring that leads to the potent stabilization by ZMP and most likely other MSAs, including those currently used in the clinic. This information provides a basis for structure-guided drug engineering to design and develop new generation MSAs with potent stabilizing activity. In addition, covalent binding of ZMP means that it is able to avoid drug efflux pumps and thus evade the main mechanism of resistance presented to MSAs in the clinic. It was shown by studying structure-activity relationships that there are a number of key chemical motifs in ZMP responsible for its potent activity. Simpler analog structures that retain significant stabilizing activity could be used as lead compounds for further drug development. Moreover, MSAs have clinically relevant anti-angiogenic and vascular-disrupting properties, and ZMP was also shown to potently inhibit cell migration and thus have possible benefits as a vasculature-targeting compound. It was concluded that ZMP is a potent covalently-binding MSA in both cells and in vitro. Given these promising results, further preclinical development of the compound is warranted.</p>

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“…It is currently in clinical trials for a number of different solid tumors, including brain metastases in breast and ovarian cancer, melanoma and other solid tumors (Dumontet & Jordan, 2010) . It has shown promising effects in a phase II study in refractory brain metastases in non-small cell lung cancer (Abrey et al, 2007). Compared to PTX, patupilone is up to 20 times more potent and is effective in taxane-resistant cells.…”

Section: The Epothilonesmentioning

confidence: 99%

Characterisation of Zampanolide as a Microtubule-Stabilizing Agent

Field¹

0

View full text Add to dashboard Cite

<p>Microtubule-stabilizing agents (MSAs) are extremely important chemotherapeutic drugs since microtubules (MTs) are one of the most successful cancer drug targets. Currently there are four MSAs that are clinically used for the treatment of cancer. Cancer cells, however, can develop resistance towards these drugs, the most common being over-expression of the P-glycoprotein drug efflux pump. Zampanolide (ZMP), a novel secondary metabolite isolated from a marine sponge consists of a 20-membered macrolide ring with an unusual N-acyl-hemiaminal side chain. It is a potent MSA with similar cellular effects to the clinically relevant MSAs, Taxol®, Taxotere® and Ixempra®. ZMP has a small number of stereogenic centers and therefore is relatively easier to synthesize than other macrolide natural products. Using established cancer cell lines and isolated bovine brain tubulin ZMP in the present study was further characterized as a potential anti-cancer compound and was shown to have significant advantages over currently used MSAs. These studies provided insight into how this important drug class induces MT assembly, suggesting strategies for the development of new generation MSAs for use in the clinic. ZMP and its less active analog dactylolide competed with paclitaxel for binding to MTs and represented a novel MSA chemotype. Unlike traditional taxoid site ligands, ZMP remained significantly more cytotoxic in cell lines with mutations in the taxoid binding site, and behaved in an unusual manner in vitro. This was later found to be due to its mechanism of binding which involved covalent modification of two amino acids in the taxoid binding site, histidine 229 as the major product and asparagine 228 as the minor product. Alkylation of both these luminal site residues was also detected in unassembled tubulin, providing the first direct evidence that the taxoid binding site exists in unassembled tubulin and suggesting that the induction of MT nucleation by MSAs may proceed through an allosteric mechanism. X-ray crystallography data confirmed the presence of this binding site in unassembled tubulin and indicated that covalent modification occurs at C9 of ZMP with the NE2 of the histidine side chain. The potent stabilization of MTs observed with ZMP occurred due to its side chain interaction with the stabilizing M-loop of β-tubulin. In unassembled tubulin the M-loop is unordered. Upon ZMP binding, it is restructured into a short, well-defined helix. It is this restructuring that leads to the potent stabilization by ZMP and most likely other MSAs, including those currently used in the clinic. This information provides a basis for structure-guided drug engineering to design and develop new generation MSAs with potent stabilizing activity. In addition, covalent binding of ZMP means that it is able to avoid drug efflux pumps and thus evade the main mechanism of resistance presented to MSAs in the clinic. It was shown by studying structure-activity relationships that there are a number of key chemical motifs in ZMP responsible for its potent activity. Simpler analog structures that retain significant stabilizing activity could be used as lead compounds for further drug development. Moreover, MSAs have clinically relevant anti-angiogenic and vascular-disrupting properties, and ZMP was also shown to potently inhibit cell migration and thus have possible benefits as a vasculature-targeting compound. It was concluded that ZMP is a potent covalently-binding MSA in both cells and in vitro. Given these promising results, further preclinical development of the compound is warranted.</p>

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Epothilones: A Novel Class of Microtubule-Stabilizing Drugs for the Treatment of Cancer

Trivedi¹,

Budihardjo²,

Loureiro³

et al. 2008

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Microtubule-targeted anticancer drugs are effective in treating various cancers but are limited in use due to development of resistance and unacceptable toxicities. The epothilones are a novel class of microtubule-stabilizing anticancer drugs and may have a role in treating taxane-resistant cancers. Revised and updated data from several clinical studies for ixabepilone were recently published and subsequently resulted in ixabepilone becoming the first epothilone approved as monotherapy or in combination for treatment of locally advanced or metastatic breast cancer. BMS-310705, patupilone, KOS-862, KOS-1584 and ZK-EPO are epothilones that have been developed. Although peripheral sensory neuropathy and neutropenia are the dose-limiting toxicities for ixabepilone, these dose-limiting toxicities are ixabepilone specific. This review will discuss the current preclinical, clinical pharmacokinetic and pharmacodynamic, efficacy and toxicity data of the epothilones.

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6549 POSTER Treatment of recurrent or progressive brain metastases with patupilone in patients with non-small cell lung cancer (NSCLC): results of a multicenter, open-label phase II study

Cited by 3 publications

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Characterisation of Zampanolide as a Microtubule-Stabilizing Agent

Characterisation of Zampanolide as a Microtubule-Stabilizing Agent

Characterisation of Zampanolide as a Microtubule-Stabilizing Agent

Epothilones: A Novel Class of Microtubule-Stabilizing Drugs for the Treatment of Cancer

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