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Current Opinion in Investigational... Dec 2009Sagopilone (ZK-EPO), under development by Bayer Schering Pharma AG, is a novel, fully synthetic epothilone B analog that is representative of a new class of... (Review)
Review
Sagopilone (ZK-EPO), under development by Bayer Schering Pharma AG, is a novel, fully synthetic epothilone B analog that is representative of a new class of microtubule-stabilizing agents that have a similar mechanism of action to taxanes, but have a decreased propensity for drug resistance. In preclinical studies, sagopilone inhibited cell growth in a wide range of human cancer cell lines. Moreover, sagopilone was not recognized by multidrug-resistant (MDR) cellular efflux mechanisms, and maintained its activity in MDR tumor models. Phase I clinical trials established that the sagopilone side-effect profile was similar to that reported for taxanes, with neuropathy and neutropenia being the most commonly reported toxicities. Initial reports revealed that sagopilone was clinically active in advanced ovarian cancer, advanced melanoma and metastatic chemotherapy-naïve castration-resistant prostate cancer. In contrast, clinical activity demonstrated by sagopilone in NSCLC or metastatic breast cancer was similar to, or less than, the clinical activity observed with other, more clinically advanced epothilones. At the time of publication, sagopilone was being investigated in a broad phase II clinical trial program, including in patients with glioblastoma, NSCLC, melanoma, and small-cell lung, prostate, ovarian and breast cancers.
Topics: Animals; Antineoplastic Agents; Benzothiazoles; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Epothilones; Humans; Microtubules; Neoplasms
PubMed: 19943207
DOI: No ID Found -
Expert Opinion on Investigational Drugs Nov 2008Tubulin is among the most established and clinically validated targets in oncology. The taxanes, paclitaxel and docetaxel, stabilize microtubules and have shown... (Review)
Review
BACKGROUND
Tubulin is among the most established and clinically validated targets in oncology. The taxanes, paclitaxel and docetaxel, stabilize microtubules and have shown significant clinical activity, but factors such as the development of resistance can limit their clinical use. The epothilones are a novel class of natural microtubule-stabilizing products with potential activity in an expanded spectrum of tumour indications.
OBJECTIVE
In an extensive lead optimization programme, we selected sagopilone from 350 compounds produced by total synthesis because of its combination of potent activity and good tolerability in tumour models. It is the first fully synthetic epothilone in clinical development.
METHODS
Here we review the directed optimization of the natural product epothilone B to produce sagopilone, along with its mechanism of action, preclinical data and emerging clinical results.
RESULTS/CONCLUSIONS
We show how this optimization process translated into superior preclinical activity, coupled with a favourable tolerability profile. Activity has been determined in a number of animal models, including those from tumours resistant to other systemic treatments. The approach used to develop sagopilone may become more common as structure-driven research is increasingly employed to exploit the enormous potential of natural products, in parallel with other targeted approaches, heralding a new era of anticancer therapy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Benzothiazoles; Biological Products; Drug Evaluation, Preclinical; Epothilones; Humans; Tubulin
PubMed: 18922109
DOI: 10.1517/13543784.17.11.1735 -
Neuro-oncology Apr 2009The aim of this study was to determine the efficacy of sagopilone (ZK-EPO), a novel epothilone, compared with other anticancer agents in orthotopic models of human... (Comparative Study)
Comparative Study
The aim of this study was to determine the efficacy of sagopilone (ZK-EPO), a novel epothilone, compared with other anticancer agents in orthotopic models of human primary and secondary brain tumors. Autoradiography and pharmacokinetic analyses were performed on rats and mice to determine passage across the blood-brain barrier and organ distribution of sagopilone. Mice bearing intracerebral human tumors (U373 or U87 glioblastoma, MDA-MB-435 melanoma, or patient-derived non-small-cell lung cancer [NSCLC]) were treated with sagopilone 5-10 mg/kg, paclitaxel 8-12.5 mg/kg (or temozolomide, 100 mg/kg) or control (vehicle only). Tumor volume was measured to assess antitumor activity. Sagopilone crossed the blood-brain barrier in both rat and mouse models, leading to therapeutically relevant concentrations in the brain with a long half-life. Sagopilone exhibited significant antitumor activity in both the U373 and U87 models of human glioblastoma, while paclitaxel showed a limited effect in the U373 model. Sagopilone significantly inhibited the growth of tumors from CNS metastasis models (MDA-MB-435 melanoma and patient-derived Lu7187 and Lu7466 NSCLC) implanted in the brains of nude mice, in contrast to paclitaxel or temozolomide. Sagopilone has free access to the brain. Sagopilone demonstrated significant antitumor activity in orthotopic models of both glioblastoma and CNS metastases compared with paclitaxel or temozolomide, underlining the value of further research evaluating sagopilone in the treatment of brain tumors. Sagopilone is currently being investigated in a broad phase II clinical trial program, including patients with glioblastoma, NSCLC, breast cancer, and melanoma.
Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Benzothiazoles; Blood-Brain Barrier; Brain; Brain Neoplasms; Cell Line, Tumor; Dacarbazine; Epothilones; Female; Half-Life; Humans; Male; Mice; Mice, Nude; Paclitaxel; Rats; Rats, Wistar; Survival Rate; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 18780814
DOI: 10.1215/15228517-2008-072 -
Clinical Cancer Research : An Official... Jun 2009Bone metastases have a considerable impact on quality of life in patients with breast and other cancers. Tumors produce osteoclast-activating factors, whereas bone...
PURPOSE
Bone metastases have a considerable impact on quality of life in patients with breast and other cancers. Tumors produce osteoclast-activating factors, whereas bone resorption promotes the growth of tumor cells, thus leading to a "vicious cycle" of bone metastasis. Sagopilone, a novel, fully synthetic epothilone, inhibits the growth of breast cancer cells in vitro and in vivo, and here we report its activity in the MDA-MB-231(SA) breast cancer bone metastasis mouse model.
EXPERIMENTAL DESIGN
The potency of sagopilone was determined in treatment models simulating the adjuvant (preventive) and metastatic (therapeutic) settings in the clinic.
RESULTS
We showed that sagopilone inhibited tumor burden and bone destruction, in addition to reducing tumor-induced cachexia and paraplegia. The reduction in osteolytic lesions, tumor growth in bone, and weight loss was statistically significant in the preventive model compared with the vehicle group. In the therapeutic model, sagopilone treatment significantly lowered the number of activated osteoclasts and significantly reduced the osteolytic lesion area, bone volume loss, and bone resorption compared with vehicle treatment while simultaneously inhibiting tumor burden. An in vitro assay confirmed that sagopilone inhibited osteoclast activation without cytotoxic effects, whereas paclitaxel resulted in lower inhibition and high levels of cytotoxicity.
CONCLUSIONS
Sagopilone seems to inhibit the vicious cycle at both the tumor growth and bone resorption stages, suggesting the possibility for substantial benefit in the treatment of patients with breast cancer at risk from bone metastases or with bone lesions already present. Phase II clinical trials with sagopilone in patients with breast cancer are ongoing.
Topics: Acid Phosphatase; Animals; Antineoplastic Agents, Phytogenic; Benzothiazoles; Bone Neoplasms; Bone Resorption; Bone and Bones; Cachexia; Cell Line, Tumor; Dose-Response Relationship, Drug; Epothilones; Female; Humans; Isoenzymes; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Osteoclasts; Osteolysis; Paclitaxel; Tartrate-Resistant Acid Phosphatase; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 19470728
DOI: 10.1158/1078-0432.CCR-08-3123 -
Annals of Oncology : Official Journal... Sep 2011Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.
Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.
BACKGROUND
Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.
PATIENTS AND METHODS
Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points.
RESULTS
Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination.
CONCLUSIONS
No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.
Topics: Adult; Aged; Antineoplastic Agents; Astrocytoma; Benzothiazoles; Brain Neoplasms; Disease Progression; Disease-Free Survival; Epothilones; Female; Glioblastoma; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Young Adult
PubMed: 21321091
DOI: 10.1093/annonc/mdq729 -
Neurotoxicity Research Aug 2012Since peripheral sensory neuropathy is the major, clinically relevant side effect of sagopilone we investigated the general and peripheral neurotoxicity of sagopilone...
Since peripheral sensory neuropathy is the major, clinically relevant side effect of sagopilone we investigated the general and peripheral neurotoxicity of sagopilone administered intravenously with different doses (1.2 and 2.4 mg/kg) and schedules in 48 Wistar rats and we performed in parallel a pharmacokinetic/pharmacodynamic (PK/PD) study. A trend toward a different peripheral neurotoxicity could be assessed after 2 weeks of treatment (bolus > 30-min infusion > 3-h infusion) with both doses of sagopilone. Although sagopilone concentrations in peripheral nerve tissue above 100 ng/g were associated with a reduction in nerve conduction velocity (NCV), a clear dose-dependence of this reduction on the level of systemic exposure to sagopilone was not observed. The PK/PD evaluation revealed no consistent effect of the infusion duration on serum PK parameters or the PD read-out NCV. Sagopilone concentrations in brain, sciatic nerve, liver, and kidney were higher after bolus compared to infusion, but there were no influence of infusion duration on these concentrations. No correlation between sagopilone concentrations in any organ/tissue with NCV changes was detected. This study evidences that the PD of sagopilone is not the main determinant of the onset and severity of sagopilone-induced peripheral neurotoxicity in the investigated clinically-relevant dose range, thus indicating that further investigation might identify neuronal-specific mechanisms of action able to drive a focused strategy to prevent peripheral neurotoxicity without reducing the anticancer effectiveness of the epothilones.
Topics: Animals; Area Under Curve; Benzothiazoles; Blood Cell Count; Blood Chemical Analysis; Body Weight; Data Interpretation, Statistical; Epothilones; Female; Infusions, Intravenous; Kidney; Liver; Neural Conduction; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Sciatic Nerve
PubMed: 22190114
DOI: 10.1007/s12640-011-9302-7 -
Cancer Research Jul 2008Sagopilone (ZK-EPO) is the first fully synthetic epothilone undergoing clinical trials for the treatment of human tumors. Here, we investigate the cellular pathways by...
Sagopilone (ZK-EPO) is the first fully synthetic epothilone undergoing clinical trials for the treatment of human tumors. Here, we investigate the cellular pathways by which sagopilone blocks tumor cell proliferation and compare the intracellular pharmacokinetics and the in vivo pharmacodynamics of sagopilone with other microtubule-stabilizing (or tubulin-polymerizing) agents. Cellular uptake and fractionation/localization studies revealed that sagopilone enters cells more efficiently, associates more tightly with the cytoskeleton, and polymerizes tubulin more potently than paclitaxel. Moreover, in contrast to paclitaxel and other epothilones [such as the natural product epothilone B (patupilone) or its partially synthetic analogue ixabepilone], sagopilone is not a substrate of the P-glycoprotein efflux pumps. Microtubule stabilization by sagopilone caused mitotic arrest, followed by transient multinucleation and activation of the mitochondrial apoptotic pathway. Profiling of the proapoptotic signal transduction pathway induced by sagopilone with a panel of small interfering RNAs revealed that sagopilone acts similarly to paclitaxel. In HCT 116 colon carcinoma cells, sagopilone-induced apoptosis was partly antagonized by the knockdown of proapoptotic members of the Bcl-2 family, including Bax, Bak, and Puma, whereas knockdown of Bcl-2, Bcl-X(L), or Chk1 sensitized cells to sagopilone-induced cell death. Related to its improved subcellular pharmacokinetics, however, sagopilone is more cytotoxic than other epothilones in a large panel of human cancer cell lines in vitro and in vivo. In particular, sagopilone is highly effective in reducing the growth of paclitaxel-resistant cancer cells. These results underline the processes behind the therapeutic efficacy of sagopilone, which is now evaluated in a broad phase II program.
Topics: Animals; Antineoplastic Agents; Apoptosis; Benzothiazoles; Epothilones; HCT116 Cells; HeLa Cells; Humans; Mice; Mitochondria; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Tissue Distribution; Tubulin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 18593931
DOI: 10.1158/0008-5472.CAN-08-0237 -
Osteoporosis International : a Journal... Nov 2011Sagopilone, a fully synthetic epothilone and very potent anti-tumor agent, has proved to be efficient in inhibiting bone destruction and tumor burden in a mouse model of... (Comparative Study)
Comparative Study Randomized Controlled Trial
UNLABELLED
Sagopilone, a fully synthetic epothilone and very potent anti-tumor agent, has proved to be efficient in inhibiting bone destruction and tumor burden in a mouse model of breast cancer bone metastasis. In addition to its antiproliferative effects, this study shows direct effects of sagopilone on bone resorption and osteoclast activity.
INTRODUCTION
Sagopilone, a novel fully synthetic third-generation epothilone, has proved to be efficient in inhibiting bone destruction and tumor burden in a mouse model of breast cancer bone metastasis. The aim of this study was to investigate whether the effect was primarily due to sagopilone's antiproliferative effect and consequent inhibition of tumor cell growth, or if sagopilone exerts direct effects on bone resorption and osteoclast activity.
METHODS
Sagopilone was studied and compared to paclitaxel in vitro in human osteoclast differentiation and activity cultures. For studying the potential of sagopilone for inhibiting bone resorption in vivo, a mouse model of ovariectomy (ovx)-induced osteoporosis was utilized.
RESULTS
Sagopilone inhibited osteoclast differentiation and activity more efficiently than paclitaxel and showed less cytotoxicity. Whereas sagopilone showed inhibitory effects on human osteoclast differentiation and activity already at 5 and 15 nM, respectively, paclitaxel started to show effects only at 20 and 100 nM concentrations, respectively. Sagopilone treatment increased BMD In the mouse ovx model even though a non-optimized dose was used which is effective in tumor-bearing mice.
CONCLUSION
This is the first study to evaluate sagopilone's effects on bone resorption in non-cancerous situation. The evidence that sagopilone is beneficial for bone will strengthen the status of sagopilone as an anti-cancer compound compared to other microtubule stabilizing agents.
Topics: Animals; Benzothiazoles; Bone Density; Bone Resorption; Disease Models, Animal; Epothilones; Female; Humans; Mice; Osteoclasts; Osteoporosis; Ovariectomy; Paclitaxel; Tubulin Modulators
PubMed: 21104229
DOI: 10.1007/s00198-010-1486-9 -
ChemMedChem Jul 2015For the antitumour agent sagopilone, an epothilone analogue, a large-scale synthesis was developed to synthesise the active pharmaceutical ingredient for clinical...
For the antitumour agent sagopilone, an epothilone analogue, a large-scale synthesis was developed to synthesise the active pharmaceutical ingredient for clinical trials, exploring enzymatic and microbial methods to produce chiral building blocks on a multi-kilogram scale. The three building blocks were identified as key intermediates in the synthesis and needed to be produced with high optical purity in yields higher than those previously published. The improved syntheses of two of these building blocks are detailed herein. For building block A, the chemical research synthesis was abandoned, and a novel chemical route was developed leading to building block A via an enzymatic hydrolysis process. For building blocks C, replacement of a chemical catalytic procedure by a microbial process meant that the development of a new starting material could be avoided, thereby accelerating the development process. For the clinical development process, a human metabolite of sagopilone was required as a reference. To accelerate the synthesis of the metabolite, no chemical synthesis was investigated; rather, we relied solely on oxidoreductases. The human metabolite of sagopilone was synthesised on a multi-gram scale in a single-step process using genetically engineered E. coli expressing human cytochrome P450 enzyme 2C19. The integration of enzymatic and microbial processes provided tools that enable the synthesis of highly functionalised intermediates and metabolites.
Topics: Benzothiazoles; Biocatalysis; Cytochrome P-450 CYP2C19; Epothilones; Genetic Engineering; Humans; Oxidoreductases
PubMed: 26018455
DOI: 10.1002/cmdc.201500138 -
European Journal of Cancer (Oxford,... Jul 2013Sagopilone (ZK219477) is a new and fully synthetic epothilone with activity against multi-drug resistant tumour cell lines. It has demonstrated clinical activity in...
BACKGROUND
Sagopilone (ZK219477) is a new and fully synthetic epothilone with activity against multi-drug resistant tumour cell lines. It has demonstrated clinical activity in several solid tumours like ovarian cancer and melanoma. Data about clinical efficacy of sagopilone in small-cell lung cancer are lacking. Here we report the first phase-I trial of sagopilone in combination with cisplatin in previously untreated metastatic small-cell lung cancer patients.
METHODS
Chemonaive patients with metastatic small-cell lung cancer (SCLC) received sagopilone in four different dosing schedules ranging from 12 to 22 mg/m(2) (on day 1 as 3-h infusion) followed by a fixed dose of cisplatin of 75 mg/m(2) as 1-h infusion on day 1. Chemotherapy was administered every 3 weeks to a maximum of six cycles. The primary objective was determination of dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in this setting. Secondary objectives were assessment of objective response rates (ORR) as well as investigation of sagopilone pharmacokinetics.
RESULTS
Twenty-six patients received a total of 107 treatment cycles of the platinum-sagopilone doublet. The recommended phase-II dose (RD) and schedule was found to be 19 mg/m(2) sagopilone followed by 75 mg/m(2) cisplatin. Peripheral neuropathy turned out as dose-limiting toxicity when the combination was administered over a median of four cycles. Objective responses were observed in six out of seven SCLC patients (85.7%) treated with the RD.
CONCLUSIONS
Sagopilone and cisplatin can be safely combined in the first-line treatment of metastasised SCLC. This combination demonstrated preliminary efficacy and should be further evaluated within phase-II trials.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Carcinoma, Non-Small-Cell Lung; Cisplatin; Epothilones; Female; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Prospective Studies
PubMed: 23692812
DOI: 10.1016/j.ejca.2013.03.029