Clinical and pharmacokinetic study of sunitinib and docetaxel in women with advanced breast cancer
Jonas BerghGabriella MarianiFátima CardosoAnnelie LiljegrenAhmad AwadaLucia ViganòXin HuangLev VerkhKenneth A. KernC. GiorgettiLuca Gianni
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This exploratory study examined the pharmacokinetics, safety, and antitumor activity of sunitinib plus docetaxel in patients with HER-2-negative advanced breast cancer.Patients with HER-2-negative disease who had received prior adjuvant anthracycline-based therapy received docetaxel (75 mg/m(2)) on day 1 of each 3-week cycle followed by sunitinib (37.5 mg/day for 2 weeks on Schedule 2/1) starting on day 2 (day 3 on cycle 2).Twenty-two patients were enrolled. No clinically significant drug-drug interactions were observed. The most common non-hematologic AE (any grade) was fatigue/asthenia. Grade 4 neutropenia occurred in 20/22 patients (91%; n = 7 had neutropenic fever). The safety profile was similar to each agent given individually. 14/19 (73.7%) evaluable patients had a PR and 5/19 (26.3%) had SD.Sunitinib plus docetaxel on Schedule 2/1 did not result in any clinically significant drug-drug interactions. This combination was manageable and exhibited antitumor activity.4194 Background: In vitro chemosensitivity testing for individualized chemotherapy is known to improve the reponse rates although the impact on survival has not been adequately addressed. In vitro testing concentrations for new anticancer drugs such as the taxanes are unknown. Methods: Chemosensitivity tests for 30 gastric carcinoma tissues obtained at surgery were performed with Histoculture Drug Response Assay (HDRA) at 150μg/mL for 5FU and at three different concentrations for docetaxel (3, 30, 100 μg/mL) and paclitaxel (10, 60, 100 μg/mL). Inhibition rates (IR) were calculated using the formlula: (1-A/B) × 100% where A and B represent the mean absorbances of drug-treated and control wells, respectively. Results: For both drugs, the inhibition rates rose significantly as the testing concentration was elevated. Valid testing concentrations were determined as 10 μg/mL for paclitaxel and 30 μg/mL for docetaxel, based on the distribution of IRs between 0 and 100%. Five, 10 and 8 tumors were ranked as sensitive to 5FU, paclitaxel, and docetaxel, respectively. IRs of 5FU correlated significantly with those of docetaxel (R=0.37, p=0.0336), but not with those of paclitaxel, suggesting that paclitaxel may be more useful for combined or sequential administration with 5FU. Of the 30 patients, 5 underwent non-curative resection and another 5 had recurrences. Nine of these 10 patients underwent chemotherapy with S-1 (oral tegafur + Gimestat, an inhibitor of dihydroxylpyrimidine dehydrogenase), of which two patients responded, but none had been ranked as sensitive for 5FU. Two of the patients went on to receive weekly paclitaxel as a second line chemotherapy despite not being ranked as sensitive, and were found not to respond. Conclusions: Recommended concentration for HDRA was determined as 10 μg/mL for paclitaxel and 30 μg/mL for docetaxel, respectively. Correlation between the results of HDRA and clinical responses remains unclear. Given that S-1 is the most widely used front line treatment, HDRA should in future be modified to test the effect of 5FU in combination with Gimestat. No significant financial relationships to disclose.
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Drug response
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OBJECTIVE: To review the mechanism involved in paclitaxel-induced hypersensitivity reactions and to evaluate the potential use of docetaxel after acute hypersensitivity reactions (HSRs) to paclitaxel. DATA SOURCES: Literature identified through a MEDLINE search (1966–September 2000) and through secondary sources. DATA SYNTHESIS: HSRs to paclitaxel can be life-threatening. The exact etiology involved in paclitaxel-induced HSRs has not been fully elucidated; the reactions may be due to the Cremophor EL vehicle or to paclitaxel itself. Options for treatment following HSRs are limited. A rechallenge attempt can be made, but is not always successful. Docetaxel, a semisynthetic taxane, may have a role in therapy for patients unable to tolerate paclitaxel therapy. This review examines the etiology of paclitaxel-induced HSRs and the potential role of docetaxel following these acute reactions. CONCLUSIONS: Docetaxel may be a viable alternative for patients who experience HSRs to paclitaxel.
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The taxoid drugs, docetaxel (Taxotere) and paclitaxel (Taxol), represent a new class of antitumour agents which act by promoting the assembly and inhibiting the disassembly of microtubules. Docetaxel has been shown to be more potent than paclitaxel with regard to the formation and stabilization of microtubules in vitro. Docetaxel also has a higher cell uptake than paclitaxel and a longer intracellular retention time. Docetaxel is a more potent antitumour agent than paclitaxel in most model systems. The observation that the cytotoxic concentration for docetaxel is lower than that for paclitaxel in cultures of human haematopoietic cells supports the clinical observation that dose-limiting neutropenia is seen at a lower dose of docetaxel than paclitaxel. The concentration of docetaxel required to kill tumour cells in vitro is well within the plasma concentrations recorded in clinical studies, and docetaxel has shown extensive clinical activity against a variety of solid tumours. Most drugs are used in combination regimens in the clinic and combinations of docetaxel with other agents are under active investigation. The agents to be combined with docetaxel include those which showed synergism with docetaxel in vitro and can be delivered at optimal doses without additive toxicity.
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e13567 Background: Paclitaxel and docetaxel share major parts of their structures and mechanism of action, but differ in several aspects. Both paclitaxel and docetaxel act at microtubule causing tubulin polymer generation but exhibit pharmacodynamic differences. These pharmacological differences may account for the differences observed between taxanes in their clinical activity and toxicity. Methods: Review of articles providing details of taxane pharmacology was conducted to evaluate pharmacological basis. Results: Greater uptake and slower efflux of docetaxel from tumor cells leads to longer retention time; whereas equal uptake and efflux of paclitaxel shorter retention time for paclitaxel. Hence, apoptotic and mitotic responses of paclitaxel is complete within 4 days implying that more frequent (weekly) administration of paclitaxel will be superior. High affinity to β-tubulin with docetaxel (1.9) than with paclitaxel (1.0) allows higher inhibition of tumor growth. Secondly, drug concentration causing maximum polymerization is 0.2 µM and 0.4 µM for docetaxel and paclitaxel, respectively; indicating that docetaxel is twice as potent as paclitaxel in causing microtubule polymerization. Docetaxel arrests cells in the radiosensitive G2/M phase of the cell cycle making it a potent radiosensetizer than paclitaxel. Mechanisms consistent with allosteric modulation of the reductases increase doxorubicinol formation at clinically relevant concentrations of paclitaxel when it is administered with doxorubicin. Enhanced formation of doxorubicinol aglycone, a metabolite potentially involved in the reversible phase of cardiotoxicity causes higher cardiotoxicty when doxorubicin is administered with paclitaxel than with docetaxel. Non linear pharmacokinetics and hypersensitivity with paclitaxel and fluid retention with docetaxel is attributed to excepient of the drug rather than drug itself. Conclusions: Influx and efflux mechanism support superior weekly administration of Paclitaxel. Pharmacological differences between taxanes justify the incomplete resistance seen between taxanes. The incomplete cross resistance is specifically related to docetaxelactivity in paclitaxel resistant cases.
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis and Structure-Activity Relationships of New Antitumor Taxoids. Effects of Cyclohexyl Substitution at the C-3' and/or C-2 of Taxotere (Docetaxel)Iwao Ojima, Olivier Duclos, Martine Zucco, Marie-Christine Bissery, C. Combeau, P. Vrignaud, J. F. Riou, and Francois LavelleCite this: J. Med. Chem. 1994, 37, 16, 2602–2608Publication Date (Print):August 5, 1994Publication History Published online1 May 2002Published inissue 5 August 1994https://pubs.acs.org/doi/10.1021/jm00042a013https://doi.org/10.1021/jm00042a013research-articleACS PublicationsRequest reuse permissionsArticle Views538Altmetric-Citations33LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
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Objective To provide the basis for the clinical application of paclitaxel and docetaxel,compare their differences on pharmacological profiles and patterns of clinical activity. Methods The literature of taxanes was analyzed. Results The two taxanes differed in structures,pharmacokinetic charateristics,drug interactions,toxicity and administrations. Conclusion The rational use of the two taxanes should be based on their differences.
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