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Beijing Da Xue Xue Bao. Yi Xue Ban =... Jun 2019Larotaxel is a new chemical structure drug, which has not been marketed worldwide. Accordingly, the standard identification and quantification methods for larotaxel...
OBJECTIVE
Larotaxel is a new chemical structure drug, which has not been marketed worldwide. Accordingly, the standard identification and quantification methods for larotaxel remain unclear. The spectrometric analyses were performed for verifying weight molecular formula, molecular weight and chemical structure of larotaxel. Besides, a quantification method was developed for measuring larotaxel in the liposomes.
METHODS
The molecular formula, molecular weight and chemical structure of larotaxel were studied by using mass spectrometry (MS), infra-red (IR), nuclear magnetic resonance (NMR) and ultraviolet-visible (UV-vis) spectrometric techniques. The absorption wavelength of larotaxel was investigated by UV-vis spectrophotometry full-wavelength scanning. Besides, a quantification method was developed by high performance liquid chromatography (HPLC), and then validated by measuring the encapsulation efficacy of larotaxel liposomes.
RESULTS
The four spectral characteristics of larotaxel were revealed and the corresponding standard spectra were defined. It was confirmed that larotaxel had the structure of tricyclic diterpenoids, with the molecular formula of C45H53NO14, the molecular weight of 831.900 1, and the maximum absorption wavelength of 230 nm. The quantitative method of larotaxel was established by using HPLC with a reversed phase C18 column (5 μm, 250 mm×4.6 mm), a mobile phase of acetonitrile-water (75:25, volume/volume), and a detection wavelength of 230 nm. The validation study exhibited that the established HPLC method was stable, and had a high recovery and precision in the quantitative measurement of larotaxel in liposomes. In addition, a new kind of larotaxel liposomes was also successfully prepared. The particle size of the liposomes was about 105 nm, with an even size distribution. And the encapsulation efficiency of larotaxel in the liposomes was above 80%.
CONCLUSION
The present study offers reference standard spectra of larotaxel, including MS, IR, NMR, and UV-vis, and confirms the molecular formula, molecular weight and chemical structure of larotaxel. Besides, the study develops a rapid HPLC method for quality control of larotaxel liposomes.
Topics: Chromatography, High Pressure Liquid; Liposomes; Magnetic Resonance Spectroscopy; Taxoids
PubMed: 31209418
DOI: 10.19723/j.issn.1671-167X.2019.03.014 -
Journal of Pharmaceutical Analysis Apr 2017Larotaxel, a new taxane compound prepared by partial synthesis from 10-deacetyl baccatin III, is active against tumors. In this research, a selective LC-MS method was...
Larotaxel, a new taxane compound prepared by partial synthesis from 10-deacetyl baccatin III, is active against tumors. In this research, a selective LC-MS method was developed and validated for the study of degradation kinetics of larotaxel, which was carried out in aqueous solutions with different pH (1.5, 3.0, 5.0, 6.5, 7.4, 9.0, 10 and 11.0) and temperature (0, 25, 37 and 45 °C). The linear range was 0.5-25 μg/mL, the intra- and inter-day precisions were less than 7.0%, and accuracy ranged from 97.4-104.5% for each analyte. The observed rate obtained by measuring the remaining intact larotaxel was shown to follow first-order kinetics. The activation energies for degradation were 126.7 and 87.01 kJ/mol at pH 1.5 and 11, respectively. Although larotaxel was stable in pH 5, 6.5 and 7.4 buffers at 37 °C for 24 h during our study, increasing or decreasing the pH of the solutions would decrease its stabilities. Moreover, three main degradation products in alkaline condition were separated by HPLC and identified by Q-TOF-MS. The three degradation products were confirmed as 10-deacetyl larotaxel, 7, 8-cyclopropyl baccatin Ⅲ and 10-deacetyl-7, 8-cyclopropyl baccatin Ⅲ.
PubMed: 29404026
DOI: 10.1016/j.jpha.2016.11.002 -
Chemical Science Apr 2018We introduce fluorogenic tubulin probes based on the recently reported fluorescent dyes (510R, 580CP, GeR and SiR) and chemotherapy agents - taxanes (docetaxel,...
We introduce fluorogenic tubulin probes based on the recently reported fluorescent dyes (510R, 580CP, GeR and SiR) and chemotherapy agents - taxanes (docetaxel, cabazitaxel and larotaxel). The cytotoxicity of the final probe, its staining performance and specificity strongly depend on both components. We found correlation between the aggregation efficiency (related to the spirolactonization of fluorophore) and cytotoxicity. Probe optimization allowed us to reach 29 ± 11 nm resolution in stimulated emission depletion (STED) microscopy images of the microtubule network in living human fibroblasts. Application to living fruit fly () tissues highlighted two distinct structures: microtubules and tracheoles. We identified 6-carboxy isomers of 580CP and SiR dyes as markers for chitin-containing taenidia, a component of tracheoles. STED microscopy revealed correlation between the taenidia periodicity and the diameter of the tracheole. Combined tubulin and taenidia STED imaging showed close interaction between the microtubules and respiratory networks in living tissues of the insect larvae.
PubMed: 29780462
DOI: 10.1039/c7sc05334g -
Seminars in Oncology Jun 2021The present systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) aimed to compare the mortality rates related to adverse events (AEs)... (Meta-Analysis)
Meta-Analysis Review
Adverse events of different chemotherapy regimens in the first-line treatment of patients with advanced or metastatic urothelial cancer: A systematic review and network meta-analysis of randomized controlled trials.
INTRODUCTION
The present systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) aimed to compare the mortality rates related to adverse events (AEs) and discontinuation of treatment due to toxicity as well as all AEs of currently used chemotherapy regimens for first-line therapy of advanced or metastatic urothelial carcinoma of the bladder (UCB).
MATERIAL AND METHODS
The MEDLINE and EMBASE databases were searched for articles published between January 2000 and June 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis extension statement for NMA. Eligible studies included RCTs comparing different first-line chemotherapy regimens for treating advanced or metastatic UCB and AEs as outcome measures. A NMA was performed to assess the mortality rates related to AEs and discontinuation of treatment due to toxicity as well as all AEs.
RESULTS
Fourteen trials comprising 2,615 patients met our eligibility criteria and formal NMAs were conducted. Results revealed that gemcitabine plus carboplatin had the lowest likelihood of mortality related to AEs (P score: 0.8079), while larotaxel plus cisplatin and paclitaxel, cisplatin plus gemcitabine had both a lower toxicity rate leading to discontinuation (P score: 0.7295 and P score: 0.7242, respectively). Compared with gemcitabine plus cisplatin (GC), most chemotherapy regimens were associated with a lower likelihood of thrombocytopenia, anemia, and cardiovascular toxicity. In contrast, most chemotherapy regimens compared with GC were associated with a higher likelihood of neutropenia, central (fatigue, neuropathy) and gastrointestinal AEs, infections, as well as renal and pulmonary toxicities.
CONCLUSION
Results of the present study demonstrated that hematological toxicity was the most prevalent AE associated with gemcitabine-containing regimens, while central AEs and febrile neutropenia were more commonly in taxane-containing regimens. GC had the lowest rate of gastrointestinal AEs, infection disorders, and pulmonary toxicities. Cisplatin-containing regimens were associated with a higher rate of renal and cardiovascular toxicity. These differential AEs may help in the detection of the personalized therapy in addition of efficacy data.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Female; Humans; Male; Network Meta-Analysis; Randomized Controlled Trials as Topic; Urinary Bladder Neoplasms
PubMed: 34749886
DOI: 10.1053/j.seminoncol.2021.09.005 -
Journal of Thoracic Oncology : Official... Aug 2008This randomized phase II study investigated the efficacy and safety of a new taxane, larotaxel (XRP9881), in combination with either cisplatin or gemcitabine in the... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized multicenter phase II study of larotaxel (XRP9881) in combination with cisplatin or gemcitabine as first-line chemotherapy in nonirradiable stage IIIB or stage IV non-small cell lung cancer.
INTRODUCTION
This randomized phase II study investigated the efficacy and safety of a new taxane, larotaxel (XRP9881), in combination with either cisplatin or gemcitabine in the first-line treatment of patients with nonirradiable stage IIIB or stage IV non-small cell lung cancer to select the combination having the most promising antitumor activity.
METHODS
Patients received either larotaxel (50 mg/m) as a 1-hour infusion, followed by a 1-hour infusion of cisplatin (75 mg/m), every 3 weeks (arm A), or gemcitabine (800 mg/m) as a 30 minute infusion, on days 1 and 8, and larotaxel (60 mg/m) as a 1-hour infusion, on day 8 (following gemcitabine), every 3 weeks (arm B). The primary end point was the objective response rate (per-protocol population).
RESULTS
Thirty-two patients were randomized to arm A and 30 to arm B. The response rate was higher in arm A compared with arm B in both the per-protocol (26.7% versus 18.2%) and intention-to-treat (28.1% versus 13.3%) populations. In the intention-to-treat population, median progression-free survival for arm A versus arm B was 4.7 versus 3.3 months and median overall survival was 8.6 versus 7.3 months, respectively. Fifty percent of patients in arm A and 66.7% in arm B experienced at least one National Cancer Institute common toxicity criteria grade 3/4 adverse event and grade 3/4 neutropenia was observed in 46.9% and 41.4% of patients, respectively.
CONCLUSIONS
Both larotaxel combinations were effective and manageable, however all measured efficacy parameters (response rate, progression free survival, and survival) seemed to favor the combination with cisplatin.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Survival Rate; Taxoids; Gemcitabine
PubMed: 18670308
DOI: 10.1097/JTO.0b013e31817e6669 -
Annals of Oncology : Official Journal... Mar 2012Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in... (Review)
Review
BACKGROUND
Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in cytotoxic therapy for patients with metastatic breast cancer (MBC).
MATERIALS AND METHODS
Medline searches were conducted for English language studies using the term 'MBC' and 'cytotoxic drugs'. The data search was restricted to the period 2000-2011.
RESULTS
Several novel cytotoxic compounds, all microtubule inhibitors, have been approved for clinical use in MBC: (i) nab-paclitaxel, reported to improve tumour response and decrease hypersensitivity reactions in comparison with other taxanes; (ii) ixabepilone, shown to have clinical benefit in taxane- and anthracycline-resistant disease and (iii) eribulin, shown to improve overall survival in heavily pre-treated patients, when compared with best available standard treatment. Agents, such as larotaxel, vinflunine, trabectidin and formulations, including cationic liposomal paclitaxel or paclitaxel poliglumex, are currently under evaluation in phase II/III trials.
CONCLUSION
Toxicity and chemotherapy resistance are still major limitations in the treatment of patients with MBC. Further research into new cytotoxic compounds is needed in order to maximise benefit, whilst minimising toxicity.
Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cytotoxins; Female; Humans
PubMed: 21896541
DOI: 10.1093/annonc/mdr382 -
Annals of Oncology : Official Journal... Jul 2008Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against...
BACKGROUND
Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against taxane-resistant breast cancer. The current phase II trial of larotaxel was conducted in women with taxane-treated MBC.
PATIENTS AND METHODS
Patients were stratified by response to prior taxane therapy (resistant or nonresistant). Larotaxel 90 mg/m(2) was administered as a 1-h infusion every 3 weeks. Patients were evaluated for tumor response every two cycles. A blinded external response review committee determined the overall response rate (ORR), duration of response (DOR), and time to progression (TtP) of the disease. Median survival time (MST) and safety were also evaluated.
RESULTS
One hundred and thirty patients were treated. In the nonresistant group, the ORR was 42%; median DOR 5.3 months; median TtP 5.4 months; and MST 22.6 months. In the resistant group, the ORR was 19%; median DOR 5.0 months; median TtP 1.6 months; and MST 9.8 months. The most common grade 3/4 adverse events were neutropenia (82%), fatigue (15%), diarrhea (12%), febrile neutropenia (9%), neutropenic infection (8%), and sensory neuropathy (7%).
CONCLUSIONS
Larotaxel has good activity, manageable toxicity, and a favorable therapeutic index in women with taxane-pretreated MBC.
Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Diarrhea; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Fatigue; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Neutropenia; Prospective Studies; Taxoids; Time Factors; Treatment Outcome
PubMed: 18381372
DOI: 10.1093/annonc/mdn060 -
Magyar Onkologia Mar 2010The treatment of recurrent, progressing, metastatic breast cancer, which has previously been exposed to anthracyclines and/or taxanes is not only a major clinical... (Review)
Review
The treatment of recurrent, progressing, metastatic breast cancer, which has previously been exposed to anthracyclines and/or taxanes is not only a major clinical challenge, but has a significant social impact too. In the absence of formal guidelines, this review has aimed to summarize the published evidence that is needed to guide clinical decision-making. Four new agents are approved for use in this setting: capecitabine, gemcitabine, ixabepilone, and nanoparticle albumin-bound paclitaxel. Nevertheless this review summarizes the results of studies with other active agents, as liposomal doxorubicin, rotation of taxanes, larotaxel, vinorelbine, and other biological agents.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease Progression; Doxorubicin; Epothilones; Female; Fluorouracil; Humans; Paclitaxel; Salvage Therapy; Taxoids; Vinblastine; Vinorelbine; Gemcitabine
PubMed: 20350863
DOI: 10.1556/MOnkol.54.2010.1.2 -
Advanced Science (Weinheim,... Sep 2022Spatiotemporal delivery of nanoparticles (NPs) at the "cellular level" is critical for nanomedicine, which is expected to deliver as much cytotoxic drug into cancer...
Spatiotemporal delivery of nanoparticles (NPs) at the "cellular level" is critical for nanomedicine, which is expected to deliver as much cytotoxic drug into cancer cells as possible when NPs accumulate in tumors. However, macrophages and cancer-associated fibroblasts (CAFs) that are present within tumors limit the efficiency of spatiotemporal delivery. To overcome this limitation, glutathion pulse therapy is designed to promote reduction-sensitive Larotaxel (LTX) prodrug NPs to escape the phagocytosis of macrophages and penetrate through the stromal barrier established by CAFs in the murine triple negative breast cancer model. This therapy improves the penetration of NPs in tumor tissues as well as the accumulation of LTX in cancer cells, and remodels the immunosuppressive microenvironment to synergize PD-1 blockade therapy. More importantly, a method is established that can directly observe the biodistribution of NPs between different cells in vivo to accurately quantify the target drugs accumulated in these cells, thereby advancing the spatiotemporal delivery research of NPs at the "cellular level."
Topics: Animals; Glutathione; Humans; Mice; Nanoparticles; Neoplasms; Prodrugs; Programmed Cell Death 1 Receptor; Taxoids; Tissue Distribution; Tumor Microenvironment
PubMed: 35896947
DOI: 10.1002/advs.202202744 -
Translational Oncology Jun 2015Combination chemotherapy with gemcitabine and cisplatin in patients with metastatic urothelial cancer of the bladder frequently results in the development of acquired...
Combination chemotherapy with gemcitabine and cisplatin in patients with metastatic urothelial cancer of the bladder frequently results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance could help to identify candidate treatments for an efficient second-line therapy. Six cisplatin- and six gemcitabine-resistant cell lines were established. Cell viability assays were performed to evaluate the sensitivity to 16 different chemotherapeutic substances. The activity of the drug transporter ATP-binding cassette transporter, subfamily B, member 1 (ABCB1, a critical mediator of multidrug resistance in cancer) was evaluated using fluorescent ABCB1 substrates. For functional assessment, cells overexpressing ABCB1 were generated by transduction with a lentiviral vector encoding for ABCB1, while zosuquidar was used for selective inhibition. In this study, 8 of 12 gemcitabine- or cisplatin-resistant cell lines were cross-resistant to carboplatin, 5 to pemetrexed, 4 to methotrexate, 3 to oxaliplatin, 5-fluorouracil, and paclitaxel, and 2 to cabazitaxel, larotaxel, docetaxel, topotecan, doxorubicin, and mitomycin c, and 1 of 12 cell lines was cross-resistant to vinflunine and vinblastine. In one cell line with acquired resistance to gemcitabine (TCC-SUP(r)GEMCI(20)), cross-resistance seemed to be mediated by ABCB1 expression. Our model identified the vinca alkaloids vinblastine and vinflunine, in Europe an already approved second-line therapeutic for metastatic bladder cancer, as the most effective compounds in urothelial cancer cells with acquired resistance to gemcitabine or cisplatin. These results demonstrate that this in vitro model can reproduce clinically relevant results and may be suitable to identify novel substances for the treatment of metastatic bladder cancer.
PubMed: 26055179
DOI: 10.1016/j.tranon.2015.04.002