Cell metabolomics analyses revealed a role of altered fatty acid oxidation in neurotoxicity pattern difference between nab-paclitaxel and solvent-based paclitaxel.
Ontology highlight
ABSTRACT:
SUBMITTER: Huang JW
PROVIDER: S-EPMC7978375 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The pharmacokinetics, safety, and anticancer efficacy profiles of nanoparticle albumin-bound (nab)-paclitaxel formulations are superior to those of solvent-based paclitaxel formulations. The aims of the present study were to study the effects of nab-paclitaxel and solvent-based paclitaxel formulations on the metabolic profiles of the model cell line (A549) and attempt to elucidate the associated metabolic pathways. A mass spectrometry-based cell metabolomics approach and viability evaluation were used to explore the potential difference. Western blotting was utilized to measure the levels of relevant proteins, and carnitine palmitoyltransferase 1 (CPT1) activities were quantified. Fold changes normalized to controls in levels of carnitine and several acylcarnitines were significantly different (p < 0.05) between A549 cells treated with nab-paclitaxel and those treated with solvent-based paclitaxel. Relative to the controls, there were also significant fold change differences in palmitic and linoleic acid levels in the cell lysates, mitochondrial CPT1 activities, and mitochondrial medium-chain acyl-CoA dehydrogenase (MCAD) protein levels in the A549 cells subjected to the nab-paclitaxel and solvent-based paclitaxel formulations. Results suggested that the two formulations differentially modulated fatty acid oxidation in the A549 cells. While cell viability results did not reveal significant differences, the findings implied that a mass spectrometry-based cell metabolomics approach could be a sensitive tool to explore the differences caused by formulation changes without using animals. Since uncertainties of products containing nanomaterials warrant holistic screening to address safety concerns, the aforementioned approach may be of regulatory importance and is worth further investigation.
| S-EPMC7931197 | biostudies-literature
Project description:The aim of this study was to characterize population pharmacokinetics and the exposure-neutropenia relationship with nanoparticle albumin-bound (nab)-paclitaxel in patients with solid tumors. Plasma and blood concentrations of paclitaxel and neutrophil data were collected from 150 patients with various solid tumors over the nab-paclitaxel dose range of 80-375 mg/m(2). Data were analyzed using nonlinear mixed-effect modeling or logistic regression. Pharmacokinetics of nab-paclitaxel were described by a 3-compartment model with saturable distribution and elimination. The rapid disappearance of circulating paclitaxel was driven by its fast distribution to peripheral compartments; maximum rate for saturable distribution (325000 ?g/h) was 40-fold greater than that for saturable elimination (8070 ?g/h). Albumin was a significant covariate of paclitaxel elimination (P <?.001), while total bilirubin, creatinine clearance, body size, age, sex, and tumor type had no significant or clinically relevant effect. The probability of experiencing a ? 50% reduction in neutrophils was best correlated to the duration above the drug concentration of 720 ng/mL. At a given exposure level, neutropenia development was positively correlated with increasing age but not significantly influenced by hepatic function, tumor type, sex, or dosing schedule. Covariate analyses supports exposure-matched dose adjustments in patients with moderate to severe hepatic impairment.
| S-EPMC4302229 | biostudies-literature
Project description:nab-Paclitaxel is approved for the treatment of metastatic breast cancer on an every-3-week schedule based on positive findings from a pivotal phase III trial in which nab-paclitaxel 260 mg/m(2) every 3 weeks was superior to solvent-based paclitaxel 175 mg/m(2) every 3 weeks for the primary endpoint of overall response rate (33 % vs 19 %; P = 0.001). Subsequently, a number of trials have examined different schedules, doses, and combinations in efforts to optimize nab-paclitaxel-based therapy for metastatic and early-stage breast cancer. The goal of this review is to evaluate the clinical experiences to date with nab-paclitaxel as a single agent or in combination with targeted agents in different treatment settings - with a focus on the feasibility of administration, adverse event profile, and standard efficacy endpoints, such as overall survival, progression-free survival, overall response rate, and pathologic complete response rate. In general, weekly dosing during the first 3 of 4 weeks appears to achieve the best clinical benefit in both the metastatic and early-stage settings. Furthermore, the data suggest that high doses of nab-paclitaxel, such as 150 mg/m(2) during first 3 of 4 weeks or 260 mg/m(2) every 2 weeks, may be more feasible and appropriate for treatment of early-stage disease compared with metastatic disease. Intense regimens of nab-paclitaxel may not be the best treatment approach for unselected patients with metastatic breast cancer, but may suit a subset of patients for whom immediate disease control is required. The growing number of nab-paclitaxel trials in breast cancer will lead to greater refinements in tailoring therapy to patients based on their individual disease and patient characteristics.
| S-EPMC4465168 | biostudies-other
Project description:We present a rare phenomenon of a soft tumor hanging on the woman's left upper arm that underwent necrosis from the distal aspect during chemotherapy for pancreatic cancer. The benign tumor, pedunculated lipofibroma, originally had normal color for 10 years and then became necrotic when she was treated with gemcitabine and nab-paclitaxel. Necrosis stopped in conjunction with chemotherapy cessation. Dermatologists must remember that nab-paclitaxel could develop necrosis of a skin tumor.
| S-EPMC10293937 | biostudies-literature
Project description:BackgroundTo compare the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and solvent-based taxanes (sb-taxanes) as neoadjuvant therapy in the treatment of breast cancer.MethodsWe systematically searched the PubMed, Embase, and Cochrane Central Register databases. Randomized controlled trials (RCTs) and cohort studies, published in English, about the comparison between nab-paclitaxel and sb-taxanes as neoadjuvant therapy in patients with breast cancer were searched up to September 2019.ResultsThe primary outcome was the proportion of patients with pathological complete response (pCR, defined as ypT0 ypN0 or ypT0/is ypN0). Other main outcomes included long-term survival and adverse events (AEs). Seven studies (five RCTs and two cohorts) and 2949 patients were included. Neoadjuvant nab-paclitaxel improved pCR compared with sb-taxanes (ypT0 ypN0: OR = 1.52, 95%CI: 1.27-1.83, P < 0.001; ypT0/is ypN0: OR = 1.40, 95%CI: 1.17-1.68, P < 0.001). The benefits of nab-paclitaxel on pCR were persistent in HER2-negative, hormone receptor (HR)-positive breast cancer (OR = 1.53, 95%CI: 1.07-2.19, P = 0.020), triple-negative breast cancer (weekly/every 2 weeks regimen; OR = 2.95, 95%CI: 1.54-5.67, P < 0.001), and tumors with Ki-67 > 20% (OR = 1.63, 95%CI: 1.26-2.12, P < 0.001). Patients treated with nab-paclitaxel had better event-free survival (EFS; HR = 0.69, 95%CI: 0.57-0.85, P < 0.001) than with sb-taxanes. There were no differences in most of grade > 3 AEs between nab-paclitaxel and sb-taxanes (all P > 0.05), besides of any grade hypersensitivity (OR = 0.29, 95%CI: 0.11-0.72, P = 0.008), any grade (OR = 2.10, 95%CI: 1.37-3.23, P = 0.001) and grade > 3 (OR = 4.01, 95%CI: 2.51-6.41, P < 0.001) neuropathy.ConclusionNab-paclitaxel is effective for the treatment of non-metastatic breast cancer in the neoadjuvant setting. Nab-paclitaxel could improve pCR rate and EFS compared with sb-taxanes and with reasonable toxicities.
| S-EPMC7863369 | biostudies-literature
Project description:Paclitaxel (Px) is an effective chemotherapeutic agent for the treatment of various cancers. However, it is often associated with neurological side effects, including chemotherapy-associated cognitive impairment (CACI), such as "chemobrain". Previously, we reported that endoplasmic reticulum (ER) stress is involved in Px-induced neurotoxicity, and immunoglobulin heavy chain binding protein (BiP) inducer X (BIX) alleviates Px-induced neurotoxicity. However, BIX has not been used in clinical practice yet. We recently reported that fluvoxamine (Flv) alleviates ER stress via induction of sigma-1 receptor (Sig-1R). The purpose of this study was to investigate whether Flv could alleviate Px-induced neurotoxicity in vitro. SK-N-SH cells were pre-treated for 12 h with or without 10 μg/ml Flv followed by treatment with 1 μM Px with or without co-existence of 10 μg/ml Flv for 24 h. To investigate the involvement of Sig-1R in alleviation effect on Px-induced neurotoxicity,1 μM NE100, an antagonist of Sig-1R, was added for 24 h. Neurotoxicity was assessed using the MTS viability assay and ER stress-mediated neurotoxicity was assessed by evaluating the expression of C/EBP homologous protein (CHOP), cleaved caspase 4, and cleaved caspase 3. Pre-treatment with Flv significantly alleviated the induction of CHOP, cleaved caspase 4, and cleaved caspase 3 in SK-N-SH cells. At the same time, pre-treatment with Flv significantly induced Sig-1R in SK-N-SH cells. In addition, viability was significantly higher in Flv-treated cells than in untreated cells, which was reversed by treatment with NE100. Our results suggest that Flv alleviates Px-induced neurotoxicity in part through the induction of Sig-1R. Our findings should contribute to one of the novel approaches for the alleviation of Px-induced neurotoxicity, including chemobrain.
| S-EPMC5668922 | biostudies-literature
Project description:BACKGROUND:This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity. MATERIALS AND METHODS:This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated. RESULTS:Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ?2 polyneuropathy was shorter, and the median time to recovery from grade ?2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients' experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy. CONCLUSION:The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 IMPLICATIONS FOR PRACTICE: The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.
| S-EPMC6853092 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel has been added to the arsenal of first line therapies, and the combination of gemcitabine and nab-paclitaxel has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying nab-paclitaxel (n-PTX) resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naive PDAC patients. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the nab-paclitaxel-resistant cells. Depletion of c-Myc restored nab-paclitaxel sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small molecule activator of protein phosphatase 2a (SMAP). Implications: The strategies we have devised, including the patient-derived primary cells and the unique drug resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis
2019-05-31 | GSE131762 | GEO
Project description:Purposenab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL-paclitaxel and the underlying mechanisms.MethodsUptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation.ResultsLive imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL-paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose.ConclusionsCompared with CrEL-paclitaxel, nab-paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel.
| S-EPMC4768222 | biostudies-literature
Project description:PurposeConcurrent gemcitabine and nab-paclitaxel treatment is one of the preferred chemotherapy regimens for metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC). Previous studies demonstrate that caveolin-1 (Cav-1) expression is critical for nab-paclitaxel uptake into tumors and correlates with response. Gemcitabine increases nab-paclitaxel uptake by increasing Cav-1 expression. Thus, we hypothesized that pretreatment with gemcitabine would further enhance the sensitivity of PDAC to nab-paclitaxel by increasing Cav-1 expression and nab-paclitaxel uptake.Experimental designWe investigated the sensitivity of different gemcitabine and nab-paclitaxel treatment regimens in a panel of PDAC cell lines and orthotopic xenograft models. The sensitivity of different treatment regimens was compared with the standard concurrent treatment.ResultsPretreatment with gemcitabine before nab-paclitaxel increased Cav-1 and albumin uptake and significantly decreased proliferation and clonogenicity compared with concurrent treatment, which correlated with increased levels of apoptosis. Cav-1 silencing reduced the uptake of albumin, and therapeutic advantage was observed when cells were pretreated with gemcitabine prior to nab-paclitaxel. In addition, we observed that pretreatment with gemcitabine resulted in partial synchronization of cells in the G2-M-phase at the time of nab-paclitaxel treatment, providing another mechanism for the benefit of altered scheduling. In heterotopic and orthotopic xenograft models, the altered schedule of gemcitabine prior to nab-paclitaxel significantly delayed tumor growth compared with concurrent delivery without added toxicity.ConclusionsPretreatment with gemcitabine significantly increased nab-paclitaxel uptake and correlated with an increased treatment efficacy and survival benefit in preclinical models, compared with standard concurrent treatment. These results justify preclinical and clinical testing of this altered scheduling combination.
| S-EPMC7855515 | biostudies-literature