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ACS Nano Aug 2023Modest tissue penetrance, nonuniform distribution, and suboptimal release of drugs limit the potential of intracranial therapies against glioblastoma. Here, a...
Modest tissue penetrance, nonuniform distribution, and suboptimal release of drugs limit the potential of intracranial therapies against glioblastoma. Here, a conformable polymeric implant, μMESH, is realized by intercalating a micronetwork of 3 × 5 μm poly(lactic--glycolic acid) (PLGA) edges over arrays of 20 × 20 μm polyvinyl alcohol (PVA) pillars for the sustained delivery of potent chemotherapeutic molecules, docetaxel (DTXL) and paclitaxel (PTXL). Four different μMESH configurations were engineered by encapsulating DTXL or PTXL within the PLGA micronetwork and nanoformulated DTXL (nanoDTXL) or PTXL (nanoPTXL) within the PVA microlayer. All four μMESH configurations provided sustained drug release for at least 150 days. However, while a burst release of up to 80% of nanoPTXL/nanoDTXL was documented within the first 4 days, molecular DTXL and PTXL were released more slowly from μMESH. Upon incubation with U87-MG cell spheroids, DTXL-μMESH was associated with the lowest lethal drug dose, followed by nanoDTXL-μMESH, PTXL-μMESH, and nanoPTXL-μMESH. In orthotopic models of glioblastoma, μMESH was peritumorally deposited at 15 days post-cell inoculation and tumor proliferation was monitored via bioluminescence imaging. The overall animal survival increased from ∼30 days of the untreated controls to 75 days for nanoPTXL-μMESH and 90 days for PTXL-μMESH. For the DTXL groups, the overall survival could not be defined as 80% and 60% of the animals treated with DTXL-μMESH and nanoDTXL-μMESH were still alive at 90 days, respectively. These results suggest that the sustained delivery of potent drugs properly encapsulated in conformable polymeric implants could halt the proliferation of aggressive brain tumors.
Topics: Animals; Glioblastoma; Pharmaceutical Preparations; Nanoparticles; Paclitaxel; Docetaxel; Polymers; Polyvinyl Alcohol; Cell Line, Tumor
PubMed: 37379253
DOI: 10.1021/acsnano.3c01574 -
Scientific Reports Mar 2021Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin....
Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Docetaxel; Doxorubicin; Female; Humans; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays
PubMed: 33782404
DOI: 10.1038/s41598-021-85962-4 -
Drug Design, Development and Therapy 2022To evaluate the prostate cancer therapy efficiency of the synergistic combination docetaxel (DTX) and formononetin (FMN) in one nano-sized drug delivery system....
Prostate Cancer Therapy Using Docetaxel and Formononetin Combination: Hyaluronic Acid and Epidermal Growth Factor Receptor Targeted Peptide Dual Ligands Modified Binary Nanoparticles to Facilitate the in vivo Anti-Tumor Activity.
OBJECTIVE
To evaluate the prostate cancer therapy efficiency of the synergistic combination docetaxel (DTX) and formononetin (FMN) in one nano-sized drug delivery system. Hyaluronic acid (HA) and epidermal growth factor receptor-targeted peptide (GE11) dual ligands were applied to modify the nano-systems.
METHODS
In this study, GE11-modified nanoparticles (GE-NPs) were applied for the loading of DTX, and HA-decorated NPs (HA-NPs) were used to encapsulate FMN. HA and GE11 dual ligand-modified binary nanoparticles (HAGE-DTX/FMN-NPs) were constructed by the self-assembling of GE-NPs and HA-NPs. The anti-PCa ability of the system was evaluated in vitro on PC-3 human prostate carcinoma cells (PC3 cells) and in vivo on PC3 tumor-bearing mice in comparison with single NPs and free drugs formulations.
RESULTS
HA/GE-DTX/FMN-NPs were nano-sized particles with smaller particles coating on the inner core and achieved a size of 189.5 nm. HA/GE-DTX/FMN-NPs showed a cellular uptake efficiency of 59.6%, and a more efficient inhibition effect on PC3 cells compared with single ligand-modified NPs and free drugs. HA/GE-DTX/FMN-NPs showed significantly higher tumor inhibition efficiency than their single drug-loaded counterparts and free drugs.
CONCLUSION
HA/GE-DTX/FMN-NPs have a synergistic anti-tumor effect and also could the reduce unexpected side effects during the cancer therapy. It could be used as a promising anti-PCa system.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Docetaxel; Drug Carriers; ErbB Receptors; Humans; Hyaluronic Acid; Isoflavones; Ligands; Male; Mice; Nanoparticles; Peptides; Prostate; Prostatic Neoplasms; Taxoids
PubMed: 35983428
DOI: 10.2147/DDDT.S366622 -
European Urology Dec 2023In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel...
Clinical and Genomic Differences Between Advanced Molecular Imaging-detected and Conventional Imaging-detected Metachronous Oligometastatic Castration-sensitive Prostate Cancer.
In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel therapy, metastasis-directed therapy, and radiation to the prostate. Although there are multiple definitions of disease volume, they have commonly been studied in the context of metastases detected via conventional imaging (CIM). One such numeric definition of disease volume, termed oligometastasis, is heavily dependent on the sensitivity of the imaging modality. We performed an international multi-institutional retrospective review of men with metachronous oligometastatic CSPC (omCSPC), detected via either advanced molecular imaging alone (AMIM) or CIM. Patients were compared with respect to clinical and genomic features using the Mann-Whitney U test, Pearson's χ test, and Kaplan-Meier overall survival (OS) analyses with a log-rank test. A total of 295 patients were included for analysis. Patients with CIM-omCSPC had significantly higher Gleason grade group (p = 0.032), higher prostate-specific antigen at omCSPC diagnosis (8.0 vs 1.7 ng/ml; p < 0.001), more frequent pathogenic TP53 mutations (28% vs 17%; p = 0.030), and worse 10-yr OS (85% vs 100%; p < 0.001). This is the first report of clinical and biological differences between AMIM-detected and CIM-detected omCSPC. Our findings are particularly important for ongoing and planned clinical trials in omCSPC. PATIENT SUMMARY: Metastatic prostate cancer with just a few metastases only detected via newer scanning methods (called molecular imaging) is associated with fewer high-risk DNA mutations and better survival in comparison to metastatic cancer detected via conventional scan methods.
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Molecular Imaging; Genomics; Castration
PubMed: 37173210
DOI: 10.1016/j.eururo.2023.04.025 -
Cancer Medicine Aug 2023This study examined the health-related quality of life (HRQoL) of patients with advanced non-small cell lung cancer (NSCLC) receiving tislelizumab versus docetaxel in... (Randomized Controlled Trial)
Randomized Controlled Trial
This study examined the health-related quality of life (HRQoL) of patients with advanced non-small cell lung cancer (NSCLC) receiving tislelizumab versus docetaxel in the open-label, multicenter, Phase 3 trial called RATIONALE-303 (NCT03358875). HRQoL was assessed with the EORTC QLQ-C30, EORTC QLQ-LC13, and the EQ-5D-5L instruments. A longitudinal analysis of covariance assessed the change from baseline to Week 12 and from baseline to Week 18. A time to deterioration analysis was also performed using the Kaplan-Meier method. Eight hundred and five patients were randomized to either tislelizumab (n = 535) or docetaxel, respectively (535 and 270 to tislelizumab and docetaxel, respectively). The tislelizumab arm improved while the docetaxel arm worsened in the QLQ-C30 global health status/QoL scale score (difference LS mean change Week 18: 5.7 [95% CI: 2.38, 9.07, p = 0.0008]), fatigue (Week 12: -3.2 [95% CI: -5.95, -0.37, p < 0.0266]; Week 18: -4.9 [95% CI: -8.26, -1.61, p = 0.0037]), and QLQ-LC13 symptom index score (Week 12: -5.5 [95% CI: -6.93, -4.04, P < 0.0001]; Week 18: -6.6 [95% CI: -8.25, -4.95, p < 0.0001]). The tislelizumab arm had improvements in coughing versus the docetaxel arm (Week 12: -4.7 [95% CI: -8.57, -0.78, p = 0.0188]; Week 18: -8.3 [95% CI: -13.02, -3.51, p = 0.0007]). The patients who received tislelizumab were less at risk for clinically meaningful worsening in the overall lung cancer symptom index scale (hazard ratio (HR): 0.24 [95% CI: 0.162, 0.356], p < 0.0001), dyspnea (HR: 0.74 [95% CI: 0.567, 0.958], p = 0.0109), coughing (HR: 0.74 [95% CI: 0.534, 1.019], p = 0.0309), and peripheral neuropathy (HR: 0.55 [95% CI: 0.370, 0.810] p = 0.0011). In general, tislelizumab versus docetaxel was associated with improved HRQoL and symptoms of lung cancer in patients who previously failed treatment with platinum-containing chemotherapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Quality of Life; Docetaxel; Cough
PubMed: 37587845
DOI: 10.1002/cam4.6361 -
Deutsches Arzteblatt International Sep 2022For many years, the standard treatment of metastatic, hormone-sensitive prostatic carcinoma (mHSPC) was androgen deprivation therapy (ADT) alone. By lowering the...
BACKGROUND
For many years, the standard treatment of metastatic, hormone-sensitive prostatic carcinoma (mHSPC) was androgen deprivation therapy (ADT) alone. By lowering the testosterone level into the castration range, ADT deprives the tumor of a key growth factor.
METHODS
For this article, we evaluated the treatment recommendations contained in national and international guidelines (German S3 guidelines and those of the European Society for Medical Oncology [ESMO], European Association of Urology [EAU], and National Comprehensive Cancer Network [NCCN]), as well as pertinent publications revealed by a PubMed search and the congress abstracts of the ESMO and of the American Society of Clinical Oncology [ASCO].
RESULTS
The past few years have witnessed fundamental changes in the treatment of mHSPC. Treatment intensification with docetaxel or with the new drugs directed against the androgen receptor signal pathway (abiraterone, apalutamide and enzalutamide) has been found to lower mortality by 19-40% and is now an integral component of first-line therapy. Relevant new findings have also been obtained with threefold combinations of ADT, docetaxel, and abiraterone or darolutamide. For patients with a light tumor burden, local radiotherapy of the primary tumor improves the probability of survival at 3 years by 8% (45.4 versus 49.1 months, difference 3.6 months; 95% confidence interval, 1.0 to 6.2 months).
CONCLUSION
The treatment of mHSPC is constantly changing. Phase III trials that are now in the recruitment stage, as well as our continually improving understanding of the underlying molecular-pathological mechanisms, will be altering the treatment landscape still further in the years to come.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Docetaxel; Carcinoma; Hormones
PubMed: 35912436
DOI: 10.3238/arztebl.m2022.0294 -
The Korean Journal of Internal Medicine Nov 2020We evaluated the efficacy of docetaxel and epirubicin as neoadjuvant chemotherapy in locally advanced breast cancer and assessed the predictive factors for response to...
BACKGROUND/AIMS
We evaluated the efficacy of docetaxel and epirubicin as neoadjuvant chemotherapy in locally advanced breast cancer and assessed the predictive factors for response to neoadjuvant chemotherapy and prognostic factors related to relapse-free survival.
METHODS
Forty patients who received docetaxel and epirubicinas neoadjuvant chemotherapy for locally advanced breast cancer were evaluated retrospectively. Neoadjuvant chemotherapy consisted of intravenous injection of 75 mg/m2 docetaxel and 60 mg/m2 epirubucin on day 1, every 21 days, and two to six cycles.
RESULTS
Twenty-five (62.5%) patients showed a partial response, and 15 (37.5%) patients showed a stable disease in the first response evaluation after two or three cycles of neoadjuvant chemotherapy. In the second response evaluation of nine patients who received six cycles of neoadjuvant chemotherapy, one patient achieved a complete response, but two patients with hormone receptor-negative, human epidermal growth factor receptor 2-positive breast cancer experienced disease progression. Twenty-five (62.5%) patients experienced downstaging after neoadjuvant chemotherapy. Patients with > 20% pretreatment Ki-67 and decrease of Ki-67 between pre- and post-neoadjuvant chemotherapy showed a trend for better response. In multivariate analysis, advanced pathological stage showed a significant negative effect on relapse-free survival.
CONCLUSION
Docetaxel and epirubicin neoadjuvant chemotherapy showed a good response in locally advanced breast cancer. Pretreatment Ki-67 and change of Ki-67 may play a role as predictive factor for response to neoadjuvant chemotherapy.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Epirubicin; Female; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Retrospective Studies; Taxoids; Treatment Outcome; Young Adult
PubMed: 32069523
DOI: 10.3904/kjim.2019.031 -
Gastric Cancer : Official Journal of... Nov 2023A phase III trial comparing S-1 and docetaxel with S-1 alone as postoperative chemotherapy for pathologically Stage III gastric cancer was conducted and clarified the... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
A phase III trial comparing S-1 and docetaxel with S-1 alone as postoperative chemotherapy for pathologically Stage III gastric cancer was conducted and clarified the superiority of the doublet in terms of 3-year relapse-free survival as the primary endpoint (67.7% versus 57.4%, hazard ratio [HR] 0.715, 95% confidence interval [CI] 0.587-0.871; p = 0.0008). This final report analyzed 5-year survival outcomes along with the incidence and pattern of late recurrences.
PATIENTS AND METHODS
Patients with histologically confirmed Stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive adjuvant chemotherapy with either S-1 plus docetaxel or S-1 alone. The same 912 patients who were evaluated for 3-year survival outcomes in the previous report were analyzed.
RESULTS
Five-year overall survival rate of the S-1 plus docetaxel group (67.91%) was significantly superior to that in the S-1 group (60.27%; HR 0.752, 95% CI 0.613-0.922; p = 0.0059). The incidence of late recurrence at > 3 years after randomization was similar in both groups (7.3% versus 7.2%). Peritoneal dissemination was the most common pattern of late recurrence. Addition of docetaxel significantly suppressed relapse through the lymphatic (6.8% [95% CI 4.52-9.17] versus 15% [95% CI 11.76-18.30]; p < 0.0001) and hematogenous (10.2% [95% CI 7.37-12.94] versus 15.7% [95% CI 12.36-19.01]; p < 0.0137) pathways throughout the 5 years of follow-up.
CONCLUSION
The survival benefit of postoperative chemotherapy with S-1 and docetaxel in terms of 5-year overall survival rate was confirmed for patients with pathologically Stage III gastric cancer, although late recurrences were not prevented.
Topics: Humans; Stomach Neoplasms; Docetaxel; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Proportional Hazards Models; Neoplasm Staging; Gastrectomy
PubMed: 37548812
DOI: 10.1007/s10120-023-01419-9 -
Arteriosclerosis, Thrombosis, and... May 2023The recent identification of the cell-surface protein DSC1 (desmocollin 1) as a negative regulator of HDL (high-density lipoprotein) biogenesis has attracted us to... (Review)
Review
The recent identification of the cell-surface protein DSC1 (desmocollin 1) as a negative regulator of HDL (high-density lipoprotein) biogenesis has attracted us to revisit the old HDL biogenesis hypothesis: HDL biogenesis reduces atherosclerosis. The location and function of DSC1 suggest that DSC1 is a druggable target for the promotion of HDL biogenesis, and the discovery of docetaxel as a potent inhibitor of the DSC1 sequestration of apolipoprotein A-I has provided us with new opportunities to test this hypothesis. The FDA-approved chemotherapy drug docetaxel promotes HDL biogenesis at low-nanomolar concentrations that are far lower than used in chemotherapy. Docetaxel has also been shown to inhibit atherogenic proliferation of vascular smooth muscle cells. In accordance with these atheroprotective effects of docetaxel, animal studies have shown that docetaxel reduces dyslipidemia-induced atherosclerosis. In the absence of HDL-directed therapies for atherosclerosis, DSC1 constitutes an important new target for the promotion of HDL biogenesis, and the DSC1-targeting compound docetaxel serves as a model compound to prove the hypothesis. In this brief review, we discuss opportunities, challenges, and future directions for using docetaxel in the prevention and treatment of atherosclerosis.
Topics: Animals; Lipoproteins, HDL; Docetaxel; Atherosclerosis; Cholesterol, HDL
PubMed: 36861478
DOI: 10.1161/ATVBAHA.122.318275 -
British Journal of Clinical Pharmacology Feb 2023We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure.
AIMS
We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure.
METHODS
A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75-100 mg/m infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300-350 mg/m ). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence.
RESULTS
Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P < .05). Fatigue and decrease in haemoglobin and haematocrit levels were related to docetaxel AUC and Cmax and pain to AUC. AUC and Cmax >4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence.
CONCLUSION
We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients.
Topics: Humans; Female; Docetaxel; Breast Neoplasms; Neoplasm Recurrence, Local; Bayes Theorem; Taxoids; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36098504
DOI: 10.1111/bcp.15526