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Cancer Letters Feb 2023Quiescent cancer cells (QCCs), also known as dormant cancer cells, resist and survive chemo- and radiotherapy, resulting in treatment failure and later cancer recurrence...
Quiescent cancer cells (QCCs), also known as dormant cancer cells, resist and survive chemo- and radiotherapy, resulting in treatment failure and later cancer recurrence when QCCs resume cell cycle progression. However, drugs selectively targeting QCCs are lacking. Saikosaponin A (SSA) derived from Bupleurum DC., is highly potent in eradicating multidrug-resistant prostate QCCs compared with proliferative prostate cancer cells. By further exacerbating the already increased autophagy through inactivation of Akt-mTOR signaling, SSA triggered cell death in QCCs. Contrarily, inhibition of autophagy or activation of Akt signaling pathway prevented SSA-induced cell death. The multicycle of Docetaxel treatments increased the proportion of QCCs, whereas administering SSA at intervals of Docetaxel treatments aggravated cell death in vitro and led to tumor growth arrest and cell death in vivo. In conclusion, SSA is posed as a novel QCCs-eradicating agent by aggravating autophagy in QCCs. In combination with the current therapy, SSA has potential to improve treatment effectiveness and to prevent cancer recurrence.
Topics: Male; Humans; Docetaxel; Proto-Oncogene Proteins c-akt; Prostate; Cell Line, Tumor; Neoplasm Recurrence, Local; Prostatic Neoplasms; Autophagy; Apoptosis; Cell Proliferation
PubMed: 36442771
DOI: 10.1016/j.canlet.2022.216011 -
Drug Design, Development and Therapy 2023To compare the short-term treatment response and survival of the three induction chemotherapy (IC) regimens, including gemcitabine and cisplatin (GP), docetaxel and...
PURPOSE
To compare the short-term treatment response and survival of the three induction chemotherapy (IC) regimens, including gemcitabine and cisplatin (GP), docetaxel and cisplatin (TP), and docetaxel, cisplatin, and fluoropyrimidines (TPF) in locally advanced nasopharyngeal carcinoma (LANPC).
METHODS
We included stage III-IVA NPC patients who received ≥3 cycles of IC in this study. The chi-square test, multivariate logistic regression analysis, and Kaplan-Meier method were used for statistical analysis.
RESULTS
A total of 227 patients were included. The overall response rate (ORR) of the primary nasopharyngeal tumors after IC with GP, TP, and TPF was 91.9%, 83.8%, and 91.7%, respectively (P=0.729), and the ORR of the cervical lymph nodes was 94.6%, 72.3%, and 85.0%, respectively (P<0.001). For the primary nasopharyngeal tumor, there was no significant difference in the ORR among the three IC regimens. For cervical lymph nodes, patients treated with GP had significantly higher ORR compared to those treated with the TP regimen (P=0.014), and comparable ORR was found between TPF and GP regimens (P=0.161). Similar progression-free survival (PFS) (P=0.501) and overall survival (OS) (P=0.504) were found among three IC regimens. There were comparable PFS (P=0.123) and OS (P=0.478) among those with complete response (CR), partial response (PR), and stable disease (SD)/progressive disease (PD) in the primary nasopharyngeal tumors. However, patients who had CR in the primary nasopharyngeal tumor (P=0.014) and the cervical lymph nodes (P=0.022) had better PFS compared to those who had PR or SD/PD.
CONCLUSION
GP and TPF regimens are equivalent to the TP regimen in the response to primary nasopharyngeal tumors after IC, but with better ORR in the cervical lymph nodes than the TP regimen. The response to IC may be a powerful indicator for predicting prognosis and developing individualized follow-up and treatment strategies for LANPC patients.
Topics: Humans; Nasopharyngeal Carcinoma; Induction Chemotherapy; Nasopharyngeal Neoplasms; Cisplatin; Docetaxel
PubMed: 36855516
DOI: 10.2147/DDDT.S399937 -
Journal For Immunotherapy of Cancer Nov 2023It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab. (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer-Immun-HER trial (GOIRC-01-2016).
BACKGROUND
It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.
METHODS
In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD).
RESULTS
Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms.
CONCLUSIONS
SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response.
TRIAL REGISTRATION NUMBER
NCT03144947, and EudraCT number: 2016-000435-41.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; B7-H1 Antigen; Docetaxel; Neoadjuvant Therapy; Neoplasm, Residual; Receptor, ErbB-2; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38016718
DOI: 10.1136/jitc-2023-007667 -
Frontiers in Public Health 2023A total of 11 treatment sequences for advanced wild-type squamous non-small cell lung cancer are recommended by Chinese Society of Clinical Oncology Guidelines,... (Meta-Analysis)
Meta-Analysis
Effectiveness and cost-effectiveness analysis of 11 treatment paths, seven first-line and three second-line treatments for Chinese patients with advanced wild-type squamous non-small cell lung cancer: A sequential model.
BACKGROUND
A total of 11 treatment sequences for advanced wild-type squamous non-small cell lung cancer are recommended by Chinese Society of Clinical Oncology Guidelines, consisting of seven first-line and three second-line treatments. Five of these treatments were newly approved in China between 2021 and 2022. We evaluated the effectiveness and cost-effectiveness of these strategies from the Chinese healthcare system perspective.
METHODS
Network meta-analysis with non-proportional hazards was used to calculate the relative efficacy between interventions. A sequential model was developed to estimate costs and quality-adjusted life years (QALY) for treatment sequences with first-line platinum- and paclitaxel-based chemotherapy (SC) with or without nedaplatin, tislelizumab, camrelizumab, sintilimab, sugemalimab or pembrolizumab, followed by second-line docetaxel, tislelizumab or nivolumab. SC and docetaxel were used as comparators for first-line and second-line treatments, respectively. QALY and incremental cost-effectiveness ratio (ICER) were used to evaluate effectiveness and cost-effectiveness, respectively. Cost-effective threshold was set as USD 19,091. Subgroup analysis was conducted to determine the best first-line and second-line therapy.
RESULTS
Pembrolizumab + SC, followed by docetaxel (PED) was the most effective treatment sequence. QALYs for patients received SC, nedaplatin + SC, tislelizumab + SC, sintilimab + SC, camrelizumab + SC, sugemalimab + SC, pembrolizumab + SC followed by docetaxel were 0.866, 0.906, 1.179, 1.266, 1.179, 1.266, 1.603, 1.721, 1.807; QALYs for SC, nedaplatin + SC followed by tislelizumab were 1.283, 1.301; QALYs for SC, nedaplatin + SC followed by nivolumab were 1.353, 1.389. Camrelizumab + SC, followed by docetaxel (CAD) was the most cost-effective. Compared to SC with or without nedaplatin, tislelizumab, or sintilimab followed by docetaxel, ICERs of CAD were USD 12,276, 13,210, 6,974, 9,421/QALY, respectively. Compared with nedaplatin or SC followed by tislelizumab, the ICERs of CAD were USD 4,183, 2,804/QALY; CAD was dominant compared with nedaplatin or SC followed by nivolumab; The ICER of sugemalimab + SC followed by docetaxel and PED were USD 522,023, 481,639/QALY compared with CAD. Pembrolizumab + SC and camrelizumab + SC were the most effective and cost-effective first-line options, respectively; tislelizumab was the most effective and cost-effective second-line therapy. Tislelizumab used in second-line was more effective than first-line, no significant differences between their cost-effectiveness. Sensitivity and scenario analysis confirmed robustness of the results.
CONCLUSIONS
PED and CAD are the most effective and cost-effective treatment sequence, respectively; pembrolizumab + SC and camrelizumab + SC are the most effective and cost-effective first-line choice, respectively; tislelizumab is the most effective and cost-effective second-line choice.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Docetaxel; Nivolumab; Lung Neoplasms; Cost-Effectiveness Analysis; Carcinoma, Squamous Cell
PubMed: 36908446
DOI: 10.3389/fpubh.2023.1051484 -
Scientific Reports Nov 2017A sensitive and specific liquid chromatographic/tandem mass spectrometric (LC-MS/MS) method was developed and validated for quantifying total and unbound docetaxel drug...
A sensitive and specific liquid chromatographic/tandem mass spectrometric (LC-MS/MS) method was developed and validated for quantifying total and unbound docetaxel drug concentrations in plasma. Calibration curves for unbound and total docetaxel were linear over the respective ranges of 0.108~10.8 and 0.54~216 ng/mL. The intra- and interday assay accuracy and precision did not exceed 15%. The methods were validated to show the standard range linearity, sensitivity, selectivity, accuracy, precision, and stability of docetaxel in the matrices tested. In addition, this method is fast and simple with a short run time of 4.5 min and a small plasma sample volume (500 µL). The validated method was successfully applied to a pharmacokinetic study of a docetaxel micelle formulation in rat plasma after intravenous administration at a dose of 10 mg/kg. Docetaxel micelles slowly released their drug payload, and protein-bound, unbound, and micellar drug pools existed simultaneously. These various forms in plasma pools were also measured in the study. We confirmed that most of the docetaxel in plasma was micelle-associated (96.52% at 24 h and 83.14% at 72 h) after micellar docetaxel administration, as a result of sequestration of the drug in long-circulating micelles.
Topics: Animals; Antineoplastic Agents; Blood Chemical Analysis; Calibration; Chromatography, Liquid; Docetaxel; Male; Micelles; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Ultrafiltration
PubMed: 29097770
DOI: 10.1038/s41598-017-15176-0 -
Journal of Natural Products Mar 2018Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as... (Review)
Review
Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop next-generation taxoid anticancer agents with better pharmacological properties and improved activity especially against drug-resistant and metastatic cancers. The SAR studies by the authors have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3' positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the next-generation taxoids also exhibited excellent potency against cancer stem cells. This account summarizes concisely investigations into taxoids over 25 years based on a strong quest for the discovery and development of efficacious next-generation taxoids. Discussed herein are SAR studies on different types of taxoids, a common pharmacophore proposal for microtubule-stabilizing anticancer agents and its interesting history, the identification of the paclitaxel binding site and its bioactive conformation, characteristics of the next-generation taxoids in cancer cell biology, including new aspects of their mechanism of action, and the highly efficacious tumor-targeted drug delivery of potent next-generation taxoids.
Topics: Animals; Antineoplastic Agents; Docetaxel; Drug Resistance, Neoplasm; Humans; Neoplasms; Paclitaxel; Taxoids
PubMed: 29468872
DOI: 10.1021/acs.jnatprod.7b01012 -
PloS One 2022Upfront docetaxel or novel hormonal agents (NHA) such as abiraterone and enzalutamide have become the standard of care for metastatic hormone sensitive prostate cancer...
BACKGROUND
Upfront docetaxel or novel hormonal agents (NHA) such as abiraterone and enzalutamide have become the standard of care for metastatic hormone sensitive prostate cancer (mHSPC). We evaluated real-world management of patients treated with these agents at a single center.
PATIENTS AND METHODS
Patients with de novo mHSPC treated with upfront docetaxel or an NHA between January 2014 and April 2019 at Mount Sinai Health System were included. We evaluated time to next treatment (TTNT), PSA progression free survival (PFS) and overall survival (OS) after initial treatment with these drugs. Kaplan Meier method and multivariable Cox proportional hazards models were used for analysis. We additionally assessed the prognostic value of post-treatment PSA.
RESULTS
We identified 94 de novo mHSPC patients; 52 and 42 treated with upfront docetaxel and NHAs, respectively. NHAs were associated with a median TTNT of 20.7 months compared to 10.1 months with docetaxel (log-rank p = 0.023). We also observed median PSA PFS of 19 months for NHAs and 13.2 months for docetaxel (p = 0.069). However, OS between the two treatment groups was unchanged. Among docetaxel treated patients, TTNT was shorter among those with high metastasis burden (9.63 vs 25.5 months, p = 0.026) which was not observed among NHA treated patients (25.1 vs 20.7 months, p = 0.79). Regardless of treatment, lower post-treatment PSA levels were associated with improved TTNT (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, >0.4ng/ml, respectively; p<0.001).
CONCLUSION
Real world data demonstrated a shorter duration of treatment with docetaxel than NHAs, reflecting the time-limited nature of docetaxel regimens compared to the treat-till-progression approach of NHAs. While TTNT was generally longer for NHAs than docetaxel, some docetaxel-treated patients achieved significant periods of time off treatment. In addition, the depth of PSA response following combination treatment may hold prognostic value for mHSPC outcomes.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Hormones; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome
PubMed: 35984843
DOI: 10.1371/journal.pone.0264800 -
Scientific Reports Oct 2022Insight into the mechanism of docetaxel resistance in breast cancer may help to improve prognosis. We aimed to investigate the role of N6-methyladenosine (m6A) and the...
Insight into the mechanism of docetaxel resistance in breast cancer may help to improve prognosis. We aimed to investigate the role of N6-methyladenosine (m6A) and the METTL3/LINC00662/miR-186-5p pathway in regulating docetaxel resistance in triple negative breast cancer (TNBC). We have recruited 193 pathologically diagnosed TNBC patients from 2016 to 2017 in our hospital. Quantitative real-time PCR was used to evaluate the expression of LINC00662 and miR-186-5p both in vivo and in vitro. CCK8 tests were used to assess cell viability. ELISA was used for protein expression evaluation. Dual luciferase reporter gene assay and RNA pull-down were used to evaluate the interaction between LINC00662 and miR-186-5p. m6A levels were enhanced in breast cancer tissues and cells. LINC00662, miR-186-5p and METTL3 were differentially expressed in vivo, and METTL3 expression was associated with LINC00662 and miR-186-5p expression. LINC00662 and miR-186-5p were differentially expressed in vitro; LINC00662 promoted cell viability and decreased the apoptosis rate, whereas miR-186-5p inhibited cell viability and increased the apoptosis rate. Furthermore, we found that METTL3 regulated m6A levels in docetaxel-resistant breast cancer cells by regulating the expression of LINC00662. Moreover, LINC00662 and miR-186-5p regulated the cell viability rate of docetaxel-resistant breast cancer cells. Further experiments showed that LINC00662 directly interacted with miR-186-5p to exert biological functions; besides miR-186-5p could regulate the expression of METTL3. METTL3 promotes m6A levels and docetaxel resistance in breast cancer by regulating the expression of LINC00662 and miR-186-5p; more experiments are needed to clarify the role of m6A regulation in drug resistance.
Topics: Cell Line, Tumor; Cell Proliferation; Docetaxel; Feedback; Gene Expression Regulation, Neoplastic; Humans; Methyltransferases; MicroRNAs; Triple Negative Breast Neoplasms
PubMed: 36202872
DOI: 10.1038/s41598-022-20477-0 -
Molecules (Basel, Switzerland) Jul 2021Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to...
Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to construct a nanocrystal-loaded micelles delivery system to enhance the blood circulation of docetaxel (DOC). We employed high-pressure homogenization to prepare docetaxel nanocrystals (DOC(Nc)), and then produced docetaxel nanocrystal-loaded micelles (DOC(Nc)@mPEG-PLA) by a thin-film hydration method. The particle sizes of optimized DOC(Nc), docetaxel micelles (DOC@mPEG-PLA), and DOC(Nc)@mPEG-PLA were 168.4, 36.3, and 72.5 nm, respectively. The crystallinity of docetaxel was decreased after transforming it into nanocrystals, and the crystalline state of docetaxel in micelles was amorphous. The constructed DOC(Nc)@mPEG-PLA showed good stability as its particle size showed no significant change in 7 days. Despite their rapid dissolution, docetaxel nanocrystals exhibited higher bioavailability. The micelles prolonged the retention time of docetaxel in the circulation system of rats, and DOC(Nc)@mPEG-PLA exhibited the highest retention time and bioavailability. These results reveal that constructing nanocrystal-loaded micelles may be a promising way to enhance the in vivo circulation and bioavailability of rapidly metabolized drugs such as docetaxel.
Topics: Animals; Antineoplastic Agents; Docetaxel; Drug Carriers; Male; Micelles; Nanoparticles; Rats; Rats, Sprague-Dawley
PubMed: 34361634
DOI: 10.3390/molecules26154481 -
Lung Cancer (Amsterdam, Netherlands) May 2024Given the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Given the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in combination with docetaxel compared to docetaxel monotherapy as a second-line therapy for patients with advanced NSCLC.
MATERIALS AND METHODS
In this phase II study, patients with advanced NSCLC experiencing failure with first-line platinum-based regimens were randomized in a 1:1 ratio to receive either anlotinib plus docetaxel or docetaxel alone. Primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety as secondary endpoints.
RESULTS
A total of 83 patients were randomized. The combination of anlotinib and docetaxel significantly extended median PFS to 4.4 months compared to 1.6 months for docetaxel alone (hazard ratio [HR] = 0.38, 95 % confidence interval [CI]: 0.23-0.63, P = 0.0002), and also demonstrated superior ORR (32.5 % vs. 9.3 %, P = 0.0089) and DCR (87.5 % vs. 53.5 %, P = 0.0007). Median OS was observed at 12.0 months in the combination group vs. 10.9 months in the monotherapy group (HR = 0.82, 95 % CI: 0.47-1.43, P = 0.4803). For patients previously treated with immunotherapy, the median PFS was notably longer at 7.8 vs. 1.7 months (HR = 0.22, 95 % CI: 0.09-0.51, P = 0.0290). The incidence of grade ≥ 3 treatment-related adverse events, predominantly leukopenia (15.0 % vs. 7.0 %) and neutropenia (10.0 % vs. 5.0 %), was manageable across both groups.
CONCLUSION
Anlotinib plus docetaxel offers a viable therapeutic alternative for patients with advanced NSCLC who failed first-line platinum-based treatments.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Docetaxel; Male; Lung Neoplasms; Female; Middle Aged; Aged; Indoles; Antineoplastic Combined Chemotherapy Protocols; Quinolines; Adult; Neoplasm Staging; Treatment Outcome; Aged, 80 and over
PubMed: 38552544
DOI: 10.1016/j.lungcan.2024.107538