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BMC Cancer Nov 2022Triple negative breast cancer (TNBC) is clinically aggressive breast cancer with a poor prognosis. Approximately 20% of TNBC has been found to express programmed death... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Triple negative breast cancer (TNBC) is clinically aggressive breast cancer with a poor prognosis. Approximately 20% of TNBC has been found to express programmed death ligand 1 (PD-L1), making it a potential therapeutic target. As a PD-L1 inhibitor, atezolizumab is a recently approved immunotherapeutic drug for TNBC, this meta-analysis (MA) was aimed to review the randomized controlled trial studies (RCTs) of combined atezolizumab and nab-paclitaxel in the treatment of TNBC and synthesize the evidence-based results on its effectiveness and safety.
METHOD
We searched PubMed, Embase, EBSCOhost and ClinicalTrials.gov for the eligible RCTs which compared the efficacy and safety of combined atezolizumab and nab-paclitaxel with nab-paclitaxel alone. The outcomes analyzed included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse effects (AEs).
RESULTS
A total of six RCTs were included in this MA. For efficacy, although OS was not significantly prolonged with combined atezolizumab and nab-paclitaxel (HR 0.90, 95% CI [0.79, 1.01], p=0.08), this combination therapy significantly improved PFS (HR 0.72, 95% CI [0.59, 0.87], p=0.0006) and ORR (RR 1.25, 95% CI [0.79, 1.01] p<0.00001). For safety, any AEs, haematological, gastrointestinal, and liver AEs showed no statistically significant differences between the atezolizumab and nab-paclitaxel combination group and nab-paclitaxel alone group. However, serious AEs, high grade, dermatological, pulmonary, endocrine, and neurological AEs were significantly lower with nab-paclitaxel alone compared to atezolizumab and nab-paclitaxel combined (p-value range from <0.00001 to 0,02).
CONCLUSION
Atezolizumab combined with nab-paclitaxel was associated with improved outcomes in the treatment of TNBC; however, this combination resulted in more toxicity compared to nab-paclitaxel alone. While nab-paclitaxel alone produced chemotherapy-related AEs, the combination of atezolizumab with nab-paclitaxel produced AEs, especially immune-related AEs such as haematological, pulmonary, endocrine, and neurological AEs.
TRIAL REGISTRATION
This research work of systematic review has been registered on PROSPERO (Registration number: CRD42022297952).
Topics: Humans; Albumins; Antineoplastic Combined Chemotherapy Protocols; Paclitaxel; Randomized Controlled Trials as Topic; Triple Negative Breast Neoplasms
PubMed: 36335316
DOI: 10.1186/s12885-022-10225-y -
Chemical & Pharmaceutical Bulletin Nov 2022A CCO-NalLeuVal (C10NLV) tripeptide was synthesized and explored as a carrier for paclitaxel (TAX) delivery. Five types of TAX-loaded micelles were produced by loading...
A CCO-NalLeuVal (C10NLV) tripeptide was synthesized and explored as a carrier for paclitaxel (TAX) delivery. Five types of TAX-loaded micelles were produced by loading TAX with different doses of C10NLV. 3-(4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay showed that TAX-loaded micelles dramatically reduced TAX IC values of TAX-resistant A549 (A549/TAX) and Lewis lung carcinoma (LLC) cells in a C10NLV-dose-dependent manner, with micelles 4 and 5 exhibited comparable inhibitory effects on A549/TAX proliferation. Flow cytometry analysis showed that TAX-loaded micelles 4 promoted lung cancer cell apoptosis in a TAX-dose-dependent manner. Immunofluorescent staining and Western blotting revealed that TAX-loaded micelles 4 dramatically reduced the protein levels of F-actin, p53, Bcl-2, and LC3A/B in A549/TAX cells. Wound healing, cell adhesion, migration, and invasion assays demonstrated that TAX-loaded micelles 4 suppressed the metastatic abilities of lung cancer cells. Furthermore, compared with the same dose of free TAX, TAX-loaded micelles 4 significantly reduced the volumes and weights of A549/TAX-generated tumors as well as the numbers of LLC-generated pulmonary metastatic foci in mice, without affecting the organ/body weight ratios, body weights, and blood cell counts. Histological analysis demonstrated that TAX-loaded micelles 4 administration resulted in tubulin and CD206 downregulation as well as cytoplasm disappearance and nuclear shrinkage in xenograft tumors. These data suggest that TAX-loaded micelles 4 inhibits the proliferative and metastatic capacity of lung cancer cells, despite TAX resistance. TAX-loaded micelles 4 suppresses lung tumor growth and metastasis in vivo without inducing systemic toxicity. Thus, the C10NLV-based TAX delivery is effective and safe to combat TAX resistance and metastasis in lung cancer.
Topics: Humans; Mice; Animals; Paclitaxel; Micelles; Lung Neoplasms; A549 Cells; Apoptosis; Cell Line, Tumor; Drug Carriers
PubMed: 36002259
DOI: 10.1248/cpb.c22-00178 -
ELife Mar 2023Paclitaxel (Taxol) is a taxane and a chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the...
Paclitaxel (Taxol) is a taxane and a chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the lack of high-resolution structural information on a tubulin-taxane complex precludes a comprehensive description of the binding determinants that affect its mechanism of action. Here, we solved the crystal structure of baccatin III the core moiety of paclitaxel-tubulin complex at 1.9 Å resolution. Based on this information, we engineered taxanes with modified C13 side chains, solved their crystal structures in complex with tubulin, and analyzed their effects on microtubules (X-ray fiber diffraction), along with those of paclitaxel, docetaxel, and baccatin III. Further comparison of high-resolution structures and microtubules' diffractions with the apo forms and molecular dynamics approaches allowed us to understand the consequences of taxane binding to tubulin in solution and under assembled conditions. The results sheds light on three main mechanistic questions: (1) taxanes bind better to microtubules than to tubulin because tubulin assembly is linked to a βM-loopconformational reorganization (otherwise occludes the access to the taxane site) and, bulky C13 side chains preferentially recognize the assembled conformational state; (2) the occupancy of the taxane site has no influence on the straightness of tubulin protofilaments and; (3) longitudinal expansion of the microtubule lattices arises from the accommodation of the taxane core within the site, a process that is no related to the microtubule stabilization (baccatin III is biochemically inactive). In conclusion, our combined experimental and computational approach allowed us to describe the tubulin-taxane interaction in atomic detail and assess the structural determinants for binding.
Topics: Tubulin; Taxoids; Microtubules; Paclitaxel
PubMed: 36876916
DOI: 10.7554/eLife.84791 -
Proceedings of the National Academy of... May 2022Despite recent advances in cancer therapy, hard-to-reach, unidentified tumors remain a significant clinical challenge. A promising approach is to treat locatable and...
Despite recent advances in cancer therapy, hard-to-reach, unidentified tumors remain a significant clinical challenge. A promising approach is to treat locatable and accessible tumors locally and stimulate antitumor immunity in situ to exert systemic effects against distant tumors. We hypothesize that a carrier of immunotherapeutics can play a critical role in activating antitumor immunity as an immunoadjuvant and a local retainer of drug combinations. Here, we develop a polyethyleneimine-lithocholic acid conjugate (2E′), which forms a hydrophobic core and cationic surface to codeliver hydrophobic small molecules and anionic nucleic acids and activates antigen-presenting cells via the intrinsic activities of 2E′ components. 2E′ delivers paclitaxel and small-interfering RNA (siRNA) targeting PD-L1 (or cyclic dinucleotide, [CDN]) to induce the immunogenic death of tumor cells and maintain the immunoactive tumor microenvironment, and further activates dendritic cells and macrophages, leveraging the activities of loaded drugs. A single local administration of 2E′ or its combination with paclitaxel and PD-L1–targeting siRNA or CDN induces strong antitumor immunity, resulting in immediate regression of large established tumors, tumor-free survival, an abscopal effect on distant tumors, and resistance to rechallenge and metastasis in multiple models of murine tumors, including CT26 colon carcinoma, B16F10 melanoma, and 4T1 breast cancer. This study supports the finding that local administration of immunotherapeutics, when accompanied by the rationally designed carrier, can effectively protect the host from distant and recurrent diseases.
Topics: Cell Line, Tumor; Humans; Immunotherapy; Neoplasms; Nucleic Acids; Paclitaxel; Polymers
PubMed: 35609195
DOI: 10.1073/pnas.2122595119 -
Arquivos Brasileiros de Cirurgia... 2023Peritoneal carcinomatosis in gastric cancer is considered a fatal disease, without expectation of definitive cure. As systemic chemotherapy is not sufficient to contain...
BACKGROUND
Peritoneal carcinomatosis in gastric cancer is considered a fatal disease, without expectation of definitive cure. As systemic chemotherapy is not sufficient to contain the disease, a multimodal approach associating intraperitoneal chemotherapy with surgery may represent an alternative for these cases.
AIMS
The aim of this study was to investigate the role of intraperitoneal chemotherapy in stage IV gastric cancer patients with peritoneal metastasis.
METHODS
This study is a single institutional single-arm prospective clinical trial phase II (NCT05541146). Patients with the following inclusion criteria undergo implantation of a peritoneal catheter for intraperitoneal chemotherapy: Stage IV gastric adenocarcinoma; age 18-75 years; Peritoneal carcinomatosis with peritoneal cancer index<12; Eastern Cooperative Oncology Group 0/1; good clinical status; and lab exams within normal limits. The study protocol consists of four cycles of intraperitoneal chemotherapy with paclitaxel associated with systemic chemotherapy. After treatment, patients with peritoneal response assessed by staging laparoscopy undergo conversion gastrectomy.
RESULTS
The primary outcome is the rate of complete peritoneal response. Progression-free and overall survivals are other outcomes evaluated. The study started in July 2022, and patients will be screened for inclusion until 30 are enrolled.
CONCLUSIONS
Therapies for advanced gastric cancer patients have been evaluated in clinical trials but without success in patients with peritoneal metastasis. The treatment proposed in this trial can be promising, with easy catheter implantation and ambulatory intraperitoneal chemotherapy regime. Verifying the efficacy and safety of paclitaxel with systemic chemotherapy is an important progress that this study intends to investigate.
Topics: Adolescent; Adult; Aged; Humans; Middle Aged; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Paclitaxel; Peritoneal Neoplasms; Prospective Studies; Stomach Neoplasms
PubMed: 37466566
DOI: 10.1590/0102-672020230026e1744 -
Molecules (Basel, Switzerland) Apr 2023Paclitaxel-triethylenetetramine hexaacetic acid conjugate (PTX-TTHA), a novel semi-synthetic taxane, is designed to improve the water solubility and cosolvent toxicity...
Paclitaxel-triethylenetetramine hexaacetic acid conjugate (PTX-TTHA), a novel semi-synthetic taxane, is designed to improve the water solubility and cosolvent toxicity of paclitaxel in several aminopolycarboxylic acid groups. In this study, the in vitro and in vivo antitumor effects and mechanisms of PTX-TTHA against triple-negative breast cancer (TNBC) and its intravenous toxicity were evaluated. Results showed the water solubility of PTX-TTHA was greater than 5 mg/mL, which was about 7140-fold higher than that of paclitaxel (<0.7 µg/mL). PTX-TTHA (10-10 nmol/L) could significantly inhibit breast cancer proliferation and induce apoptosis by stabilizing microtubules and arresting the cell cycle in the G2/M phase in vitro, with its therapeutic effect and mechanism similar to paclitaxel. However, when the MDA-MB-231 cell-derived xenograft (CDX) tumor model received PTX-TTHA (13.73 mg/kg) treatment once every 3 days for 21 days, the tumor inhibition rate was up to 77.32%. Furthermore, PTX-TTHA could inhibit tumor proliferation by downregulating Ki-67, and induce apoptosis by increasing pro-apoptotic proteins (Bax, cleaved caspase-3) and TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and reducing anti-apoptotic protein (Bcl-2). Moreover, PTX-TTHA demonstrated no sign of acute toxicity on vital organs, hematological, and biochemical parameters at the limit dose (138.6 mg/kg, i.v.). Our study indicated that PTX-TTHA showed better water solubility than paclitaxel, as well as comparable in vitro and in vivo antitumor activity in TNBC models. In addition, the antitumor mechanism of PTX-TTHA was related to microtubule regulation and apoptosis signaling pathway activation.
Topics: Humans; Paclitaxel; Triple Negative Breast Neoplasms; Cell Cycle; Water; Cell Line, Tumor; Apoptosis
PubMed: 37175072
DOI: 10.3390/molecules28093662 -
Cancer Dec 2019According to the statement from the 5th Ovarian Cancer Consensus Conference in 2015, the primary systemic chemotherapy for advanced ovarian cancer is a combination of... (Review)
Review
According to the statement from the 5th Ovarian Cancer Consensus Conference in 2015, the primary systemic chemotherapy for advanced ovarian cancer is a combination of paclitaxel plus carboplatin administered every 3 weeks (PCq3w). Optional alternatives include weekly dose-dense paclitaxel, in combination and maintenance therapy with bevacizumab, and intraperitoneal chemotherapy. Since then, in addition to the PCq3w strategy, there has been emerging new evidence, especially for poly(adenosine diphosphate-ribose) polymerase inhibitors. Moreover, there are multiple randomized, phase 3 trials testing the addition of antiangiogenic and/or immune checkpoint inhibitors in this patient population. In this article, current and future perspectives of systemic chemotherapy for advanced ovarian cancer are discussed.
Topics: Antineoplastic Agents, Phytogenic; Female; History, 20th Century; Humans; Ovarian Neoplasms; Paclitaxel
PubMed: 31967679
DOI: 10.1002/cncr.32475 -
Scientific Reports Jun 2022A series of new paclitaxel-benzoxazoles hybrids were designed based on both the molecular docking mode of beta-tubulin with paclitaxel derivatives (7a and 7g), and the...
A series of new paclitaxel-benzoxazoles hybrids were designed based on both the molecular docking mode of beta-tubulin with paclitaxel derivatives (7a and 7g), and the activity-structure relationship of C-13 side chain in paclitaxel. Palladium-catalyzed direct Csp-H arylation of benzoxazoles with different aryl-bromides was used as the key synthetic strategy for the aryl-benzoxazoles moieties in the hybrids. Twenty-six newly synthesized hybrids were screened for their antiproliferative activity against human cancer cell lines such as human breast cancer cells (MDA-MB-231) and liver hepatocellular cells (HepG2) by the MTT assay and results were compared with paclitaxel. Interestingly, most hybrids (7a-7e, 7i, 7k, 7l, 7A, 7B, 7D and 7E) showed significantly active against both cell lines at concentration of 50 µM, which indicated that the hybrid strategy is effective to get structural simplified paclitaxel analogues with high anti-tumor activity.
Topics: Antineoplastic Agents; Benzoxazoles; Catalysis; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Neoplasms; Paclitaxel; Palladium; Structure-Activity Relationship
PubMed: 35705688
DOI: 10.1038/s41598-022-14172-3 -
Journal of Materials Science. Materials... Dec 2021In this study, paclitaxel (PTX)-loaded pH-responsive niosomes modified with ergosterol were developed. This new formulation was characterized in terms of size,...
In this study, paclitaxel (PTX)-loaded pH-responsive niosomes modified with ergosterol were developed. This new formulation was characterized in terms of size, morphology, encapsulation efficiency (EE), and in vitro release at pH 5.2 and 7.4. The in vitro efficacy of free PTX and niosome/PTX was assessed using MCF7, Hela, and HUVEC cell lines. In order to evaluate the in vivo efficacy of niosomal PTX in rats as compared to free PTX, the animals were intraperitoneally administered with 2.5 mg/kg and 5 mg/kg niosomal PTX for two weeks. Results showed that the pH-responsive niosomes had a nanometric size, spherical morphology, 77% EE, and pH-responsive release in pH 5.2 and 7.4. Compared with free PTX, we found markedly lower IC50s when cancer cells were treated for 48 h with niosomal PTX, which also showed high efficacy against human cancers derived from cervix and breast tumors. Moreover, niosomal PTX induced evident morphological changes in these cell lines. In vivo administration of free PTX at the dose of 2.5 mg/kg significantly increased serum biochemical parameters and liver lipid peroxidation in rats compared to the control rats. The situation was different when niosomal PTX was administered to the rats: the 5 mg/kg dosage of niosomal PTX significantly increased serum biochemical parameters, but the group treated with the 2.5 mg/kg dose of niosomal PTX showed fewer toxic effects than the group treated with free PTX at the same dosage. Overall, our results provide proof of concept for encapsulating PTX in niosomal formulation to enhance its therapeutic efficacy.
Topics: Animals; Antineoplastic Agents; Drug Liberation; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen-Ion Concentration; Lipid Peroxidation; Liposomes; MCF-7 Cells; Male; Paclitaxel; Rats; Rats, Sprague-Dawley
PubMed: 34862910
DOI: 10.1007/s10856-021-06623-6 -
Medicine Feb 2022In addition to advanced non-small cell lung cancer, nanoparticle albumin-bound paclitaxel (nab-PTX) may also harbor potential benefit for patients with relapsed small... (Observational Study)
Observational Study
In addition to advanced non-small cell lung cancer, nanoparticle albumin-bound paclitaxel (nab-PTX) may also harbor potential benefit for patients with relapsed small cell lung cancer (SCLC), since weekly paclitaxel (PTX) shows modest activity for relapsed SCLC. We evaluated the efficacy and safety of both weekly nab-PTX and PTX for relapsed SCLC.We retrospectively reviewed 52 consecutive relapsed SCLC patients who were treated with weekly nab-PTX or PTX at our hospital.The response rate, median progression-free survival and overall survival with nab-PTX and PTX were 5.6 vs 8.8%, 3.2 vs 1.7 months, and 5.4 vs 4.5 months, respectively. No statistically significant differences were observed. There was no statistical difference between the 2 groups for ≥Grade 3 adverse events.Weekly nab-PTX and PTX showed similar activity for relapsed SCLC. The toxicity profile of nab-PTX was equally tolerable to that of PTX.
Topics: Albumin-Bound Paclitaxel; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Nanoparticles; Neoplasm Recurrence, Local; Paclitaxel; Retrospective Studies; Small Cell Lung Carcinoma
PubMed: 35147134
DOI: 10.1097/MD.0000000000028863