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Pharmacology Research & Perspectives Jun 2022The IMpower trials reported significant effects of atezolizumab-containing chemotherapies on Caucasian patients. Chinese patients differ from their Western counterparts...
Atezolizumab plus carboplatin and nab-paclitaxel versus carboplatin and nab-paclitaxel as treatments for Chinese, treatment-naïve, stage IV, non-squamous, non-small-cell lung cancer patients: A retrospective analysis.
The IMpower trials reported significant effects of atezolizumab-containing chemotherapies on Caucasian patients. Chinese patients differ from their Western counterparts in terms of driver mutations, etiologies, and regimen tolerance. In China, atezolizumab-containing chemotherapies are not cost-effective. Atezolizumab addition triggers grade >3 adverse events. Here, we evaluated the effectiveness and the safety profile of atezolizumab plus carboplatin and nab-paclitaxel compared to carboplatin and nab-paclitaxel in treatment-naïve Chinese patients with confirmed stage IV, non-squamous, non-small-cell lung cancer. All patients completed six cycles of 1200 mg of atezolizumab/3 weeks plus 6 mg/ml/min area-under-the-curve carboplatin/3 weeks plus 100 mg/m nab-paclitaxel/week (n = 115; ACN cohort) or 6 mg/ml/min area-under-the-curve carboplatin/3 weeks plus 100 mg/m nab-paclitaxel/week (n = 130; CNP cohort). The progression-free survival (12.98 ± 2.57 months vs. 10.89 ± 2.18 months, p < .0001) and overall survival (38.04 ± 19.8 months vs. 33.59 ± 87 months, p = .012) of patients in the ACN cohort were higher than those of patients in the CNP cohort after 48 weeks of follow-up. A total of 97 (84%) patients in the ACN cohort and 94 (72%) in the CNP cohort developed grade ≥3 adverse events (p = .030). A total of 84 (73%) patients from the ACN cohort and 107 (82%) from the CNP cohort died during 48 weeks of follow-up (p = .091). The addition of atezolizumab to carboplatin and nab-paclitaxel enhanced progression-free and overall survival but increased the risk of grade ≥3 adverse events in Chinese, treatment-naïve, stage IV, non-squamous, non-small-cell lung cancer patients who completed treatment (Level of Evidence: III; Technical Efficacy Stage: 4).
Topics: Albumins; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Paclitaxel; Retrospective Studies
PubMed: 35568997
DOI: 10.1002/prp2.941 -
International Journal of Nanomedicine 2020Synergistic chemoradiotherapy (CRT) has become a primary effective curative approach for many solid cancers. However, CRT is still associated with several obstacles,...
BACKGROUND
Synergistic chemoradiotherapy (CRT) has become a primary effective curative approach for many solid cancers. However, CRT is still associated with several obstacles, including the increases in side effects and systemic toxicity. Incorporating nanocarriers into CRT is a new and exciting approach to solve these obstacles. The purpose of the present study was to design a unique pH- and ultrasound-responsive perfluoropentane-encapsulated, paclitaxel (PTX)-loaded carboxymethyl chitosan nanodroplets (NDs) for combined imaging and synergistic CRT.
MATERIALS AND METHODS
The NDs were prepared by a homogenization/emulsion method. Their physicochemical properties, echogenicity and biocompatibility were evaluated. PTX-loaded NDs with a high loading efficiency and encapsulation efficiency were prepared and their pH-responsive drug release profile was determined by dialysis sack method. Then, PC3 cells were exposed to (1) PTX (4 μg/mL), (2) NDs (30 μg/mL), (3) PTX-loaded NDs (34 μg/mL), (4) RT (6 Gy), (5) RT (10 Gy), (6) combination of PTX (4 μg/mL), ultrasound (0.5 W/cm, 30 s) and RT (6 Gy), (7) combination of NDs (30 μg/mL), ultrasound (0.5 W/cm, 30 s) and RT (6Gy), (8) combination of PTX-loaded NDs (30 μg/mL), ultrasound (0.5 W/cm, 30 s) and RT (6 Gy). 24 hrs later, CCK-8 assay, flow cytometry and migration assay were carried out to evaluate their therapeutic effects in CRT.
RESULTS
The desired NDs were successfully prepared, which were with round, spherical shapes, relatively smooth surfaces, core-shell structures and uniform in sizes (<300 nm with PDI<0.3 when at pH≧6.0). The NDs exhibited good abilities in pH-dependent charge conversion, biocompatibility and ultrasound contrast echogenicity. The in vitro drug release from PTX-loaded NDs (the highest loading efficiency and encapsulation efficiency were 20.35% and 91.58%) was pH dependent and exhibited an initial burst followed by a sustained drug release. The results of the CCK-8 assay, flow cytometry and migration assay all showed PTX-loaded NDs combined ultrasound and RT significantly enhanced cell responses in CRT.
CONCLUSION
The pH- and ultrasound-responsive PTX-loaded NDs, which exhibited a high echogenicity, drug delivery ability and radiosensitization ability, could be a feasible option for combined imaging and novel enhancing approach in synergistic CRT.
Topics: Cell Line, Tumor; Chemoradiotherapy; Chitosan; Delayed-Action Preparations; Drug Delivery Systems; Drug Liberation; Fluorocarbons; Humans; Hydrogen-Ion Concentration; Male; Nanostructures; Paclitaxel; Particle Size; Prostatic Neoplasms; Ultrasonography
PubMed: 32021193
DOI: 10.2147/IJN.S233669 -
Cancer Medicine Jul 2023Propofol is a drug with potential anticancer effect. This study aimed to explore the effect of propofol on chemosensitivity of cervical cancer cells to paclitaxel.
BACKGROUND
Propofol is a drug with potential anticancer effect. This study aimed to explore the effect of propofol on chemosensitivity of cervical cancer cells to paclitaxel.
METHODS
HeLa and CaSki cells were selected for drug experiments. Cell viability was evaluated via CCK-8 assay, and the combination index (CI) was calculated by CompuSyn software. A clinically relevant concentration and IC30 of propofol were selected in combination with 5 nM paclitaxel. BrdU incorporation, transwell, and flow cytometry assays were utilized to evaluate cell proliferation, migration, invasion, and apoptosis. The expression of β-tubulin, stathmin 1, and GAPDH proteins was evaluated by Western blot. The stathmin 1 cDNA plasmid was used to establish stathmin 1-overexpressing CaSki cells.
RESULTS
At clinically relevant concentrations (0-80 μM), propofol did not affect cancer cell viability, but high concentrations (100-800 μM) reduced cell viability. The CI values of propofol with IC30 (200 μM in HeLa; 400 μM in CaSki) combined with 5 nM paclitaxel were <1. The effect of propofol with IC30 combined with paclitaxel on cell proliferation, migration, invasion, and apoptosis were stronger than individual effect, while 30 μM propofol had no effect. The Western blot results showed 30 μM propofol did not affect β-tubulin and stathmin 1 expression in cells, although paclitaxel upregulated β-tubulin expression while downregulating stathmin 1 expression. Compared with paclitaxel alone, cotreatment with propofol at its IC30 and paclitaxel decreased stathmin 1 expression but had no effect on β-tubulin expression. High stathmin 1 expression weakened the effect of paclitaxel on cell viability and apoptosis, while propofol partially reversed these effect.
CONCLUSION
Propofol at clinically relevant concentrations had no effect on the malignant biological behaviors of cervical cancer cells, while propofol at high concentrations decreased.Propofol with IC30 and paclitaxel had synergetic effect on cancer cells through a reduction in stathmin 1 expression.
Topics: Female; Humans; Paclitaxel; Propofol; Uterine Cervical Neoplasms; Tubulin; Stathmin; Cell Line, Tumor; Apoptosis; Cell Proliferation
PubMed: 37162289
DOI: 10.1002/cam4.6064 -
Expert Opinion on Drug Metabolism &... Feb 2021: Peripheral neuropathy (PN) is an adverse effect of several classes of chemotherapy including the taxanes. Predictive PN biomarkers could inform individualized taxane... (Review)
Review
Exploring pharmacogenetics of paclitaxel- and docetaxel-induced peripheral neuropathy by evaluating the direct pharmacogenetic-pharmacokinetic and pharmacokinetic-neuropathy relationships.
: Peripheral neuropathy (PN) is an adverse effect of several classes of chemotherapy including the taxanes. Predictive PN biomarkers could inform individualized taxane treatment to reduce PN and enhance therapeutic outcomes. Pharmacogenetics studies of taxane-induced PN have focused on genes involved in pharmacokinetics, including enzymes and transporters. Contradictory findings from these studies prevent translation of genetic biomarkers into clinical practice. : This review discusses the progress toward identifying pharmacogenetic predictors of PN by assessing the evidence for two independent associations; the effect of pharmacogenetics on taxane pharmacokinetics and the evidence that taxane pharmacokinetics affects PN. Assessing these direct relationships allows the reader to understand the progress toward individualized taxane treatment and future research opportunities. : Paclitaxel pharmacokinetics is a major determinant of PN. Additional clinical trials are needed to confirm the clinical benefit of individualized dosing to achieve target paclitaxel exposure. Genetics does not meaningfully contribute to paclitaxel pharmacokinetics and may not be useful to inform dosing. However, genetics may contribute to PN sensitivity and could be useful for estimating patients' optimal paclitaxel exposure. For docetaxel, genetics has not been demonstrated to have a meaningful effect on pharmacokinetics and there is no evidence that pharmacokinetics determines PN.
Topics: Animals; Antineoplastic Agents; Biomarkers; Docetaxel; Dose-Response Relationship, Drug; Humans; Paclitaxel; Peripheral Nervous System Diseases; Pharmacogenetics; Precision Medicine
PubMed: 33401943
DOI: 10.1080/17425255.2021.1856367 -
British Journal of Pharmacology Jul 2022Paclitaxel produces a chemotherapy-induced peripheral neuropathy that persists in 50-60% of cancer patients upon treatment. Evidence from animal models suggests an...
BACKGROUND AND PURPOSE
Paclitaxel produces a chemotherapy-induced peripheral neuropathy that persists in 50-60% of cancer patients upon treatment. Evidence from animal models suggests an axonopathy of peripheral A- and C-type fibres that affects their excitability. However, direct effects of paclitaxel on sensory neuron excitability and sexual dimorphism remain poorly understood.
EXPERIMENTAL APPROACH
We used a long-lasting (10 days in vitro) primary culture of rat dorsal root ganglion (DRG) neurons to investigate the time course effect of paclitaxel on the electrical activity of IB4(-) and IB4(+) sensory neurons of female and male adult Wistar rats.
KEY RESULTS
Paclitaxel strongly and reversibly stimulated spontaneous activity and augmented action potential tonic firing in IB4(-) and IB4(+) neurons in both sexes, peaking at 48 h post-treatment and virtually disappearing at 96 h. Paclitaxel decreased the current rheobase for action potential firing by reducing and accelerating the after-hyperpolarization phase. Molecularly, paclitaxel modulated Na and K ion currents. Particularly, the drug significantly augmented the function of Na 1.8, TRPV1 and TRPM8 channels. Furthermore, paclitaxel increased Na 1.8 and TRPV1 expression at 48 h post-treatment. Notably, we observed that female DRG neurons appear more sensitive to paclitaxel sensitization than their male counterparts.
CONCLUSIONS AND IMPLICATIONS
Our data indicate that paclitaxel similarly potentiated IB4(-) and IB4(+) electrogenicity and uncover a potential sex dimorphism in paclitaxel-induced chemotherapy-induced peripheral neuropathy. Our in vitro, pre-clinical, chemotherapy-induced peripheral neuropathy paradigm provides a tool for studying the dynamics and underlying molecular mechanisms contributing to nociceptor sensitization in peripheral neuropathies and for testing desensitizing compounds.
Topics: Animals; Antineoplastic Agents; Female; Ganglia, Spinal; Humans; Male; Paclitaxel; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sensory Receptor Cells
PubMed: 35102580
DOI: 10.1111/bph.15809 -
Current Medicinal Chemistry 2021Paclitaxel (PTX) is the first natural plant-derived chemotherapeutic drug approved by the Food and Drug Administration. However, the clinical applications of PTX are... (Review)
Review
Paclitaxel (PTX) is the first natural plant-derived chemotherapeutic drug approved by the Food and Drug Administration. However, the clinical applications of PTX are limited by some drawbacks, such as poor water solubility, rapid blood clearance, nonspecific distribution, and adverse side effects. Nanocarriers have made important contributions to drug delivery and cancer therapy in recent years. However, low drug loading capacity, nanocarrier excipients-induced toxicity or immunogenicity, and complicated synthesis technologies pose a challenge for the clinical application of nanocarriers. To address these issues, the self-delivery nanomedicine (SDNs), in which pure drug molecules directly self-assemble into nanomedicine, have been developed for drug delivery and enhancing antitumor efficacy. In this review, we comprehensively summarize the recent advances in PTX-based SDNs for cancer therapy. First, the self-assembly strategies to develop pure PTX nanodrugs are discussed. Then, the emerging strategies of co-assembly PTX and other therapeutic agents for effective combination therapy are presented, composing of combination chemotherapy, chemo-photothermal therapy, chemo-photodynamic therapy, chemo-immunotherapy, and chemo-gene therapy. Finally, the limitations and future outlook of SDNs are discussed. The rational design of these unique nanoplatforms may make a new direction to develop highly efficient drug delivery systems for cancer therapy.
Topics: Cell Line, Tumor; Drug Delivery Systems; Drug Therapy, Combination; Humans; Nanomedicine; Nanoparticles; Neoplasms; Paclitaxel
PubMed: 33176629
DOI: 10.2174/0929867327666201111143725 -
BMC Pharmacology & Toxicology Mar 2023Albumin-bound paclitaxel (nab-paclitaxel), as a special targeted preparation of paclitaxel, has the advantages of good curative effect and less side effects in...
BACKGROUND
Albumin-bound paclitaxel (nab-paclitaxel), as a special targeted preparation of paclitaxel, has the advantages of good curative effect and less side effects in anti-tumor therapy. The existence of the plasma-peritoneal barrier and insufficient blood supply make intravenous drugs hard to reach the peritoneum, while hyperthermic intraperitoneal chemotherapy can solve the difficulty. And compared with systemic medications, HIPEC can also give higher concentrations of chemotherapy drugs in the abdominal cavity, while ensuring lower systemic toxicity. However, at present, there is no relevant report on the clinical study of nab-paclitaxel during intraperitoneal hyperthermic chemotherapy, and its stability under special temperature conditions has not been reported either.
METHODS
In this study, We examined three batches of albumin-bound paclitaxel dissolved in saline at different temperatures (25 °C, 37 °C, 41 °C, 42 °C and 43 °C) for the changes of human serum albumin content, human serum albumin polymer content, related substance content, in-vitro release rate, paclitaxel binding rate and paclitaxel content at different temperatures.
RESULTS
Our results demonstrated that the indicators including human serum albumin content, human serum albumin polymer content, in-vitro release rate, paclitaxel binding rate and paclitaxel content were stable to the several temperatures, except that Taxane (0.1%) and other individual impurities in the determination of related substance content fluctuated comparatively widely with the change of temperature. In addition, only Taxane (0.1%) and 7-Epitaxol (1%) were detected.
CONCLUSIONS
Overall, albumin-bound paclitaxel is relatively stable to different temperatures (25 °C, 37 °C, 41 °C, 42 °C and 43 °C). This study will lay a foundation for further studies on the albumin-bound paclitaxel during hyperthermic intraperitoneal chemotherapy.
Topics: Humans; Albumin-Bound Paclitaxel; Hyperthermic Intraperitoneal Chemotherapy; Paclitaxel; Taxoids; Serum Albumin, Human; Polymers
PubMed: 36859304
DOI: 10.1186/s40360-023-00653-2 -
Technology in Cancer Research &... 2020Breast cancer remains the most threatening triggers of cancer death in women. Drug resistance inevitably leads to the weakness of treatment for breast cancer....
OBJECTIVE
Breast cancer remains the most threatening triggers of cancer death in women. Drug resistance inevitably leads to the weakness of treatment for breast cancer. Macrophages, as one of the most abundant immune cells in tumor immune-infiltrating microenvironment, involves in cell survival, migration, and invasion of breast cancer.
METHODS
In this study, we compared the proportions of macrophages in patients with breast cancer with and without paclitaxel treatment, and investigated the targeted genes associated with macrophages for paclitaxel response. To explore the relationship between drug-related genes and breast cancer prognosis, survival analysis based on the drug-related genes were performed by website of Kaplan-Meier plotter with the threshold of significant value < .05.
RESULTS
Compared to the normal samples, we revealed that paclitaxel significantly enhanced the ratio of macrophages in the tumor microenvironment. Furthermore, the expression of 3 drug-related genes (IFT46, PEX11A, and TMEM223) were significantly negatively associated with the proportions of macrophages. And it is worth to notice that PEX11A and TMEM223 were associated with better progression-free survival outcomes of patients with breast cancer. Moreover, PEX11A was associated with longer overall survival time of breast cancer.
CONCLUSION
Taken all together, all the findings support to gain a better understanding to the development of more effective therapies targeted with paclitaxel.
Topics: Antineoplastic Agents, Phytogenic; Biomarkers, Tumor; Breast Neoplasms; Disease Progression; Female; Humans; Lymphocytes, Tumor-Infiltrating; Neoplasm Grading; Neoplasm Staging; Paclitaxel; Prognosis; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 32783527
DOI: 10.1177/1533033820945821 -
Molecules (Basel, Switzerland) Nov 2023Paclitaxel, a natural secondary metabolite isolated and purified from the bark of the tree, is considered one of the most successful natural anticancer drugs due to its... (Review)
Review
Paclitaxel, a natural secondary metabolite isolated and purified from the bark of the tree, is considered one of the most successful natural anticancer drugs due to its low toxicity, high potency and broad-spectrum anticancer activity. trees are scarce and slow-growing, and with extremely low paclitaxel content, the contradiction between supply and demand in the market is becoming more and more intense. Therefore, researchers have tried to obtain paclitaxel by various methods such as chemical synthesis, artificial culture, microbial fermentation and tissue cell culture to meet the clinical demand for this drug. This paper provides a comprehensive overview of paclitaxel extraction, combination therapy, total synthesis, semi-synthesis and biosynthesis in recent years and provides an outlook, aiming to provide a theoretical basis and reference for further research on the production and application of paclitaxel in the future.
Topics: Paclitaxel; Fermentation; Taxus
PubMed: 38005238
DOI: 10.3390/molecules28227517 -
ACS Biomaterials Science & Engineering Dec 2023In this study, we developed a novel hybrid collagen-binding nanocarrier for potential intraductal administration and local breast cancer treatment. The particles were...
In this study, we developed a novel hybrid collagen-binding nanocarrier for potential intraductal administration and local breast cancer treatment. The particles were formed by the encapsulation of nanostructured lipid carriers (NLCs) containing the cytotoxic drug paclitaxel within a shell of poly(-isopropylacrylamide) (pNIPAM), and were functionalized with SILY, a peptide that binds to collagen type I (which is overexpressed in the mammary tumor microenvironment) to improve local retention and selectivity. The encapsulation of the NLCs in the pNIPAM shell increased nanoparticle size by approximately 140 nm, and after purification, a homogeneous system of hybrid nanoparticles (∼96%) was obtained. The nanoparticles exhibited high loading efficiency (<76%) and were capable of prolonging paclitaxel release for up to 120 h. SILY-modified nanoparticles showed the ability to bind to collagen-coated surfaces and naturally elaborated collagen. Hybrid nanoparticles presented cytotoxicity up to 3.7-fold higher than pNIPAM-only nanoparticles on mammary tumor cells cultured in monolayers. In spheroids, the increase in cytotoxicity was up to 1.8-fold. Compared to lipid nanoparticles, the hybrid nanoparticle modified with SILY increased the viability of nontumor breast cells by up to 1.59-fold in a coculture model, suggesting the effectiveness and safety of the system.
Topics: Humans; Female; Paclitaxel; Breast Neoplasms; Drug Carriers; Antineoplastic Agents; Nanoparticles; Tumor Microenvironment
PubMed: 37982792
DOI: 10.1021/acsbiomaterials.3c01332