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Journal of the American Chemical Society Jun 2020Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both...
Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural (plant material) or biosynthetically derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol.
Topics: Antineoplastic Agents, Phytogenic; Molecular Conformation; Paclitaxel
PubMed: 32406238
DOI: 10.1021/jacs.0c03592 -
Natural Product Reports Jul 2023Many researchers in the natural product sciences dream of discovering a successful drug. For almost all of us, this dream will never be realized. Among the heroes of our... (Review)
Review
Many researchers in the natural product sciences dream of discovering a successful drug. For almost all of us, this dream will never be realized. Among the heroes of our past, though, there is a team whose efforts led to the discovery of not one but two new drugs. Dr Monroe Wall and Dr Mansukh Wani isolated and solved the structures for taxol and camptothecin, plant-based compounds that continue to play a critical role in cancer therapy today. Since the 1960s and 1970s when Wall, Wani and collaborators did their seminal work, there have been tremendous technological advances in the natural product sciences. With access to most sophisticated technology, it might be expected that the rate of discovery of new drugs from plants and other sources would have sped up. However, this has not come to pass. Why is this? Is it that the promise of new drug candidates from plant-based sources has been exhausted? Has our fascination with new technologies and with the promise of the genomics revolution caused us to stop investing effort and resources in the practices that are proven to yield success? With this Viewpoint, we share the story of taxol's discovery, highlighting critical challenges that were overcome and considering their relevance to botanical natural products drug discovery today. We hope that consideration of lessons learned from the past will help fuel success by researchers currently studying plants with the goal of discovering promising therapeutic leads.
Topics: Humans; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Biological Products; Neoplasms; Paclitaxel; Plants; Population Health
PubMed: 37449327
DOI: 10.1039/d3np00017f -
Ontario Health Technology Assessment... 2015Peripheral arterial disease is a condition in which atherosclerotic plaques partially or completely block blood flow to the legs. Although percutaneous transluminal... (Review)
Review
BACKGROUND
Peripheral arterial disease is a condition in which atherosclerotic plaques partially or completely block blood flow to the legs. Although percutaneous transluminal angioplasty and metallic stenting have high immediate success rates in treating peripheral arterial disease, long-term patency and restenosis rates in long and complex lesions remain unsatisfactory.
OBJECTIVE
The objective of this analysis was to evaluate the clinical effectiveness, safety, cost-effectiveness and budget impact of Zilver paclitaxel self-expanding drug-eluting stents for the treatment of de novo or restenotic lesions in above-the-knee peripheral arterial disease.
DATA SOURCES
Literature searches were performed using Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid Embase, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), and EBM Reviews. For the economic review, a search filter was applied to limit search results to economics-related literature. Data sources for the budget impact analysis included expert opinion, published literature, and Ontario administrative data.
REVIEW METHODS
Systematic reviews, meta-analyses, randomized controlled trials, and observational studies were included in the clinical effectiveness review, and full economic evaluations were included in the economic literature review. Studies were included if they examined the effect of Zilver paclitaxel drug-eluting stents in de novo or restenotic lesions in above-the-knee arteries. For the budget impact analysis, 3 scenarios were constructed based on different assumptions.
RESULTS
One randomized controlled trial reported a significantly higher patency rate with Zilver paclitaxel drug-eluting stents for lesions ≤ 14 cm than with angioplasty or bare metal stents. One observational study showed no difference in patency rates between Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons. Zilver paclitaxel drug-eluting stents were associated with a significantly higher event-free survival rate than angioplasty, but the event-free survival rate was similar for Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons. No economic evaluations compared Zilver paclitaxel drug-eluting stents with bare metal stents or angioplasty for peripheral arterial disease. A budget impact analysis showed that the cost savings associated with funding of Zilver paclitaxel drug-eluting stents would be $470,000 to $640,000 per year, assuming that the use of the Zilver paclitaxel drug-eluting stent was associated with a lower risk of subsequent revascularization.
CONCLUSIONS
Based on evidence of low to moderate quality, Zilver paclitaxel drug-eluting stents were associated with a higher patency rate than angioplasty or bare metal stents, and with fewer adverse events than angioplasty. The effectiveness and safety of Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons were similar.
Topics: Antineoplastic Agents, Phytogenic; Cost-Benefit Analysis; Drug-Eluting Stents; Humans; Paclitaxel; Peripheral Arterial Disease; Technology Assessment, Biomedical
PubMed: 26719778
DOI: No ID Found -
Advanced Science (Weinheim,... Nov 2022Chemotherapy, although effective against primary tumors, may promote metastasis by causing the release of proinflammatory factors from damaged cells. Here, polymeric...
Chemotherapy, although effective against primary tumors, may promote metastasis by causing the release of proinflammatory factors from damaged cells. Here, polymeric nanoparticles that deliver chemotherapeutics and scavenge proinflammatory factors simultaneously to inhibit chemotherapy-induced breast cancer metastasis are developed. The cationic nanoparticles can adsorb cell-free nucleic acids (cfNAs) based on charge-charge interaction, which downregulates the expression of Toll-like receptors and then reduces the secretion of inflammatory cytokines. Through in vitro structural optimization, cationic polyamidoamine (PAMAM) dendrimers modified with drug-binding dodecyl groups and diethylethanolamine surface groups (PAMAM-G3-C12 -DEEA ) exhibit the most desirable combination of nanoparticle size (≈140 nm), drug loading, cytotoxicity, cfNA binding, and anti-inflammatory activity. In the mouse models of breast cancer metastasis, paclitaxel-loaded nanoparticles reduce serum levels of cfNAs and inflammatory cytokines compared with paclitaxel treatment alone and inhibit both primary tumor growth and tumor metastasis. Additionally, no significant side effects are detected in the serum or major organs. These results provide a strategy to deliver chemotherapeutics to primary tumors while reducing the prometastatic effects of chemotherapy.
Topics: Mice; Animals; Neoplasms; Paclitaxel; Nanoparticles; Antineoplastic Agents; Cytokines
PubMed: 36220339
DOI: 10.1002/advs.202203949 -
International Journal of Oncology Sep 2023Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with...
Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with surgery in the early stages, endometrial cancer presents a significant clinical challenge in the metastatic and recurrent setting with few novel treatment strategies emerging in the past fifty years. Ipatasertib (IPAT) is an orally bioavailable pan‑AKT inhibitor, which targets all three AKT isoforms and has demonstrated anti‑tumor activity in pre‑clinical models, with clinical trials emerging for many cancer types. In the present study, the MTT assay was employed to evaluate the therapeutic efficacy of IPAT or IPAT in combination with paclitaxel (PTX) in endometrial cancer cell lines and primary cultures of endometrial cancer. The effect of IPAT and PTX on the growth of endometrial tumors was evaluated in a transgenic mouse model of endometrial cancer. Apoptosis was assessed using cleaved caspase assays and cellular stress was assessed using ROS, JC1 and tetramethylrhodamine ethyl ester assays. The protein expression levels of markers of apoptosis and cellular stress, and DNA damage were evaluated using western blotting and immunohistochemistry. IPAT significantly inhibited cell proliferation, caused cell cycle G1 phase arrest, and induced cellular stress and mitochondrial apoptosis in a dose dependent manner in human endometrial cancer cell lines. Combined treatment with low doses of IPAT and PTX led to synergistic inhibition of cell proliferation and induction of cleaved caspase 3 activity in the human endometrial cancer cell lines and the primary cultures. Furthermore, IPAT effectively reduced tumor growth, accompanied by decreased protein expression levels of Ki67 and phosphorylation of S6 in the mouse model of endometrioid endometrial cancer. The combination of IPAT and PTX resulted in increased expression of phosphorylated‑H2AX and KIF14, markers of DNA damage and microtubule dysfunction respectively, as compared with IPAT alone, PTX alone or placebo‑treated mice. The results of the present study provide a biological rationale to evaluate IPAT and the combination of IPAT and PTX in future clinical trials for endometrial cancer.
Topics: Female; Animals; Humans; Mice; Paclitaxel; Proto-Oncogene Proteins c-akt; Piperazines; Cell Proliferation; Endometrial Neoplasms; Apoptosis; Cell Line, Tumor
PubMed: 37503790
DOI: 10.3892/ijo.2023.5551 -
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 -
Journal of the American College of... Feb 2006Recent clinical studies that investigated the efficacy of the two U.S. Food and Drug Administration-approved drug-eluting stent (DES) platforms Cypher (Cordis, Johnson... (Review)
Review
Recent clinical studies that investigated the efficacy of the two U.S. Food and Drug Administration-approved drug-eluting stent (DES) platforms Cypher (Cordis, Johnson and Johnson, Miami Lakes, Florida) and Taxus (Boston Scientific, Boston, Massachusetts) suggest that there are differences between both DES concerning neointimal growth. Both DES elute compounds that inhibit the cell cycle, but at different stages: Cypher stents elute sirolimus, which induces G1 cell cycle inhibition, and Taxus stents release paclitaxel, which predominantly leads to M-phase arrest. In an attempt to explain the differences observed in human studies, the properties of these stent-based compounds on critical molecular and cellular events associated with the pathophysiology of in-stent restenosis are discussed in detail with the conclusion that both sirolimus and paclitaxel are different in their pleiotropic anti-restenotic effects. This may be in part responsible for the differences observed in recent clinical studies.
Topics: Apoptosis; Cell Proliferation; Coronary Restenosis; Endothelium, Vascular; Humans; Muscle, Smooth, Vascular; Paclitaxel; Sirolimus; Stents
PubMed: 16487832
DOI: 10.1016/j.jacc.2005.09.047 -
BMC Cancer Jul 2021Although various clinical trials and real-life studies have tried to explore the value of nab-paclitaxel mono-chemotherapy for metastatic breast cancer (MBC), the safety... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although various clinical trials and real-life studies have tried to explore the value of nab-paclitaxel mono-chemotherapy for metastatic breast cancer (MBC), the safety and efficacy of nab-paclitaxel remain unclear which need to be systematically evaluated.
METHODS
Electronic searches for prospective clinical trials evaluating nab-paclitaxel monotherapy for MBC were performed. Requisite data were extracted, integrated and analysed from the included studies according to the different study designs using systematic review and meta-analysis. Meta-regression and subgroup analysis were further performed to explore the potential risk factors affecting each individual outcome of interest following nab-paclitaxel monotherapy.
RESULTS
Twenty-two studies with 3287 MBC patients were included. A total of 1685 MBC patients received nab-paclitaxel as first-line therapy, 640 patients as further-line therapy, and 962 patients as mixed-line therapy. A total of 1966 MBC patients (60.40%) received nab-paclitaxel weekly, 1190 patients (36.56%) received nab-paclitaxel triweekly and 99 patients (3.04%) received nab-paclitaxel biweekly. The overall incidence rates of all-grade neutropenia, leukopenia, peripheral sensory neuropathy, and fatigue were 52% (95% CI, 38-66%, I = 98.97%), 58% (95% CI, 43-73%, I = 97.72%), 58% (95% CI, 48-68%, I = 97.17%), and 49% (95% CI, 41-56%, I = 94.39%), respectively. The overall response rate (ORR) was 40% (95% CI, 35-45%, I = 98.97%), and the clinical benefit rate (CBR) was 66% (95% CI, 59-73%, I = 98.97%) following nab-paclitaxel monotherapy. The median progression-free survival (PFS) was 7.64 months (95% CI, 6.89-8.40 months, I = 92.3%), and the median overall survival (OS) was 24.51 months (95% CI, 21.25-27.78 months, I = 92.7%). Treatment line, human epidermal growth factor receptor-2(Her-2)-negative status and dosage were found to be sources of heterogeneity among the included studies. According to the meta-regression and subgroup analysis, grade 3/4 neutropenia occurred less frequently in Her-2-negative patients than in the entire population (P = 0.046). Patients who received first-line nab-paclitaxel monotherapy showed a higher ORR (P = 0.006) and longer PFS (P = 0.045). Efficacy outcomes were not affected by the administration schedule. However, within the same schedule, patients appeared to have a superior ORR (P = 0.044) and longer PFS (P = 0.03) with an increasing dosage of nab-paclitaxel administered.
CONCLUSIONS
The benefits brought by nab-paclitaxel mono-chemotherapy in the treatment of MBC are considerable while the harm is generally manageable. Further study and validation are needed to figure out the roles which the dosage, schedule and other factors play actually in nab-paclitaxel chemotherapy.
Topics: Albumins; Breast Neoplasms; Female; Humans; Neoplasm Metastasis; Paclitaxel; Risk Factors; Treatment Outcome
PubMed: 34275458
DOI: 10.1186/s12885-021-08441-z -
Drug Design, Development and Therapy 2014Paclitaxel (Taxol), one of the most important anticancer drugs, has been used for therapy of different types of cancers. Mechanistically, paclitaxel arrests cell cycle... (Review)
Review
Paclitaxel (Taxol), one of the most important anticancer drugs, has been used for therapy of different types of cancers. Mechanistically, paclitaxel arrests cell cycle and induces cell death by stabilizing microtubules and interfering with microtubule disassembly in cell division. Recently, it has been found that low-dose paclitaxel seems promising in treating non-cancer diseases, such as skin disorders, renal and hepatic fibrosis, inflammation, axon regeneration, limb salvage, and coronary artery restenosis. Future studies need to understand the mechanisms underlying these effects in order to design therapies with specificity.
Topics: Animals; Antineoplastic Agents, Phytogenic; Coronary Restenosis; Humans; Inflammation; Limb Salvage; Nerve Regeneration; Paclitaxel; Pulmonary Fibrosis; Toll-Like Receptor 4
PubMed: 24591817
DOI: 10.2147/DDDT.S56801 -
Drug Delivery Dec 2023Magnetic FeO nanoparticles were prepared via a simple hydrothermal method and utilized to load paclitaxel. The average particle size of FeO nanoparticles was found to be...
Magnetic FeO nanoparticles were prepared via a simple hydrothermal method and utilized to load paclitaxel. The average particle size of FeO nanoparticles was found to be 20.2 ± 3.0 nm, and the calculated saturation magnetization reached 129.38 emu/g, verifying superparamagnetism of nanomaterials. The specific surface area and pore volume were 84.756 m/g and 0.265 cm/g, respectively. Subsequently, FeO@mSiO nanoparticles were successfully fabricated using the FeO nanoparticles as precursors with an average size of 27.81 nm. The relevant saturation magnetization, zeta potential, and specific surface area of FeO@mSiO-NH-FA were respectively 76.3 emu/g, -14.1 mV, and 324.410 m/g. The pore volume and average adsorption pore size were 0.369 cm/g and 4.548 nm, respectively. Compared to free paclitaxel, the solubility and stability of nanoparticles loaded with paclitaxel were improved. The drug loading efficiency and drug load of the nanoformulation were 44.26 and 11.38%, respectively. The FeO@mSiO-NH-FA nanocomposites were easy to construct with excellent active targeting performance, pH sensitivity, and sustained-release effect. The nanoformulation also showed good biocompatibility, where the cell viability remained at 73.8% when the concentration reached 1200 μg/mL. The nanoformulation induced cell death through apoptosis, as confirmed by AO/EB staining and flow cytometry. Western blotting results suggested that the nanoformulation could induce iron death by inhibiting Glutathione Peroxidase 4 (GPX4) activity or decreasing Ferritin Heavy Chain 1 (FTH1) expression. Subsequently, the expression of HIF-1α was upregulated owing to the accumulation of reactive oxygen species (ROS), thus affecting the expression of apoptosis-related proteins regulated by p53, inducing cell apoptosis.
Topics: Humans; MCF-7 Cells; Paclitaxel; Magnetic Phenomena
PubMed: 36474448
DOI: 10.1080/10717544.2022.2154411