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Drug Design, Development and Therapy 2015Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities... (Review)
Review
Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel's indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice.
Topics: Albumin-Bound Paclitaxel; Albumins; Animals; Antineoplastic Agents, Phytogenic; Chemistry, Pharmaceutical; Diffusion of Innovation; Forecasting; Humans; Nanomedicine; Nanoparticles; Paclitaxel; Technology, Pharmaceutical
PubMed: 26244011
DOI: 10.2147/DDDT.S88023 -
Molecules (Basel, Switzerland) Oct 2020Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one... (Review)
Review
Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one of the most common causes of human death in the world, mainly in low and middle-income countries. According to the World Health Organization (WHO), cancer treatment services are not available in more then 70% of low-income countries (90% of high-income countries have them available), and also approximately 70% of cancer deaths are reported in low-income countries. Various approaches on how to combat cancer diseases have since been described, targeting cell division being among them. The so-called mitotic poisons are one of the cornerstones in cancer therapies. The idea that cancer cells usually divide almost uncontrolled and far more rapidly than normal cells have led us to think about such compounds that would take advantage of this difference and target the division of such cells. Many groups of such compounds with different modes of action have been reported so far. In this review article, the main approaches on how to target cancer cell mitosis are described, involving microtubule inhibition, targeting aurora and polo-like kinases and kinesins inhibition. The main representatives of all groups of compounds are discussed and attention has also been paid to the presence and future of the clinical use of these compounds as well as their novel derivatives, reviewing the finished and ongoing clinical trials.
Topics: Animals; Antineoplastic Agents; Colchicine; Docetaxel; Humans; Mitosis; Paclitaxel
PubMed: 33053667
DOI: 10.3390/molecules25204632 -
PloS One 2012Three different variants of photoactivatable caged paclitaxel (PTX) have been synthesized and their bioactivity was characterized in in vitro assays and in living cells....
Three different variants of photoactivatable caged paclitaxel (PTX) have been synthesized and their bioactivity was characterized in in vitro assays and in living cells. The caged PTXs contain the photoremovable chromophore 4,5-dimethoxy-2-nitrobenzyloxycarbonyl (Nvoc) attached to position C7, C2' and to both of these positions via a carbonate bond. Single caged PTXs remained biologically active even at low dosages. Double caging was necessary in order to fully inhibit its activity and to obtain a phototriggerable PTX that can be applied successfully at commonly used concentrations. Irradiation of solutions containing the double caged PTX allowed dose-dependent delivery of functional PTX. Light-triggered stabilization of microtubule assemblies in vitro and in vivo by controlled light exposure of tubulin solutions or cell cultures containing caged PTX was demonstrated. Short light exposure under a fluorescence microscope allowed controlled delivery of free PTX during imaging.
Topics: Cell Survival; Cytoskeleton; HeLa Cells; Humans; Mitotic Index; Paclitaxel; Photolysis; Photosensitizing Agents; Polymerization; Tubulin
PubMed: 22970137
DOI: 10.1371/journal.pone.0043657 -
Journal of Veterinary Internal Medicine 2015Paclitaxel is a commonly used chemotherapeutic agent with a broad spectrum of activity against cancers in humans. In 1992, paclitaxel was approved by the U.S. Food and... (Review)
Review
Paclitaxel is a commonly used chemotherapeutic agent with a broad spectrum of activity against cancers in humans. In 1992, paclitaxel was approved by the U.S. Food and Drug Administration (FDA) as Taxol(®) for use in advanced ovarian cancer. Two years later, it was approved for the treatment of metastatic breast cancer. Paclitaxel was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia in 1971. Taxanes are a family of microtubule inhibitors. As a member of this family, paclitaxel suppresses spindle microtubule dynamics. This activity results in the blockage of the metaphase-anaphase transitions, and ultimately in the inhibition of mitosis, and induction of apoptosis in a wide spectrum of cancer cells. Additional anticancer activities of paclitaxel have been defined that are independent of these effects on the microtubules and may include the suppression of cell proliferation as well as antiangiogenic effects. Based on its targeting of a fundamental feature of the cancer phenotype, the mitotic complex, it is not surprising that paclitaxel has been found to be active in a wide variety of cancers in humans. This review summarizes the evidence in support of paclitaxel's broad anticancer activity and introduces the rationale for, and the progress in development of novel formulations of paclitaxel that may preferentially target cancers and that are not associated with the risks for hypersensitivity in dogs. Of note, a novel nanoparticle formulation of paclitaxel that substantially limits hypersensitivity was recently given conditional approval by the FDA Center for Veterinary Medicine for use in dogs with resectable and nonresectable squamous cell carcinoma and nonresectable stage III, IV and V mammary carcinoma.
Topics: Animals; Antineoplastic Agents, Phytogenic; Chemistry, Pharmaceutical; Dog Diseases; Dogs; Humans; Neoplasms; Paclitaxel
PubMed: 26179168
DOI: 10.1111/jvim.12596 -
The Journal of Biological Chemistry Oct 2020
Review
Topics: Animals; History, 20th Century; History, 21st Century; Humans; Microtubules; Neoplasm Proteins; Neoplasms; Paclitaxel; Tubulin
PubMed: 33037081
DOI: 10.1074/jbc.CL120.015923 -
International Journal of Nanomedicine Jan 2011The purpose of this study was to develop a novel formulation of paclitaxel (PTX) that would improve its therapeutic index. Here, we combined a concept of polymer-PTX...
The purpose of this study was to develop a novel formulation of paclitaxel (PTX) that would improve its therapeutic index. Here, we combined a concept of polymer-PTX drug conjugate with a concept of polymeric micelle drug delivery to form novel free PTX-loaded poly(L-γ-glutamylglutamine) (PGG)-PTX conjugate nanoparticles. The significance of this drug formulation emphasizes the simplicity, novelty, and flexibility of the method of forming nanoparticles that contain free PTX and conjugated PTX in the same drug delivery system. The results of effectively inhibiting tumor growth in mouse models demonstrated the feasibility of the nanoparticle formulation. The versatility and potential of this dual PTX drug delivery system can be explored with different drugs for different indications. Novel and simple formulations of PTX-loaded PGG-PTX nanoparticles could have important implications in translational medicines.
Topics: Animals; Antineoplastic Agents, Phytogenic; Body Weight; Cell Line, Tumor; Drug Delivery Systems; Humans; Logistic Models; Mice; Mice, Nude; Micelles; Microscopy, Electron, Transmission; Nanoconjugates; Nuclear Magnetic Resonance, Biomolecular; Paclitaxel; Particle Size; Proteins; Transplantation, Heterologous; Xenograft Model Antitumor Assays
PubMed: 21289985
DOI: 10.2147/IJN.S15839 -
Nature Communications Aug 2023Precise and efficient image-guided immunotherapy holds great promise for cancer treatment. Here, we report a self-accelerated nanoplatform combining an...
Precise and efficient image-guided immunotherapy holds great promise for cancer treatment. Here, we report a self-accelerated nanoplatform combining an aggregation-induced emission luminogen (AIEgen) and a hypoxia-responsive prodrug for multifunctional image-guided combination immunotherapy. The near-infrared AIEgen with methoxy substitution simultaneously possesses boosted fluorescence and photoacoustic (PA) brightness for the strong light absorption ability, as well as amplified type I and type II photodynamic therapy (PDT) properties via enhanced intersystem crossing process. By formulating the high-performance AIEgen with a hypoxia-responsive paclitaxel (PTX) prodrug into nanoparticles, and further camouflaging with macrophage cell membrane, a tumor-targeting theranostic agent is built. The integration of fluorescence and PA imaging helps to delineate tumor site sensitively, providing accurate guidance for tumor treatment. The light-induced PDT effect could consume the local oxygen and lead to severer hypoxia, accelerating the release of PTX drug. As a result, the combination of PDT and PTX chemotherapy induces immunogenic cancer cell death, which could not only elicit strong antitumor immunity to suppress the primary tumor, but also inhibit the growth of distant tumor in 4T1 tumor-bearing female mice. Here, we report a strategy to develop theranostic agents via rational molecular design for boosting antitumor immunotherapy.
Topics: Female; Animals; Mice; Prodrugs; Immunotherapy; Cell Membrane; Fluorescence; Hypoxia; Paclitaxel; Neoplasms
PubMed: 37626073
DOI: 10.1038/s41467-023-40996-2 -
Molecular Medicine Reports Dec 2020Paclitaxel is a potent antineoplastic agent, but poor solubility and resistance have limited its use. Gold nanoparticles (AuNPs) are widely studied as drug carriers... (Review)
Review
Paclitaxel is a potent antineoplastic agent, but poor solubility and resistance have limited its use. Gold nanoparticles (AuNPs) are widely studied as drug carriers because they can be engineered to prevent drug insolubility, carry nucleic acid payloads for gene therapy, target specific tumor cell lines, modulate drug release and amplify photothermal therapy. Consequently, the conjugation of paclitaxel with AuNPs to improve antiproliferative and pro‑apoptotic potency may enable improved clinical outcomes. There are currently a number of different AuNPs under development, including simple drug or nucleic acid carriers and targeted AuNPs that are designed to deliver therapeutic payloads to specific cells. The current study reviewed previous research on AuNPs and the development of AuNP‑based paclitaxel delivery.
Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Gold; Humans; Metal Nanoparticles; Neoplasms; Nucleic Acids; Paclitaxel
PubMed: 33173972
DOI: 10.3892/mmr.2020.11580 -
Biomedicine & Pharmacotherapy =... May 2023Paclitaxel, a compound naturally occurring in yew, is a commonly used drug for the treatment of different types of cancer. Unfortunately, frequent cancer cell resistance... (Review)
Review
Paclitaxel, a compound naturally occurring in yew, is a commonly used drug for the treatment of different types of cancer. Unfortunately, frequent cancer cell resistance significantly decreases its anticancer effectivity. The main reason for the resistance development is the paclitaxel-induced phenomenon of cytoprotective autophagy occurring by different mechanisms of action in dependence on a cell type and possibly even leading to metastases. Paclitaxel also induces autophagy in cancer stem cells, which greatly contributes to tumor resistance development. Paclitaxel anticancer effectivity can be predicted by the presence of several autophagy-related molecular markers, such as tumor necrosis factor superfamily member 13 in triple-negative breast cancer or cystine/glutamate transporter encoded by the SLC7A11 gene in ovarian cancer. Nevertheless, the undesired effects of paclitaxel-induced autophagy can be eliminated by paclitaxel co-administration with autophagy inhibitors, such as chloroquine. Interestingly, in certain cases, it is worthy of potentiating autophagy by paclitaxel combination with autophagy inducers, for instance, apatinib. A modern strategy in anticancer research is also to encapsulate chemotherapeutics into nanoparticle carriers or develop their novel derivatives with improved anticancer properties. Hence, in this review article, we summarize not only the current knowledge of paclitaxel-induced autophagy and its role in cancer resistance but mainly the possible drug combinations based on paclitaxel and their administration in nanoparticle-based formulations as well as paclitaxel analogs with autophagy-modulating properties.
Topics: Female; Humans; Paclitaxel; Antineoplastic Agents, Phytogenic; Apoptosis; Ovarian Neoplasms; Autophagy; Cell Line, Tumor; Drug Resistance, Neoplasm
PubMed: 36889112
DOI: 10.1016/j.biopha.2023.114458 -
Journal For Immunotherapy of Cancer Jun 2023In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Association between gene expression signatures and clinical outcomes of pembrolizumab versus paclitaxel in advanced gastric cancer: exploratory analysis from the randomized, controlled, phase III KEYNOTE-061 trial.
BACKGROUND
In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial.
METHODS
Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (TcellGEP) and 10 non-TcellGEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-β, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for TcellGEP (prespecified α=0.05) and the 10 non-TcellGEP signatures (multiplicity-adjusted; prespecified α=0.10).
RESULTS
RNA sequencing data were available for 137 patients in each treatment group. TcellGEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The TcellGEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the TcellGEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel.
CONCLUSIONS
This exploratory analysis of tumor TcellGEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. TcellGEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis.
TRIAL REGISTRATION NUMBER
NCT02370498.
Topics: Humans; Paclitaxel; Stomach Neoplasms; Transcriptome; Antibodies, Monoclonal, Humanized
PubMed: 37399357
DOI: 10.1136/jitc-2023-006920