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Journal of Oncology Pharmacy Practice :... Jun 2023Paclitaxel is a chemotherapeutic agent used in the treatment of multiple types of malignant tumors which was discovered from the tree. In some patients, anaphylaxis...
BACKGROUND
Paclitaxel is a chemotherapeutic agent used in the treatment of multiple types of malignant tumors which was discovered from the tree. In some patients, anaphylaxis develops during the first exposure to paclitaxel, suggesting that primary sensitization may have occurred through hidden or unidentified allergens that produce cross-reactivity. Skin testing may be useful in identifying sensitization to these allergens. Atopy has also been reported in patients with hypersensitivity reactions (HSR) to paclitaxel.The aim of this study is to evaluate the association between atopy and sensitization to allergens with the development of immediate HSR to paclitaxel.
METHODS
Skin prick tests (SPT) for environmental and food allergens were applied to 76 patients recently diagnosed with cancer. A SPT to paclitaxel was applied and if negative, an intradermal test was performed. After paclitaxel's infusion, the development of immediate HSR was observed.
RESULTS
Of 76 skin tests, 43% of patients had allergen sensitization and 57% did not. HSR occurred in 12.1% and 11.6% of each group, respectively. Five percent of patients tested positive to paclitaxel and only one had an immediate HSR. Eighty-nine percent of patients who developed an HSR had a family or personal history of atopy.
CONCLUSIONS
Sensitization to environmental or food allergens does not appear to be a risk factor for the development of immediate HSR to paclitaxel, suggesting that there are other non-IgE-mediated immunologic mechanisms responsible for their development, however, a personal and family history of atopy increases 8x the risk of developing anaphylaxis.
Topics: Humans; Allergens; Paclitaxel; Anaphylaxis; Skin Tests; Intradermal Tests
PubMed: 35188862
DOI: 10.1177/10781552221080415 -
Journal of Pharmaceutical Sciences Aug 2022Current research has demonstrated that tumor development and progression are dependent on a multi-cellular interactome, which forms the tumor microenvironment. Multiple...
Current research has demonstrated that tumor development and progression are dependent on a multi-cellular interactome, which forms the tumor microenvironment. Multiple components of this multi-cellular ecosystem need to be targeted simultaneously for successful cancer therapy. The objective of this study was to develop a multidimensional combined chemo-immunotherapeutic modality for effective breast cancer treatment. TLR 7/8 agonist resiquimod was identified as a potent macrophage stimulant in an initial screening. To deliver paclitaxel as a chemotherapeutic drug and resiquimod as an immune activator in a tumor-targeted fashion, two different pH-sensitive nanoparticles were synthesized using two different polymers, a linear PLGA and a multi-arm, star-shaped PLGA. The star-PLGA pH-responsive nanoparticles exhibited improved pH-dependent drug release and increased penetration in a complex breast cancer spheroid model (breast cancer cell + macrophage cell). Treatment with paclitaxel and resiquimod encapsulated in the pH-responsive nanoparticles resulted in increased cancer cell death and macrophage activation, as tested in an in-vitro breast cancer spheroid model. Altogether, the current study suggests that the paclitaxel and resiquimod combination has potent chemo-immunotherapeutic activity, and delivery using a pH-sensitive nanoparticle further improves its efficacy.
Topics: Adjuvants, Immunologic; Breast Neoplasms; Cell Line, Tumor; Ecosystem; Female; Humans; Hydrogen-Ion Concentration; Immunotherapy; Nanoparticles; Paclitaxel; Tumor Microenvironment
PubMed: 35580693
DOI: 10.1016/j.xphs.2022.05.008 -
Seminars in Cancer Biology Feb 2021Breast cancer is one of the most prevalent and reoccurring cancers and the second most common reason of death in women. Despite advancements in therapeutic strategies... (Review)
Review
Breast cancer is one of the most prevalent and reoccurring cancers and the second most common reason of death in women. Despite advancements in therapeutic strategies for breast cancer, early tumor recurrence and metastasis in patients indicate resistance to chemotherapeutic medicines, such as paclitaxel due to the abnormal expression of ER and EGF2 in breast cancer cells. Therefore, the development of alternatives to paclitaxel is urgently needed to overcome challenges involving drug resistance. An increasing number of studies has revealed miRNAs as novel natural alternative substances that play a crucial role in regulating several physiological processes and have a close, adverse association with several diseases, including breast cancer. Due to the therapeutic potential of miRNA and paclitaxel in cancer research, the current review focuses on the differential roles of various miRNAs in breast cancer development and treatment. miRNA delivery to a specific target site, the development of paclitaxel and miRNA formulations, and nanotechnological strategies for the delivery of nanopaclitaxel in the management of breast cancer are discussed. These strategies involve improving the cellular uptake and bioavailability and reducing the toxicity of free paclitaxel to achieve accumulation tumor site. Furthermore, a molecular docking study was performed to ascertain the enhanced anticancer activity of the nanoformulation of ANG1005 and Abraxane. An in silico analysis revealed that ANG1005 and Abraxane nanoformulations have superior and significantly enhanced interactions with the proteins α-tubulin and Bcl-2. Therefore, ANG1005 and Abraxane may be more suitable in the therapeutic management of breast cancer than the existing free paclitaxel. miRNAs can revert abnormal gene expression to normalcy; since miRNAs serve as tumor suppressors. Therefore, restoration of particular miRNAs levels as a replacement therapy may be an effective endocrine potential strategy for treating ER positive/ negative breast cancers.
Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Computer Simulation; Disease Management; Drug Delivery Systems; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Molecular Docking Simulation; Nanoparticles; Nanotechnology; Paclitaxel; Peptides; Receptors, Estrogen
PubMed: 31891780
DOI: 10.1016/j.semcancer.2019.12.022 -
ACS Nano Aug 2023Modest tissue penetrance, nonuniform distribution, and suboptimal release of drugs limit the potential of intracranial therapies against glioblastoma. Here, a...
Modest tissue penetrance, nonuniform distribution, and suboptimal release of drugs limit the potential of intracranial therapies against glioblastoma. Here, a conformable polymeric implant, μMESH, is realized by intercalating a micronetwork of 3 × 5 μm poly(lactic--glycolic acid) (PLGA) edges over arrays of 20 × 20 μm polyvinyl alcohol (PVA) pillars for the sustained delivery of potent chemotherapeutic molecules, docetaxel (DTXL) and paclitaxel (PTXL). Four different μMESH configurations were engineered by encapsulating DTXL or PTXL within the PLGA micronetwork and nanoformulated DTXL (nanoDTXL) or PTXL (nanoPTXL) within the PVA microlayer. All four μMESH configurations provided sustained drug release for at least 150 days. However, while a burst release of up to 80% of nanoPTXL/nanoDTXL was documented within the first 4 days, molecular DTXL and PTXL were released more slowly from μMESH. Upon incubation with U87-MG cell spheroids, DTXL-μMESH was associated with the lowest lethal drug dose, followed by nanoDTXL-μMESH, PTXL-μMESH, and nanoPTXL-μMESH. In orthotopic models of glioblastoma, μMESH was peritumorally deposited at 15 days post-cell inoculation and tumor proliferation was monitored via bioluminescence imaging. The overall animal survival increased from ∼30 days of the untreated controls to 75 days for nanoPTXL-μMESH and 90 days for PTXL-μMESH. For the DTXL groups, the overall survival could not be defined as 80% and 60% of the animals treated with DTXL-μMESH and nanoDTXL-μMESH were still alive at 90 days, respectively. These results suggest that the sustained delivery of potent drugs properly encapsulated in conformable polymeric implants could halt the proliferation of aggressive brain tumors.
Topics: Animals; Glioblastoma; Pharmaceutical Preparations; Nanoparticles; Paclitaxel; Docetaxel; Polymers; Polyvinyl Alcohol; Cell Line, Tumor
PubMed: 37379253
DOI: 10.1021/acsnano.3c01574 -
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 -
Journal of Biomechanics Jan 2021Paclitaxel is an effective and widely used chemotherapeutic, but also causes debilitating peripheral sensory neuropathy. Due to its influence on microtubule stability,...
Paclitaxel is an effective and widely used chemotherapeutic, but also causes debilitating peripheral sensory neuropathy. Due to its influence on microtubule stability, we and others have hypothesized that paclitaxel alters neuromechanical properties. A prior study suggested that paclitaxel increases the tensile moduli of rat sensory nerves. However, the effects of paclitaxel on tissue level viscoelasticity have not been tested. In this study, sural branches of C57BL/6J mouse sciatic nerves were bilaterally excised. One nerve was treated with Ringer's solution containing paclitaxel, and the contralateral nerve with Ringer's alone. Nerves were then subject to a passive loading protocol in which peak stress, relaxed stress, and stress-relaxation dynamics were monitored at increasing strain. Elastic and tangent tensile moduli were calculated from both peak and relaxed stress-strain curves as well as failure stress were significantly elevated in paclitaxel-treated nerves compared to controls. Double-exponential fits (with τ and τ indicating fast and slow time constants, respectively) were successfully applied to model stress-relaxation. Though no significant differences in the τ and τ were found between groups, paclitaxel treatment significantly increased the variability of τ, suggesting heterogeneous effects on nerve biomechanical properties. Our data establish that paclitaxel effects at the cellular level influence tensile viscoelastic properties of nerves at the tissue level. These results have implications for understanding biomechanical influences on the progression and physical rehabilitation of paclitaxel-induced neuropathy.
Topics: Animals; Mice; Mice, Inbred C57BL; Microtubules; Paclitaxel; Peripheral Nervous System Diseases; Rats; Sciatic Nerve
PubMed: 33257008
DOI: 10.1016/j.jbiomech.2020.110125 -
Journal of Cellular Physiology May 2022The identification of agents that can reverse drug resistance in cancer chemotherapy, and enhance the overall efficacy is of great interest. Paclitaxel (PTX) belongs to... (Review)
Review
The identification of agents that can reverse drug resistance in cancer chemotherapy, and enhance the overall efficacy is of great interest. Paclitaxel (PTX) belongs to taxane family that exerts an antitumor effect by stabilizing microtubules and inhibiting cell cycle progression. However, PTX resistance often develops in tumors due to the overexpression of drug transporters and tumor-promoting pathways. Noncoding RNAs (ncRNAs) are modulators of many processes in cancer cells, such as apoptosis, migration, differentiation, and angiogenesis. In the present study, we summarize the effects of ncRNAs on PTX chemotherapy. MicroRNAs (miRNAs) can have opposite effects on PTX resistance (stimulation or inhibition) via influencing YES1, SK2, MRP1, and STAT3. Moreover, miRNAs modulate the growth and migration rates of tumor cells in regulating PTX efficacy. PIWI-interacting RNAs, small interfering RNAs, and short-hairpin RNAs are other members of ncRNAs regulating PTX sensitivity of cancer cells. Long noncoding RNAs (LncRNAs) are similar to miRNAs and can modulate PTX resistance/sensitivity by their influence on miRNAs and drug efflux transport. The cytotoxicity of PTX against tumor cells can also be affected by circular RNAs (circRNAs) and limitation is that oncogenic circRNAs have been emphasized and experiments should also focus on onco-suppressor circRNAs.
Topics: Drug Resistance; Drug Resistance, Neoplasm; Humans; MicroRNAs; Neoplasms; Paclitaxel; RNA, Circular; RNA, Long Noncoding; RNA, Untranslated
PubMed: 35437787
DOI: 10.1002/jcp.30751 -
Molecular Biology Reports Mar 2024This comprehensive review elucidates the multifaceted roles of paclitaxel, a key chemotherapeutic agent, in cancer therapy, with a focus on its interactions with gap... (Review)
Review
This comprehensive review elucidates the multifaceted roles of paclitaxel, a key chemotherapeutic agent, in cancer therapy, with a focus on its interactions with gap junctions and related kinases. Paclitaxel, with its complex diterpene structure, mediates its anticancer effects predominantly through specific interactions with β-tubulin, instigating cell cycle arrest and triggering various cell death pathways, including apoptosis, pyroptosis, ferroptosis, and necroptosis. The paper systematically delineates the chemical attributes and action mechanisms of paclitaxel and its analogs, underscoring their capacity to disrupt microtubule dynamics, thereby leading to mitotic arrest and subsequent cell death induction. It also scrutinizes the pivotal role of gap junctions, composed of connexin proteins, in the modulation of cancer cell behavior and chemoresistance, especially in the milieu of paclitaxel administration. The review articulates how gap junctions can either suppress tumors or contribute to cancer progression, thereby influencing chemotherapy outcomes. Furthermore, the paper provides an in-depth analysis of how paclitaxel modulates gap junction-associated kinases via phosphorylation, influencing the drug's therapeutic efficacy and resistance profiles. By integrating insights from numerous key studies, the review offers a comprehensive understanding of the interplay between paclitaxel, gap junctions, and kinases, shedding light on potential approaches to augment paclitaxel's anti-tumor effectiveness and counteract chemoresistance in cancer treatment.
Topics: Humans; Paclitaxel; Tubulin; Apoptosis; Cell Death; Neoplasms; Gap Junctions; Cell Line, Tumor
PubMed: 38551726
DOI: 10.1007/s11033-024-09411-x -
Journal of Controlled Release :... Jan 2022Triple negative breast cancer (TNBC) with easy metastasis, "cold" tumor immune microenvironment, and lack of targeted therapy remains poorly prognosed....
Triple negative breast cancer (TNBC) with easy metastasis, "cold" tumor immune microenvironment, and lack of targeted therapy remains poorly prognosed. Chemo-immunotherapy deemed as a potential treatment for TNBC is however confronted by low TNBC selectivity, pronounced systemic toxicity, and limited immunogenic cell death (ICD) induction. Here, employing clinically validated ATN peptide as a ligand and reduction-sensitive biodegradable micelles as a vehicle we constructed αβ integrin-targeted micellar paclitaxel (ATN-MPTX) to elicit strong and selective ICD and chemo-immunotherapy of TNBC. ATN-MPTX exhibited evident targetability and prominent uptake in αβ integrin-positive 4 T1 cells and induced significantly stronger ICD than free PTX and non-targeted MPTX. The therapeutic studies in 4 T1 TNBC model demonstrated that ATN-MPTX caused superior tumor accumulation and treatment efficacy to all controls. Of note, ATN-MPTX plus nano-STING agonist further augmented the immunotherapeutic effects by increasing secretion of proinflammatory cytokines and CD4 and CD8 T cells in the tumor and spleen while reducing T, leading to significantly improved inhibition of 4 T1 primary tumor and more interestingly mitigated lung metastases. This strong and selective ICD induction of ATN-MPTX renders it an interesting tool to enhance chemo-immunotherapy of TNBC.
Topics: CD8-Positive T-Lymphocytes; Humans; Immunogenic Cell Death; Immunotherapy; Paclitaxel; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 34883139
DOI: 10.1016/j.jconrel.2021.12.002 -
European Journal of Medicinal Chemistry Apr 2022In order to improve the targeting efficiency and reduce anti-breast cancer therapeutic side effects, paclitaxel (PTX), crizotinib (CRI), and Bcl-xL siRNA were co-loaded...
In order to improve the targeting efficiency and reduce anti-breast cancer therapeutic side effects, paclitaxel (PTX), crizotinib (CRI), and Bcl-xL siRNA were co-loaded in cationic liposomes (CTL), which exhibited a substantial enhanced permeability and retention effect (EPR effect) in breast cancer. CTL containing crizotinib and paclitaxel (CRI-PTX-CTL) had particle sizes of (138.63 ± 1.53) nm and zeta potentials of (50.90 ± 0.30) mV, respectively. It was spherical and uniformly dispersed under TEM. The in vitro release of CRI-PTX-CTL showed that the cumulative release rates of CRI and PTX within 12 h were 64.37% and 54.71%, and released from liposomes at the same time. At the cellular level, CRI and PTX were discovered to have synergistic effects. Cell uptake experiments demonstrated that CRI, PTX, and siRNA contained in CTL can be effectively taken up by MCF-7 cells. It was further proved that CTL-siRNA could effectively inhibit the expression of Bcl-xL in cells. CRI, PTX and Bcl-xL siRNA delivered by CTL showed enhanced cytotoxicity during in vitro experiments. Therefore, this study proved that the CRI-PTX-CTL-siRNA was a very promising delivery system for the treatment of breast cancer.
Topics: Breast Neoplasms; Cell Line, Tumor; Female; Humans; Liposomes; Paclitaxel; RNA, Small Interfering
PubMed: 35245829
DOI: 10.1016/j.ejmech.2022.114198