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Journal of Controlled Release :... Nov 2023While surgery represents a major therapy for most solid organ cancers, local recurrence is clinically problematic for cancers such as sarcoma for which adjuvant...
While surgery represents a major therapy for most solid organ cancers, local recurrence is clinically problematic for cancers such as sarcoma for which adjuvant radiotherapy and systemic chemotherapy provide minimal local control or survival benefit and are dose-limited due to off-target side effects. We describe an implantable, biodegradable poly(1,2-glycerol carbonate) and poly(caprolactone) film with entrapped and covalently-bound paclitaxel enabling safe, controlled, and extended local delivery of paclitaxel achieving concentrations 10,000× tissue levels compared to systemic administration. Films containing entrapped and covalently-bound paclitaxel implanted in the tumor bed, immediately after resection of human cell line-derived chondrosarcoma and patient-derived xenograft liposarcoma and leiomyosarcoma in mice, improve median 90- or 200-day recurrence-free and overall survival compared to control mice. Furthermore, mice in the experimental film arm show no film-related morbidity. Continuous, extended, high-dose paclitaxel delivery via this unique polymer platform safely improves outcomes in three different sarcoma models and provides a rationale for future incorporation into human trials.
Topics: Humans; Animals; Mice; Paclitaxel; Polymers; Sarcoma; Antineoplastic Agents, Phytogenic; Cell Line, Tumor
PubMed: 37776906
DOI: 10.1016/j.jconrel.2023.09.048 -
Medicinal Research Reviews Mar 2016Microtubules, tirelessly animated and highly dynamic structures, are vital for most cellular processes and their intricacies are still being revealed even after a... (Review)
Review
Microtubules, tirelessly animated and highly dynamic structures, are vital for most cellular processes and their intricacies are still being revealed even after a century since their discovery. The importance of microtubules as chemotherapeutic targets cannot be overstated, and their clinical role is unlikely to abate in the near future. Indeed, improved understanding of microtubule biology could herald a new epoch of anticancer drug design by permitting fine-tuning of microtubule-targeting agents, the clinical utility of which is presently often limited by primary or acquired resistance. Paclitaxel, one such agent belonging to the taxane family, has proven a resoundingly successful treatment for many cancer patients; however, for too many others with paclitaxel-refractory tumors, the drug has offered nothing but side effects. Accumulating evidence suggests that microtubule-binding proteins (MBPs) can regulate paclitaxel sensitivity in a wide range of cancer types. Improved understanding of how these proteins can be assayed to predict treatment responses or manipulated pharmacologically to improve clinical outcomes could transform modern chemotherapy and is urgently awaited.
Topics: Biomarkers, Tumor; Drug Resistance, Neoplasm; Humans; Microtubule Proteins; Neoplasms; Paclitaxel; Precision Medicine
PubMed: 26332739
DOI: 10.1002/med.21378 -
Biomedicine & Pharmacotherapy =... Sep 2021Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis and migration of cancer cells to neighboring cells and tissues. Morphologically,... (Review)
Review
Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis and migration of cancer cells to neighboring cells and tissues. Morphologically, epithelial cells are transformed to mesenchymal cells, and at molecular level, E-cadherin undergoes down-regulation, while an increase occurs in N-cadherin and vimentin levels. Increasing evidence demonstrates role of EMT in mediating drug resistance of cancer cells. On the other hand, paclitaxel (PTX) and docetaxel (DTX) are two chemotherapeutic agents belonging to taxene family, capable of inducing cell cycle arrest in cancer cells via preventing microtubule depolymerization. Aggressive behavior of cancer cells resulted from EMT-mediated metastasis can lead to PTX and DTX resistance. Upstream mediators of EMT such as ZEB1/2, TGF-β, microRNAs, and so on are involved in regulating response of cancer cells to PTX and DTX. Tumor-suppressing factors inhibit EMT to promote PTX and DTX sensitivity of cancer cells. Furthermore, three different strategies including using anti-tumor compounds, gene therapy and delivery systems have been developed for suppressing EMT, and enhancing cytotoxicity of PTX and DTX against cancer cells that are mechanistically discussed in the current review.
Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Neoplasms; Paclitaxel
PubMed: 34175815
DOI: 10.1016/j.biopha.2021.111824 -
Nature Communications Feb 2024This multicenter, phase II study (NCT03872791) aims to evaluate the efficacy and safety of the anti-PD-L1/CTLA-4 bispecific antibody KN046 combined with nab-paclitaxel...
The anti-PD-L1/CTLA-4 bispecific antibody KN046 in combination with nab-paclitaxel in first-line treatment of metastatic triple-negative breast cancer: a multicenter phase II trial.
This multicenter, phase II study (NCT03872791) aims to evaluate the efficacy and safety of the anti-PD-L1/CTLA-4 bispecific antibody KN046 combined with nab-paclitaxel in the first-line treatment of patients with metastatic triple-negative breast cancer (TNBC). The primary endpoints included objective response rate (ORR) and duration of response (DoR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) rate, safety, and the correlation of PD-L1 status with clinical efficacy. This trial met pre-specified endpoints. 27 female patients were enrolled sequentially to receive KN046 in two dose levels (3 mg/kg or 5 mg/kg). Among the 25 evaluable patients, the ORR achieved 44.0% (95% CI, 24.4% - 65.1%), and the median DoR was not mature. The median PFS reached 7.33 months (95%CI, 3.68 - 11.07 months), and the median OS was 30.92 months (95%CI, 14.75 - NE months). In PD-L1 positive patients, PFS was 8.61 months (versus 4.73 months) and the 2-year OS rate was 62.5% (versus 57.1%) compared to PD-L1 negative patients. Patients tolerated well the combination therapy. In general, KN046 combined with nab-paclitaxel showed favorable efficacy and survival benefits with tolerable toxicity in the first-line treatment of metastatic TNBC, especially PD-L1 positive, which is worth further investigation.
Topics: Female; Humans; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; CTLA-4 Antigen; Paclitaxel; Triple Negative Breast Neoplasms
PubMed: 38310192
DOI: 10.1038/s41467-024-45160-y -
Biological Research Aug 2023Chemotherapeutic drugs can cause reproductive damage by affecting sperm quality and other aspects of male fertility. Stem cells are thought to alleviate the damage...
Chemotherapeutic drugs can cause reproductive damage by affecting sperm quality and other aspects of male fertility. Stem cells are thought to alleviate the damage caused by chemotherapy drugs and to play roles in reproductive protection and treatment. This study aimed to explore the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) on alleviating paclitaxel (PTX)-induced spermatogenesis and male fertility defects. An in vivo PTX-induced mice model was constructed to evaluate the reproductive toxicity and protective roles of hUC-MSCs in male fertility improvement. A 14 day PTX treatment regimen significantly attenuated mice spermatogenesis and sperm quality, including affecting spermatogenesis, reducing sperm counts, and decreasing sperm motility. hUC-MSCs treatment could significantly improve sperm functional indicators. Mating experiments with normal female mice and examination of embryo development at 7.5 days post-coitum (dpc) showed that hUC-MSCs restored male mouse fertility that was reduced by PTX. In IVF experiments, PTX impaired sperm fertility and blastocyst development, but hUC-MSCs treatment rescued these indicators. hUC-MSCs' protective role was also displayed through the increased expression of the fertility-related proteins HSPA2 and HSPA4L in testes with decreased expression in the PTX-treated group. These changes might be related to the PTX-induced decreases in expression of the germ cell proliferation protein PCNA and the meiosis proteins SYCP3, MLH1, and STRA8, which were restored after hUC-MSCs treatment. In the PTX-treated group, the expression of testicular antioxidant proteins SIRT1, NRF2, CAT, SOD1, and PRDX6 was significantly decreased, but hUC-MSCs could maintain these expressions and reverse PTX-related increases in BAX/BCL2 ratios. hUC-MSCs may be a promising agent with antioxidant and anti-apoptosis characteristics that can maintain sperm quality following chemotherapy treatment.
Topics: Humans; Male; Mice; Female; Animals; Paclitaxel; Antioxidants; Umbilical Cord; Sperm Motility; Semen; Spermatogenesis; Mesenchymal Stem Cells; Fertility; Mesenchymal Stem Cell Transplantation
PubMed: 37574561
DOI: 10.1186/s40659-023-00459-w -
Supportive Care in Cancer : Official... Dec 2016Oxaliplatin and paclitaxel are commonly used chemotherapies associated with acute and chronic neuropathies. There is a need to better understand the similarities and...
PURPOSE
Oxaliplatin and paclitaxel are commonly used chemotherapies associated with acute and chronic neuropathies. There is a need to better understand the similarities and differences of these clinical syndromes.
METHODS
Neuropathy data were pooled from patients receiving adjuvant oxaliplatin and weekly paclitaxel or every 3 weeks of paclitaxel. Patients completed daily questionnaires after each chemotherapy dose and the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy before each chemotherapy cycle and for 12 months post-treatment.
RESULTS
Acute neuropathy symptoms from both drugs peaked around day 3. Acute symptoms experienced in cycle 1 predicted occurrence in subsequent cycles. Paclitaxel-induced acute symptoms were similar in intensity in each cycle and largely resolved between cycles. Oxaliplatin-induced acute symptoms were about half as severe in the first cycle as in later cycles and did not resolve completely between cycles. Both drugs caused a predominantly sensory chronic neuropathy (with numbness and tingling being more common than pain). Oxaliplatin-induced neuropathy worsened after the completion of treatment and began to improve 3 months post-treatment. In contrast, paclitaxel-induced neuropathy began improving immediately after chemotherapy cessation. During treatment, the incidence of paclitaxel sensory symptoms was similar in the hands and feet; with oxaliplatin, the hands were affected more than the feet. Both paclitaxel- and oxaliplatin-induced acute neurotoxicity appeared to predict the severity of chronic neuropathy, more prominently with oxaliplatin.
CONCLUSIONS
Knowledge of the similarities and differences between neuropathy syndromes may provide insight into their underlying pathophysiology and inform future research to identify preventative treatment approaches.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Female; Humans; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Peripheral Nervous System Diseases
PubMed: 27534963
DOI: 10.1007/s00520-016-3373-1 -
Oncology (Williston Park, N.Y.) Aug 2018The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer. This two-drug regimen, with carboplatin dosed using the...
The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer. This two-drug regimen, with carboplatin dosed using the Calvert formula, yielded convincing noninferior outcomes when compared with the prior, more toxic, regimen of cisplatin/paclitaxel. Carboplatin's dose-limiting toxicity is thrombocytopenia; however, when this drug is properly dosed and combined with paclitaxel, the doublet's cycle 1 dose in chemotherapy-naive women is generally safe. Carboplatin (unlike cisplatin) contributes minimally to the cumulative sensory neuropathy of paclitaxel, thus ensuring noticeable reversibility of neuropathy symptoms following completion of 6 cycles and only occasionally requiring cessation or substitution of the taxane. Paclitaxel is responsible for the hair loss associated with the carboplatin/paclitaxel doublet; preventive measures must be considered for patients who would otherwise refuse treatment. Several first-line phase III trials, as well as ongoing trials for which only preliminary results have been published, have fueled debates on the optimal dose and schedule; these have focused not only on weekly vs q3-weeks paclitaxel, but also on other modifications and the advisability of adding bevacizumab. Our view is that results of this doublet in the first-line treatment of ovarian cancer are driven primarily by carboplatin, given that ovarian cancer is a platinum-sensitive disease. Consequently, the roles of the accompanying paclitaxel dose and schedule and the addition of bevacizumab are currently unsettled, and questions regarding these issues should be decided based on patient tolerance and comorbidities until additional data are available.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Female; Humans; Induction Chemotherapy; Ovarian Neoplasms; Paclitaxel
PubMed: 30153322
DOI: No ID Found -
Bioengineered Mar 2022About 40% of patients with diffuse large B-cell lymphoma (DLBCL) develop drug resistance after first-line chemotherapy, which remains a major cause of morbidity and...
About 40% of patients with diffuse large B-cell lymphoma (DLBCL) develop drug resistance after first-line chemotherapy, which remains a major cause of morbidity and mortality. The emergence of DLBCL drug resistance is mainly related to Adriamycin. Our previous research shows that Paclitaxel could be a potential therapeutic drug for the treatment of Adriamycin-resistant DLBCL. Based on the results of RNA-seq and integrated network analysis, we study the potential molecular mechanism of Paclitaxel in the treatment of Adriamycin-resistant DLBCL in multiple dimensions. A CCK-8 assay showed that the inhibitory effect of Paclitaxel on Pfeiffer and Pfeiffer/ADM (Adriamycin-resistant DLBCL cell lines) is significantly higher than that of Adriamycin ( < 0.05). Five hub genes (UBC, TSR1, WDR46, HSP90AA1, and NOP56) were obtained via network analysis from 971 differentially expressed genes (DEGs) based on the RNA-seq of Paclitaxel-intervened Pfeiffer/ADM. The results of the network function module analysis showed that the inhibition of Pfeiffer/ADM by Paclitaxel was closely related to ribosome biosynthesis in eukaryotes. The results of RT-qPCR showed that the mRNA levels of the five hub genes in the Pfeiffer/ADM group were significantly lower than those in the Pfeiffer group and the Pfeiffer/ADM Paclitaxel-treated group ( < 0.05). Consistent with studies, Paclitaxel exhibited a significant inhibitory effect on Adriamycin-resistant DLBCL, which may have played a role in the five hub genes (UBC, TSR1, WDR46, HSP90AA1 and NOP56) and ribosome biosynthesis in eukaryotes pathway, but the specific regulation needs further experimental verification.
Topics: Cell Line, Tumor; Doxorubicin; Humans; Lymphoma, Large B-Cell, Diffuse; Paclitaxel; RNA-Seq
PubMed: 35263200
DOI: 10.1080/21655979.2022.2048772 -
Cardiovascular Engineering and... Jun 2018Drug coated balloons (DCB) are becoming the standard-care treatment for peripheral arterial disease (PAD). DCB use excipients to transfer and retain anti-proliferative... (Comparative Study)
Comparative Study
Drug coated balloons (DCB) are becoming the standard-care treatment for peripheral arterial disease (PAD). DCB use excipients to transfer and retain anti-proliferative drugs, such as paclitaxel. Excipients thus play a vital role in the design and function of DCB, however methods to coat balloons with excipients and anti-proliferative drugs remain unknown. The goal of this study was to thus develop an approach to coat and evaluate DCB for various excipients. An air sprayer method was developed to deposit paclitaxel and various excipients onto non-coated commercially available angioplasty balloons. The coating of the angioplasty balloons was evaluated for drug deposition and coating efficiency using high performance liquid chromatography tandem mass spectrometry. Drug transfer and retention of the coated angioplasty balloons into arterial segments were evaluated ex vivo using harvested pig arteries in a pulsatile flow bioreactor. The air sprayer method successfully delivered varying excipients including bovine serum albumin (BSA), urea and iohexol. The air spray method was configured to coat four angioplasty balloons simultaneously with paclitaxel and iohexol with an average paclitaxel load of 4.0 ± 0.70 µg/mm. The intra-day (within) and inter-day (between) coating precisions, defined as relative standard deviation (RSD), was 17.2 and 15.5%, respectively. Ex vivo deployment of iohexol-paclitaxel DCB yielded an arterial paclitaxel concentration of 123.4 ± 44.68 ng/mg (n = 3) at 1 h, 126.7 ± 25.27 ng/mg (n = 3) at 1 day, and 12.9 ± 12.88 ng/mg (n = 3) at 7 days. This work provides proof-of-concept of a quick, inexpensive approach to coat commercially available angioplasty balloons with paclitaxel and various excipients.
Topics: Angioplasty, Balloon; Animals; Bioreactors; Cardiovascular Agents; Carotid Arteries; Coated Materials, Biocompatible; Drug Liberation; Excipients; Iohexol; Materials Testing; Paclitaxel; Serum Albumin, Bovine; Surface Properties; Sus scrofa; Tissue Culture Techniques; Tissue Distribution; Urea; Vascular Access Devices
PubMed: 29497966
DOI: 10.1007/s13239-018-0346-1 -
Cardiovascular and Interventional... Oct 2018To experimentally investigate a new homogenously paclitaxel/resveratrol-coated balloon catheter in terms of transport of the coating to the treated tissue and local...
PURPOSE
To experimentally investigate a new homogenously paclitaxel/resveratrol-coated balloon catheter in terms of transport of the coating to the treated tissue and local effects including histology and functional tests.
METHODS
Adherence of the coating to the balloon was explored by in vitro simulation of its passage to the lesion. Paclitaxel and resveratrol transfer to the vessel wall was investigated in porcine coronary and peripheral arteries. Matrix-assisted laser desorption/ionization (MALDI) was used for direct microscopic visualization of paclitaxel in arterial tissue. Inhibition of neointimal proliferation and tolerance of complete coating and resveratrol-only coating was investigated in pigs 4 weeks after treatment, and the effect of resveratrol on inflammation and healing after 3 and 7 days.
RESULTS
Drug loss on the way to the lesion was < 10% of dose, while 65 ± 13% was detected at the site of balloon inflation. After treatment similar proportions of drug were detected in coronary and peripheral arteries, i.e., 7.4 ± 4.6% of dose or 125 ± 74 ng/mg tissue. MALDI showed circumferential deposition. Inhibition of neointimal proliferation by paclitaxel/resveratrol coating was significant (p = 0.001) whereas resveratrol-only coating did not inhibit neointimal proliferation. During the first week after treatment of peripheral arteries with resveratrol-only balloons, we observed nominally less inflammation and fibrin deposition along with a significant macrophage reduction and more pronounced re-endothelialization. No safety issues emerged including left ventricular ejection fraction for detection of potential distal embolization after high-dose treatment of coronary arteries.
CONCLUSIONS
Paclitaxel/resveratrol-coated balloons were effective and safe in animal studies. Beyond acting as excipient resveratrol may contribute to vascular healing.
Topics: Angioplasty, Balloon; Angioplasty, Balloon, Coronary; Animals; Coated Materials, Biocompatible; In Vitro Techniques; Neointima; Paclitaxel; Resveratrol; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stilbenes; Swine
PubMed: 29968090
DOI: 10.1007/s00270-018-2018-9