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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 -
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 -
Cancer Medicine Oct 2023Ample evidence reveals that glycolysis is crucial to tumor progression; however, the underlying mechanism of its drug resistance is still worth being further explored....
Ample evidence reveals that glycolysis is crucial to tumor progression; however, the underlying mechanism of its drug resistance is still worth being further explored. TRAF6, an E3 ubiquitin ligase, is well recognized to overexpress in various types of cancer, which predicts a poor prognosis. In our study, we discovered that TRAF6 was expressed more significantly in the case of triple-negative breast cancer (TNBC) than in other of breast cancers, promoting chemoresistance to paclitaxel; that inhibited TRAF6 expression in the chemoresistant TNBC (TNBC-CR) cells enhanced the sensitivity by decreasing glucose uptake and lactate production; that TRAF6 regulated glycolysis and facilitated chemoresistance via binding directly to PKM2; and that overexpressing PKM2 in the TNBC-CR cells with TRAF6 knocked down regained significantly TRAF6-dependent drug resistance and glycolysis. Additionally, we verified that TRAF6 could facilitate PKM2-mediated glycolysis and chemoresistance in animal models and clinical tumor tissues. Thus, we identified the novel function of TRAF6 to promote glycolysis and drug resistance in TNBC with the regulation of PKM2, which could provide a potential molecular target for TNBC treatment.
Topics: Humans; Animals; Triple Negative Breast Neoplasms; Paclitaxel; TNF Receptor-Associated Factor 6; Drug Resistance, Neoplasm; Cell Line, Tumor; Glycolysis; Cell Proliferation; Gene Expression Regulation, Neoplastic
PubMed: 37746908
DOI: 10.1002/cam4.6552 -
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 -
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 -
International Journal of Molecular... Mar 2023Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium . This review summarizes results in... (Review)
Review
Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium . This review summarizes results in the study of epothilones against cancer with preclinical results and clinical studies from 2010-2022. Epothilone have mechanisms of action similar to paclitaxel by inducing tubulin polymerization and apoptosis with low susceptibility to tumor resistance mechanisms. It is active against refractory tumors, being superior to paclitaxel in many respects. Since the discovery of epothilones, several derivatives have been synthesized, and most of them have failed in Phases II and III in clinical trials; however, ixabepilone and utidelone are currently used in clinical practice. There is robust evidence that triple-negative breast cancer (TNBC) treatment improves using ixabepilone plus capecitabine or utidelone in combination with capecitabine. In recent years innovative synthetic strategies resulted in the synthesis of new epothilone derivatives with improved activity against refractory tumors with better activities when compared to ixabepilone or taxol. These compounds together with specific delivery mechanisms could be developed in anti-cancer drugs.
Topics: Humans; Epothilones; Capecitabine; Antineoplastic Agents; Tubulin Modulators; Paclitaxel; Neoplasms
PubMed: 37047035
DOI: 10.3390/ijms24076063 -
Molecules (Basel, Switzerland) Dec 2022Cannabidiol (CBD) is a biologically active compound present in the plants of the family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently,...
Cannabidiol (CBD) is a biologically active compound present in the plants of the family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The target conjugates are characterized by the presence of different anticancer drugs (namely -desacetyl thiocolchicine, podophyllotoxin, and paclitaxel) connected to CBD through a linker able to improve drug release. These nanoparticles are formed via solvent displacement method, resulting in monodisperse and stable structures having hydrodynamic diameters ranging from 160 to 400 nm. Their biological activity is evaluated on three human tumor cell lines (MSTO-211H, HT-29, and HepG2), obtaining GI values in the low micromolar range. Further biological assays were carried out on MSTO-211H cells for the most effective NP , confirming the involvement of paclitaxel in cytotoxicity and cell death mechanism.
Topics: Humans; Cannabidiol; Antineoplastic Agents; Paclitaxel; Cell Line, Tumor; Nanoparticles
PubMed: 36615306
DOI: 10.3390/molecules28010112 -
British Journal of Cancer Dec 2003The taxanes paclitaxel and docetaxel show good activity in the management of advanced ovarian cancer when used in conjunction with platinum agents. Accumulating evidence... (Comparative Study)
Comparative Study Review
The taxanes paclitaxel and docetaxel show good activity in the management of advanced ovarian cancer when used in conjunction with platinum agents. Accumulating evidence from clinical studies, particularly the latest results from the phase III comparative SCOTROC study, indicates that the two drugs confer similar rates of tumour response and survival in women with this condition. However, it is clear that paclitaxel and docetaxel differ in their tolerability profiles and in other respects, and cannot be regarded as directly equivalent drugs. In particular, paclitaxel is associated with significant neurotoxicity; peripheral neuropathy has also been reported with docetaxel, but to a lesser extent. Neutropenia appears more prevalent with docetaxel than with paclitaxel, although clinical trial data show that this adverse effect is manageable and need not compromise dose delivery. Docetaxel is also associated with potential benefits accruing from shorter infusion times and lack of need for premedication with intravenous histamine H(1) and H(2) antagonists. Emerging quality of life data are expected to shed further light on the overall benefit of chemotherapy in women with advanced ovarian cancer in general, and on taxane-platinum combinations in particular.
Topics: Clinical Trials as Topic; Docetaxel; Female; Humans; Ovarian Neoplasms; Paclitaxel; Quality of Life; Taxoids
PubMed: 14661042
DOI: 10.1038/sj.bjc.6601496 -
Journal of B.U.ON. : Official Journal... 2021To explore the safety and effectiveness of paclitaxel and tegafur, gimeracil and oteracil potassium (S-1) combined with apatinib in the conversion therapy for...
PURPOSE
To explore the safety and effectiveness of paclitaxel and tegafur, gimeracil and oteracil potassium (S-1) combined with apatinib in the conversion therapy for unresectable advanced gastric cancer.
METHODS
A total of 66 patients with advanced gastric cancer received treatment with paclitaxel + S-1 + apatinib. Patients evaluated as resectable advanced gastric cancer by the multiple disciplinary team (MDT) underwent the surgery. The clinical efficacy and adverse reactions of the patients receiving conversion therapy and the related indicators of those undergoing operation were recorded. Later, the survival of the patients was compared between successful conversion therapy (surgery) group and unsuccessful conversion therapy (non-surgery) group.
RESULTS
All the 66 patients completed 3-7 cycles of chemotherapy, with a median of 5 cycles, and the objective response rate (ORR) after conversion therapy was 71.2% (47/66). Among them, 48 patients received operation for (225.2±37.3) min on average, with the intraoperative blood loss of (168.2±40.9) mL and (50.9±12.3) intraoperative dissected lymph nodes, including 34 (70.8%) cases of R0 resection. According to the postoperative pathological tumor regression grading (TRG), there were 2 (4.2%) TRG 0 cases, 10 (20.8%) TRG 1 cases, 28 (58.3%) TRG 2 cases and 8 (16.7%) TRG 3 cases. The follow-up results revealed that the one-year overall survival (OS) of the patients was 93.8% (45/48) in successful conversion therapy (surgery) group and 61.1% (11/18) in unsuccessful conversion therapy (non-surgery) group.
CONCLUSION
Paclitaxel and S-1 combined with apatinib can achieve a higher R0 resection rate, and improve the survival rate of patients with successful conversion therapy, showing high safety and efficacy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Female; Humans; Male; Middle Aged; Oxonic Acid; Paclitaxel; Pyridines; Stomach Neoplasms; Tegafur; Treatment Outcome
PubMed: 34565008
DOI: No ID Found -
ELife Mar 2023Paclitaxel (Taxol) is a taxane and a chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the...
Paclitaxel (Taxol) is a taxane and a chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the lack of high-resolution structural information on a tubulin-taxane complex precludes a comprehensive description of the binding determinants that affect its mechanism of action. Here, we solved the crystal structure of baccatin III the core moiety of paclitaxel-tubulin complex at 1.9 Å resolution. Based on this information, we engineered taxanes with modified C13 side chains, solved their crystal structures in complex with tubulin, and analyzed their effects on microtubules (X-ray fiber diffraction), along with those of paclitaxel, docetaxel, and baccatin III. Further comparison of high-resolution structures and microtubules' diffractions with the apo forms and molecular dynamics approaches allowed us to understand the consequences of taxane binding to tubulin in solution and under assembled conditions. The results sheds light on three main mechanistic questions: (1) taxanes bind better to microtubules than to tubulin because tubulin assembly is linked to a βM-loopconformational reorganization (otherwise occludes the access to the taxane site) and, bulky C13 side chains preferentially recognize the assembled conformational state; (2) the occupancy of the taxane site has no influence on the straightness of tubulin protofilaments and; (3) longitudinal expansion of the microtubule lattices arises from the accommodation of the taxane core within the site, a process that is no related to the microtubule stabilization (baccatin III is biochemically inactive). In conclusion, our combined experimental and computational approach allowed us to describe the tubulin-taxane interaction in atomic detail and assess the structural determinants for binding.
Topics: Tubulin; Taxoids; Microtubules; Paclitaxel
PubMed: 36876916
DOI: 10.7554/eLife.84791