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Translational Oncology Jun 2021Chemotherapy induces a variety of immunological changes. Studying these effects can reveal opportunities for successful combining chemotherapy and immunotherapy....
Chemotherapy induces a variety of immunological changes. Studying these effects can reveal opportunities for successful combining chemotherapy and immunotherapy. Immuno-chemotherapeutic combinations in ovarian cancer are currently not generating the anticipated positive effects. To date, only scattered and inconsistent information is available about the immune-induced changes by chemotherapy in ovarian cancer. In this study, we compared six common chemotherapeutics used in ovarian cancer patients (carboplatin, paclitaxel, pegylated liposomal doxorubicin, gemcitabine, carboplatin-paclitaxel and carboplatin-gemcitabine) and studied their effects on the immune system in an ovarian cancer mouse model. Mice received a single chemotherapy or vehicle injection 21 days after tumor inoculation with ID8-fluc cells. One week after therapy administration, we collected peritoneal washings for flow cytometry, serum for cytokine analysis with cytometric bead array and tumor biopsies for immunohistochemistry. Carboplatin-paclitaxel showed the most favorable profile with a decrease in immunosuppressive cells in the peritoneal cavity and an increase of interferon-gamma in serum. In contrast, carboplatin-gemcitabine seemed to promote a hostile immune environment with an increase in regulatory T-cells in tumor tissue and an increase of macrophage-inflammatory-protein-1-beta in the serum.
PubMed: 33770618
DOI: 10.1016/j.tranon.2021.101076 -
Cancer Communications (London, England) Jan 2022Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma... (Randomized Controlled Trial)
Randomized Controlled Trial
Paclitaxel liposome for injection (Lipusu) plus cisplatin versus gemcitabine plus cisplatin in the first-line treatment of locally advanced or metastatic lung squamous cell carcinoma: A multicenter, randomized, open-label, parallel controlled clinical study.
BACKGROUND
Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small-scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first-line treatment in locally advanced or metastatic LSCC.
METHODS
Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45-Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses.
RESULTS
The median duration of follow-up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF-α, IFN-γ, IL-6, and IL-8, demonstrating an overlapping trend.
CONCLUSION
The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Deoxycytidine; Humans; Liposomes; Lung; Lung Neoplasms; Middle Aged; Paclitaxel; Young Adult; Gemcitabine
PubMed: 34699693
DOI: 10.1002/cac2.12225 -
The Oncologist Jan 2024Neoadjuvant trastuzumab/pertuzumab (HP) plus chemotherapy for HER2-positive breast cancer (BC) achieved promising efficacy. The additional cardiotoxicity still existed....
BACKGROUND
Neoadjuvant trastuzumab/pertuzumab (HP) plus chemotherapy for HER2-positive breast cancer (BC) achieved promising efficacy. The additional cardiotoxicity still existed. Brecan study evaluated the efficacy and safety of neoadjuvant pegylated liposomal doxorubicin (PLD)/cyclophosphamide and sequential nab-paclitaxel based on HP (PLD/C/HP-nabP/HP).
PATIENTS AND METHODS
Brecan was a single-arm phase II study. Eligible patients with stages IIA-IIIC HER2-positive BC received 4 cycles of PLD, cyclophosphamide, and HP, followed by 4 cycles of nab-paclitaxel and HP. Definitive surgery was scheduled after 21 days for patients completing treatment or experiencing intolerable toxicity. The primary endpoint was the pathological complete response (pCR).
RESULTS
Between January 2020 and December 2021, 96 patients were enrolled. Ninety-five (99.0%) patients received 8 cycles of neoadjuvant therapy and all underwent surgery with 45 (46.9%) breast-conserving surgery and 51 (53.1%) mastectomy. The pCR was 80.2% (95%CI, 71.2%-87.0%). Four (4.2%) experienced left ventricular insufficiency with an absolute decline in LVEF (43%-49%). No congestive heart failure and ≥grade 3 cardiac toxicity occurred. The objective response rate was 85.4% (95%CI, 77.0%-91.1%), including 57 (59.4%) complete responses and 25 (26.0%) partial responses. The disease control rate was 99.0% (95%CI, 94.3%-99.8%). For overall safety, ≥grade 3 AEs occurred in 30 (31.3%) and mainly included neutropenia (30.2%) and asthenia (8.3%). No treatment-related deaths occurred. Notably, age of >30 (P = .01; OR = 5.086; 95%CI, 1.44-17.965) and HER2 IHC 3+ (P = .02; OR = 4.398; 95%CI, 1.286-15.002) were independent predictors for superior pCR (ClinicalTrials.gov Identifier NCT05346107).
CONCLUSION
Brecan study demonstrated the encouraging safety and efficacy of neoadjuvant PLD/C/HP-nabP/HP, suggesting a potential therapeutic option in HER2-positive BC.
Topics: Humans; Female; Breast Neoplasms; Neoadjuvant Therapy; Receptor, ErbB-2; Mastectomy; Treatment Outcome; Paclitaxel; Cyclophosphamide; Trastuzumab; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37279780
DOI: 10.1093/oncolo/oyad160 -
International Journal of Nanomedicine 2018In this study, a novel arginine, glycine, aspartic acid peptide (RGD)-modified paclitaxel and curcumin co-loaded liposomes were developed to evaluate their antitumor...
PURPOSE
In this study, a novel arginine, glycine, aspartic acid peptide (RGD)-modified paclitaxel and curcumin co-loaded liposomes were developed to evaluate their antitumor activity in vitro and in vivo.
MATERIALS AND METHODS
Co-loaded liposomes were prepared using the solvent evaporation method. The particles had spherical shapes under electron microscopy with sizes <130 nm.
RESULTS
By comparison with the free drug, RGD-modified paclitaxel and curcumin co-loaded liposomes and paclitaxel and curcumin co-loaded liposomes have sustained-release properties in vitro. In vivo, there was no significant difference in pharmacokinetic parameters between the RGD-modified paclitaxel and curcumin co-loaded liposomes and paclitaxel and curcumin co-loaded liposomes. A strong green fluorescence was observed in the cytoplasmic region after incubation of RGD-modified paclitaxel and curcumin co-loaded liposomes for 2 h. RGD-modified paclitaxel and curcumin co-loaded liposomes showed a superior antiproliferative effect on A549 cells with a possible mechanism that suppressed the multidrug resistance phenomenon and exhibited a clear synergistic effect.
CONCLUSION
The results indicate that RGD-modified paclitaxel and curcumin co-loaded liposomes had a better antitumor effect in vivo than the non-modified LPs. These results indicate that RGD-modified co-loaded liposomes are a promising candidate for antitumor drug delivery.
Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Drug Liberation; Female; Humans; Liposomes; Lung Neoplasms; Male; Mice, Inbred BALB C; Oligopeptides; Paclitaxel; Rats, Sprague-Dawley; Xenograft Model Antitumor Assays
PubMed: 29731631
DOI: 10.2147/IJN.S157746 -
Molecules (Basel, Switzerland) Apr 2019Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming...
The Preparation, Determination of a Flexible Complex Liposome Co-Loaded with Cabazitaxel and β-Elemene, and Animal Pharmacodynamics on Paclitaxel-Resistant Lung Adenocarcinoma.
Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and β-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, β-elemene liposome and cabazitaxel-β-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and β-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and β-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and β-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and β-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that β-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity.
Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Humans; Liposomes; Mice; Molecular Structure; Paclitaxel; Particle Size; Sesquiterpenes; Taxoids; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 31052317
DOI: 10.3390/molecules24091697 -
Medical Science Monitor : International... Dec 2020BACKGROUND This retrospective study aimed to investigate the efficacy and safety of image-guided intensity-modulated radiation therapy (IMRT) and volumetric modulated...
Efficacy and Safety of Image-Guided Intensity-Modulated Radiation Therapy and Volumetric Modulated Arc Therapy Combined with Paclitaxel Liposomes and Cisplatin for Locally Advanced Stage IIB-IIIB Cervical Cancer: A Retrospective Study at a Single Center.
BACKGROUND This retrospective study aimed to investigate the efficacy and safety of image-guided intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) combined with administration of paclitaxel liposomes and cisplatin for locally advanced stage IIB-IIIB cervical cancer at a single center in China. MATERIAL AND METHODS The clinical data of 126 patients with stage IIB-IIIB cervical cancer treated in our hospital were retrospectively analyzed. The patients were divided into the IMRT group (n=63) and the VMAT group (n=63). The short-term clinical efficacy, the incidence of adverse reactions, the quality-of-life score, and the changes in levels of T-lymphocyte subsets, serum inflammatory factors, and tumor markers were compared pre- and posttreatment between the 2 groups. RESULTS The clinical response rate was 90.5% and 96.8% in the IMRT group and the VMAT group, respectively; the difference was not statistically significant. After treatment, the levels of CD3⁺, CD4⁺, and CD4⁺/CD8⁺ subsets rose significantly, while the CD8⁺ level declined significantly in both groups compared with the pretreatment levels. After treatment, the levels of serum vascular endothelial growth factor, squamous cell carcinoma antigen, interleukin-8, tumor necrosis factor-a, carcinoembryonic antigen, and carbohydrate antigen 125 declined in both groups compared with pretreatment levels. After treatment, the Karnofsky performance scale score rose in both groups, and it was higher in the VMAT group than in the IMRT group. CONCLUSIONS IMRT and VMAT combined with paclitaxel liposomes and cisplatin have similar short-term clinical efficacy and long-term survival rates in the treatment of stage IIB-IIIB cervical cancer.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cisplatin; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Liposomes; Lymphocyte Subsets; Middle Aged; Neoplasm Staging; Paclitaxel; Quality of Life; Radiotherapy, Image-Guided; Radiotherapy, Intensity-Modulated; Retrospective Studies; Time Factors; Treatment Outcome; Uterine Cervical Neoplasms
PubMed: 33293504
DOI: 10.12659/MSM.927563 -
Acta Medica (Hradec Kralove) 2015Ovarian cancer is the fifth most common malignancy in the world's female population and with the highest lethality index among gynecological tumors. The prognosis of... (Review)
Review
Extracorporeal Elimination of Circulating Pegylated Liposomal Doxorubicin (PLD) to Enhance the Benefit of Cytostatic Therapy in Platinum-Resistant Ovarian Cancer Patients.
Ovarian cancer is the fifth most common malignancy in the world's female population and with the highest lethality index among gynecological tumors. The prognosis of metastatic disease is usually poor, especially in platinum-resistant cases. There are several options for the treatment of metastatic disease resistant to platinum derivates (e.g. paclitaxel, topotecan and pegylated liposomal doxorubicin), all of which are considered equipotent. Pegylated liposomal doxorubicin (PLD) is a liposomal form of the anthracycline antibiotic doxorubicin. It is characterized by more convenient pharmacokinetics and a different toxicity profile. Cardiotoxicity, the major adverse effect of conventional doxorubicin, is reduced in PLD as well as hematotoxicity, alopecia, nausea and vomiting. Skin toxicity and mucositis, however, emerge as serious issues since they represent dose and schedule-limiting toxicities. The pharmacokinetics of PLD (prolonged biological half-life and preferential distribution into tumor tissue) provide new possibilities to address these toxicity issues. The extracorporeal elimination of circulating liposomes after PLD saturation in the tumor tissue represents a novel and potent strategy to diminish drug toxicity. This article intends to review PLD characteristics and the importance of extracorporeal elimination to enhance treatment tolerance and benefits.
Topics: Antibiotics, Antineoplastic; Cytostatic Agents; Doxorubicin; Drug Resistance, Neoplasm; Extracorporeal Circulation; Female; Humans; Ovarian Neoplasms; Platinum Compounds; Polyethylene Glycols
PubMed: 26454800
DOI: 10.14712/18059694.2015.84 -
Acta Pharmaceutica Sinica. B Sep 2020The combination of paclitaxel (PTX) and doxorubicin (DOX) has been widely used in the clinic. However, it remains unsatisfied due to the generation of severe toxicity....
The combination of paclitaxel (PTX) and doxorubicin (DOX) has been widely used in the clinic. However, it remains unsatisfied due to the generation of severe toxicity. Previously, we have successfully synthesized a prodrug PTX--DOX (PSD). The prodrug displayed comparable cytotoxicity compared with the mixture of free PTX and DOX. Thus, we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation. Due to the fact that copper ions (Cu) could coordinate with the anthracene nucleus of DOX, we speculate that the prodrug PSD could be actively loaded into liposomes by Cu gradient. Hence, we designed a remote loading liposomal formulation of PSD (PSD LPs) for combination chemotherapy. The prepared PSD LPs displayed extended blood circulation, improved tumor accumulation, and more significant anti-tumor efficacy compared with PSD NPs. Furthermore, PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil, indicating better safety. Therefore, this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.
PubMed: 33088692
DOI: 10.1016/j.apsb.2020.04.011 -
International Journal of Nanomedicine 2018In the present study, the tumor-specific, pH-responsive peptide HK(R)-modified, theranostic liposome-containing paclitaxel (PTX) and superparamagnetic iron oxide...
BACKGROUND
In the present study, the tumor-specific, pH-responsive peptide HK(R)-modified, theranostic liposome-containing paclitaxel (PTX) and superparamagnetic iron oxide nanoparticles (SPIO NPs), PTX/SPIO-SSL-HK(R), was prepared by using HK(R) as the targeting ligand, SPIO NPs as the magnetic resonance imaging (MRI) agent, PTX as antitumor drug.
METHODS
The PTX/SPIO-SSL-HK(R) was prepared by a thin film hydration method. The characteristics of PTX/SPIO-SSL-HK(R) were evaluated. The targeting effect, MRI, and antitumor activity of PTX/SPIO-SSL-HK(R) were investigated detail in vitro and in vivo in human breast carcinoma MDA-MB-231 cell models.
RESULTS
Our results of in vitro flow cytometry, in vivo imaging, and in vivo MR imaging confirmed the pH-responsive characteristic of HK(R) in MDA-MB-231 cell line in vitro and in vivo. The results of in vivo MRI and in vivo antitumor activity confirmed the theranostic effect of PTX/SPIO-SSL-HK(R) in MDA-MB-231 tumor-bearing model.
CONCLUSION
Considering all our in vitro and in vivo results, we conclude that we developed targeting modified theranostic liposome which could achieve both role of antitumor and MRI.
Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Drug Liberation; Female; Ferric Compounds; Flow Cytometry; Humans; Hydrogen-Ion Concentration; Liposomes; Magnetic Resonance Imaging; Magnetite Nanoparticles; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Paclitaxel; Peptides; Theranostic Nanomedicine; Tissue Distribution
PubMed: 29559778
DOI: 10.2147/IJN.S157082 -
Theranostics 2019The clinical treatment of gastric cancer (GC) is hampered by the development of anticancer drug resistance and the unfavorable pharmacokinetics, off-target toxicity, and...
The clinical treatment of gastric cancer (GC) is hampered by the development of anticancer drug resistance and the unfavorable pharmacokinetics, off-target toxicity, and inadequate intratumoral accumulation of the current chemotherapy treatments. Ginsenosides combined with paclitaxel (PTX) have been shown to exert synergistic inhibition of human GC cell proliferation. In the present study, we developed a novel multifunctional liposome system, in which ginsenosides functioned as the chemotherapy adjuvant and membrane stabilizer. These had long blood circulation times and active targeting abilities, thus creating multifunctionality of the liposomes and facilitating drug administration to the GC cells. Three ginsenosides with different structures were used to formulate the unique nanocarrier, which was prepared using the thin-film hydration method. The stability of the ginsenoside liposomes was determined by particle size analysis using dynamic light scattering. The long circulation time of ginsenoside liposomes was compared with that of conventional liposome and polyethylene glycosylated liposomes . The active targeting effect of ginsenoside liposomes was examined with a GC xenograft model using an imaging system. To examine the antitumor activity of ginsenoside liposomes against GC, MTT, cell cycle, and apoptosis assays were performed on BGC-823 cells and PTX-loaded ginsenoside liposomes were prepared to evaluate the therapeutic efficacy on GC . The ginsenosides stabilized the liposomes in a manner similar to cholesterol. We confirmed the successful delivery of the bioactive combination drugs and internalization into GC cells via analysis of the glucose-related transporter recognition and longer blood circulation time. PTX was encapsulated in different liposomal formulations for use as a combination therapy, in which ginsenosides were found to exert their inherent anticancer activity, as well as act synergistically with PTX. The combination therapy using these targeted liposomes significantly suppressed GC tumor growth and outperformed most reported PTX formulations, including Lipusu and Abraxane. We established novel ginsenoside-based liposomes as a tumor-targeting therapy, in which ginsenoside functioned not only as a chemotherapy adjuvant, but also as a functional membrane material. Ginsenoside-based liposomes offer a novel platform for anticancer drug delivery and may lead to a new era of nanocarrier treatments for cancer.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Combined Modality Therapy; Drug Delivery Systems; Endocytosis; Ginsenosides; Humans; Liposomes; Mice, Nude; Paclitaxel; Stomach Neoplasms
PubMed: 31285771
DOI: 10.7150/thno.34953