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1.
Intern Med ; 62(3): 319-325, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36725064

RESUMO

Objective The aim of this study was to determine the safety and clinical efficacy of docetaxel+cisplatin+5-fluorouracil (DCF) as neoadjuvant chemotherapy (NAC). Methods In this single-center study, patient background and treatment outcomes (NAC efficacy assessment, NAC adverse events, short-term postoperative outcomes, and one-year postoperative outcomes) in patients treated with preoperative DCF and preoperative cisplatin+5-FU (CF) were compared retrospectively. Patients Seventeen patients diagnosed with esophageal squamous cell carcinoma (ESCC) and treated with preoperative DCF therapy and 50 patients treated with preoperative CF therapy between January 2013 and July 2019 were included in this study. Results There were significant differences in clinical T factor and clinical stage between the CF and DCF groups (p<0.05). All patients in the DCF therapy group were above clinical T3 and clinical stage III. The clinical response after NAC was partial response (PR) for 23 patients (46.0%) in the CF group and 13 patients (76.5%) in the DCF group (p=0.030). Regarding adverse events in NAC, neutropenia, febrile neutropenia (FN), diarrhea, and stomatitis were observed more frequently in the DCF group than in the CF group (p<0.05). The postoperative results [overall survival (OS), recurrence-free survival (RFS), one-year OS, one-year RFS] of the DCF group were comparable to those of the CF group. Conclusion DCF therapy has been recognized as an effective treatment option for advanced ESCC. However, the indication for DCF therapy should be chosen carefully because of the high incidence of adverse events.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neutropenia , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/cirurgia , Cisplatino/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Estudos Retrospectivos , Taxoides/uso terapêutico , Fluoruracila , Resultado do Tratamento , Neutropenia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
2.
Support Care Cancer ; 31(2): 139, 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36707490

RESUMO

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity of taxanes for which there is no effective intervention. Genomic CIPN risk determination has yielded promising, but inconsistent results. The present study assessed the utility of a collective SNP cluster identified using novel analytics to describe taxane-associated CIPN risk. METHODS: We analyzed GWAS data derived from ECOG-5103, first identifying SNPs that were most strongly associated with CIPN using Fisher's ratio (FR). We then ranked ordered those SNPs which discriminated CIPN-positive (CIPN +) from CIPN-negative phenotypes based on their discriminatory power and developed the cluster of SNPs which provided the highest predictive accuracy using leave-one-out cross-validation (LOOCV). RESULTS: Using aggregated genotype data obtained from the previously reported ECOG-5103 clinical trial (in which two different arrays were used, HumanOmniExpress (727,227 SNPs) and HumanOmni1-Quad1 (1,131,857 SNPs)), we identified a 267 SNP cluster which was associated with a CIPN + phenotype with an accuracy of 96.1%. CONCLUSIONS: A cluster of SNPs was identified which prospectively discriminated patients most likely to develop symptomatic CIPN following taxane exposure as part of a breast cancer chemotherapy regimen. Validation using an independent patient cohort should be performed.


Assuntos
Antineoplásicos , Neoplasias da Mama , Doenças do Sistema Nervoso Periférico , Taxoides , Humanos , Antineoplásicos/efeitos adversos , Estudo de Associação Genômica Ampla , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Polimorfismo de Nucleotídeo Único , Taxoides/efeitos adversos , Ensaios Clínicos como Assunto , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino
3.
Medicine (Baltimore) ; 102(4): e32732, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36705354

RESUMO

Many locally advanced nasopharyngeal carcinoma patients develop local recurrence or distant metastasis. Our retrospective real-world study aims to evaluate the efficacy and safety of curative sequential approach with induction chemotherapy followed by concurrent chemoradiation + nimotuzumab as first-line therapy in advanced nasopharyngeal carcinoma. From 2015 to 2021, the clinic data of 117 patients with advanced nasopharyngeal carcinoma (stage III-IV a) who were treated in the Affiliated Hospital of Guangdong Medical University were retrospectively reviewed. Fifty-four patients in observation group received taxanes, cisplatin, and 5-fluorouracil/taxanes and cisplatin induction chemotherapy and nimotuzumab (200 mg, weekly) combined with concurrent chemo-radiotherapy (cisplatin: 40 mg/m2 weekly; intensity-modulated radiation therapy); 63 patients in control group received same therapy without nimotuzumab. There was no significant difference in patients' characteristic baseline between 2 groups (P > .05). The complete response rate and objective response rate of the observational group was significantly higher than control group (46.30% vs 17.64%, P = .01; 96.30% vs 82.54%, P = .02). The median follow-up time was 24.77 (3.53-65.97) months. Both of the median progress free survival time and overall survival time were not reached. The 5-year progression-free survival rate of observation group was greater than control group (84.40% vs 63.70%, hazard ratios 0.365, 95% confidence intervals 0.147-0.909, P = .03). The 5-year overall survival rate of observation group and control group were 91.70% and 84.60%, respectively (P = .20). None of the patients withdrew from the study due to adverse events. Nimotuzumab combined with concurrent chemoradiotherapy as first-line therapy in advanced nasopharyngeal carcinoma can improve objective response rate and 5-year progress free survival rate with good safety profile.


Assuntos
Quimioterapia de Indução , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Estudos Retrospectivos , Cisplatino/uso terapêutico , Neoplasias Nasofaríngeas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de Neoplasias , Quimiorradioterapia/efeitos adversos , Taxoides/uso terapêutico
4.
Expert Rev Pharmacoecon Outcomes Res ; 23(2): 231-239, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36541133

RESUMO

INTRODUCTION: Health economic outcomes of real-world treatment sequencing of androgen receptor-targeted agents (ARTA) and docetaxel (DOC) remain unclear. MATERIAL AND METHODS: Data from the electronic Castration-resistant Prostate cancer Australian Database (ePAD) were analyzed including median overall survival (mOS) and median time-to-treatment failure (mTTF). Mean total costs (mTC) and incremental cost-effectiveness ratios (ICER) of treatment sequences were estimated using the average sample method and Zhao and Tian estimator. RESULTS: Of 752 men, 441 received ARTA, 194 DOC, and 175 both sequentially. Of participants treated with both, first-line DOC followed by ARTA was the more common sequence (n = 125, 71%). mOS for first-line ARTA was 8.38 years (95% CI: 3.48, not-estimated) vs. 3.29 years (95% CI: 2.92, 4.02) for DOC. mTTF was 15.7 months (95% CI: 14.2, 23.7) for the ARTA-DOC sequence and 18.2 months (95% CI: 16.2, 23.2) for DOC-ARTA. In first-line, ARTA cost an additional $13,244 per mTTF month compared to DOC. In second-line, ARTA cost $6726 per mTTF month. The DOC-ARTA sequence saved $2139 per mTTF compared to ARTA-DOC, though not statistically significant. CONCLUSION: ICERs show ARTA had improved clinical benefit compared to DOC but at higher cost. There were no significant cost differences between combined sequences.


Assuntos
Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Taxoides/farmacologia , Receptores Androgênicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Austrália , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Docetaxel , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
5.
Front Endocrinol (Lausanne) ; 13: 1025018, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36531475

RESUMO

Chemotherapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to the effects of chemotherapeutic agents. Different chemotherapeutic agents with varying mechanisms of action may damage ovarian function differently. Taxanes are widely used in clinical cancer treatment, but the specific reproductive toxicological information is still controversial. This review described the impact and duration of taxanes on ovarian function in women and analyzed the possible reasons for different conclusions. Furthermore, the toxicity of taxanes on ovarian function and its possible mechanisms were discussed. The potential protective strategies and agents against ovarian damage induced by taxanes are also reviewed.


Assuntos
Antineoplásicos , Insuficiência Ovariana Primária , Feminino , Humanos , Taxoides/efeitos adversos , Antineoplásicos/uso terapêutico , Insuficiência Ovariana Primária/induzido quimicamente , Folículo Ovariano
6.
Elife ; 112022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36525288

RESUMO

Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here, we utilise clonal transcriptomics with WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, in mouse models of triple-negative breast cancer (TNBC) to understand response and resistance to therapy, including BET bromodomain inhibition and taxane-based chemotherapy. These analyses revealed oxidative stress protection by NRF2 as a major mechanism of taxane resistance and led to the discovery that our tumour models are collaterally sensitive to asparagine deprivation therapy using the clinical stage drug L-asparaginase after frontline treatment with docetaxel. In summary, clonal transcriptomics with WILD-seq identifies mechanisms of resistance to chemotherapy that are also operative in patients and pin points asparagine bioavailability as a druggable vulnerability of taxane-resistant lineages.


Cancer begins when a cell multiplies again and again to form a tumour. By the time that tumour measures a centimetre across, it can contain upwards of a hundred million cells. And even though they all came from the same ancestor, they are far from identical. The tumour's family tree has many branches, and each one responds differently to treatment. If some are susceptible to a drug the cells die, the tumour shrinks, and the therapy will appear to be successful. But, if even a small number of cancer cells survive, they will regrow, often more persistently, causing a relapse. Identifying resistant cells, their characteristics, and how to kill them has been challenging due to a lack of good animal models. One way to keep track of a cancer family tree is to insert so-called genetic barcodes into the ancestral cells. As the tumour grows, the cells will pass the barcodes to their descendants. Scientists do this by using viruses that naturally paste their genes into the cells they infect. Applying this technique to an animal model of cancer could reveal which genes allow some cells to survive, and how to overcome them. Wild, Cannell et al. developed a genetic barcoding system called WILD-seq and used it to track all the cells in a mouse tumour. The mice received the same drugs used to treat patients with breast cancer. By scanning the genetic barcodes using recently developed single cell sequencing technologies, Wild, Cannell et al. were able to identify and count each type of cancer cell and work out which genes they were using. This revealed which cells the standard treatment could not kill and exposed their genetic weaknesses. Wild, Cannell et al. used this information to target the cells with a drug currently used to treat leukaemia. The drug identified by this new genetic barcoding approach is already licensed for use in humans. Further investigation could reveal whether it might help to shrink breast tumours that do not respond to standard therapy. Similar experiments could uncover more information about how other types of tumour evolve too.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Nucleares , Transcriptoma , Asparagina , Fatores de Transcrição , Neoplasias de Mama Triplo Negativas/patologia , Taxoides/farmacologia , Taxoides/uso terapêutico
7.
Acta Med Okayama ; 76(6): 661-671, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36549768

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients' quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001-3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p<0.01).


Assuntos
Neoplasias da Mama , Doenças do Sistema Nervoso Periférico , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Qualidade de Vida , Estudo de Associação Genômica Ampla , Taxoides/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Polimorfismo de Nucleotídeo Único , Protocolos de Quimioterapia Combinada Antineoplásica
8.
Acta Med Okayama ; 76(6): 689-694, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36549771

RESUMO

Taxanes are key drugs for patients with breast cancer. A major adverse effect of taxanes is peripheral neuropathy (PN). To investigate the ability of compression therapy using sleeves and stockings to prevent PN due to the taxane docetaxel, we conducted a single-center historical control trial. Patients receiving docetaxel at 75 mg/m2 every 3 weeks for 4 cycles as first-line chemotherapy for breast cancer were eligible. PN was evaluated using the common terminology criteria for adverse events version 4.0. The primary endpoint was the incidence of allgrade PN until 3 weeks after the fourth docetaxel administration. We evaluated 26 patients in the intervention group and compared their data to those collected retrospectively from 52 patients treated with docetaxel without compression. Neither the incidence of all-grade PN until 3 weeks after the fourth docetaxel administration (63.5% in the control group vs. 76.9% in the intervention group, p=0.31) nor that of PN grade ≥ 2 (13.5% vs. 15.4%, p=0.99) differed between the groups. In this study, the efficacy of compression therapy using sleeves and stockings to prevent PN induced by docetaxel was not demonstrated. Further clinical studies including medications or intervention are needed to reduce the incidence and severity of PN induced by chemotherapy.


Assuntos
Neoplasias da Mama , Doenças do Sistema Nervoso Periférico , Humanos , Feminino , Docetaxel/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Taxoides/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
9.
Cell Death Dis ; 13(12): 1034, 2022 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-36509750

RESUMO

Although second-generation therapies like abiraterone (ABI) and enzalutamide (ENZ) benefit patients with castration-resistant prostate cancer (CRPC), drug resistance frequently occurs, eventually resulting in therapy failure. In this study, we used two libraries, FDA-approved drug library and CRISP/Cas9 knockout (GeCKO) library to screen for drugs that overcome treatment resistance and to identify the potential drug-resistant genes involved in treatment resistance. Our screening results showed that the DNA-damaging agent idarubicin (IDA) overcame abiraterone and enzalutamide resistance in prostate cancer cells. IDA treatment inhibited the DNA repair protein XPA expression in a transcription-independent manner. Consistently, XPA knockout sensitized prostate cancer cells to abiraterone and enzalutamide treatment. In conclusion, IDA combats abiraterone and enzalutamide resistance by reducing XPA protein level in prostate cancer.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Idarubicina/uso terapêutico , Próstata , Docetaxel , Taxoides/uso terapêutico , Nitrilas/uso terapêutico , Proteína de Xeroderma Pigmentoso Grupo A
10.
Gan To Kagaku Ryoho ; 49(12): 1355-1359, 2022 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-36539249

RESUMO

Docetaxel(DTX)is a key drug for breast cancer treatment; however, its formulation contains alcohol, which can cause several problems. We have been preparing original DTX without using its accompanying alcohol-solubilizing solution since 2013 and switched to generic DTX without alcohol in 2015. In this study, we compared adverse events between the original and generic DTX, both of which did not contain alcohol. We retrospectively investigated the occurrence of adverse events in breast cancer patients who were treated with DTX(75 mg/m2)as neoadjuvant or adjuvant chemotherapy from January 2013 to December 2017. 201 patients participated in the study(75/126 in the original/generic groups). The incidence of febrile neutropenia, hypersensitivity reactions, and skin toxicities did not differ between the groups(p=0.620, 0.066, 0.205). The severity of edema and peripheral neuropathy was significantly worse in the patients receiving the generic DTX (p<0.01, <0.01). The findings suggest a difference in the incidence of edema and peripheral neuropathy following treatment with the original and generic DTX, regardless of the inclusion of alcohol.


Assuntos
Antineoplásicos , Neoplasias da Mama , Doenças do Sistema Nervoso Periférico , Humanos , Feminino , Docetaxel/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Taxoides/efeitos adversos , Etanol/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Edema/induzido quimicamente , Edema/tratamento farmacológico , Antineoplásicos/uso terapêutico
11.
Int J Mol Sci ; 23(24)2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36555256

RESUMO

Biologically active taxanes, present in small- to medium-sized evergreen conifers of various Taxus species, are widely used for their antioxidant, antimicrobial and anti-inflammatory effects, but mostly for their antitumour effects used in the treatment of solid tumours of the breast, ovary, lung, bladder, prostate, oesophagus and melanoma. More of the substances found in Taxus plant extracts have medical potential. Therefore, at the beginning of this review, we describe the methods of isolation, identification and determination of taxanes in different plant parts. One of the most important taxanes is paclitaxel, for which we summarize the pharmacokinetic parameters of its different formulations. We also describe toxicological risks during clinical therapy such as hypersensitivity, neurotoxicity, gastrointestinal, cardiovascular, haematological, skin and renal toxicity and toxicity to the respiratory system. Since the effect of the drug-form PTX is enhanced by various Taxus spp. extracts, we summarize published clinical intoxications and all fatal poisonings for the Taxus baccata plant. This showed that, despite their significant use in anticancer treatment, attention should also be focused on the risk of fatal intoxication due to ingestion of extracts from these plants, which are commonly found in our surroundings.


Assuntos
Neoplasias , Taxus , Masculino , Feminino , Humanos , Taxoides/farmacologia , Paclitaxel , Extratos Vegetais/farmacologia , Neoplasias/tratamento farmacológico
12.
Drug Resist Updat ; 65: 100881, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36368286

RESUMO

Taxanes (Taxol/paclitaxel, Docetaxel/taxotere) are a key group of successful drugs commonly used in chemotherapy to treat several major malignant tumors also as a front-line agent in combination with carboplatin/cisplatin, as well as a second line drug with a dose dense regimen following recurrence. Overall, the response to paclitaxel is excellent, though drug resistance inevitably develops in subsequent treatments. The commonly accepted mechanism of action is that the hindrance of microtubule function by paclitaxel leads to cell cycle arrest at mitosis, and subsequent apoptosis. The mechanisms for resistance to paclitaxel have also been extensively investigated, such as ABC transporter overexpression, altered signaling and apoptotic gene expression to resist cell death, and changes associated with microtubules to reduce influences of the drugs. Meanwhile, another important mechanism of paclitaxel resistance has been proposed: increased nuclear lamina/envelope sturdiness to retard the breaking of nuclear envelop and the paclitaxel-induced multinucleation as well as the formation of multiple micronuclei. Here in this review, we focus on experimental findings and ideas on the mechanism of paclitaxel resistance related to cancer nuclear envelope, to provide new insights on overcoming paclitaxel resistance.


Assuntos
Neoplasias , Paclitaxel , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Membrana Nuclear , Taxoides , Docetaxel , Cisplatino , Apoptose , Neoplasias/tratamento farmacológico , Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética
13.
Int J Nanomedicine ; 17: 5353-5374, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36419719

RESUMO

Introduction: Approximately 15%~30% of breast cancers have gene amplification or overexpression of the human epidermal growth factor receptor 2 (HER2), resulting in the chemotherapy resistance, a more-aggressive phenotype and poor prognosis. Methods: We propose a strategy of nanocarriers co-loaded with docetaxel (DTX) and pictilisib (PIC) at a synergistic ratio and non-covalently bound with dual anti-HER2 epitopes bispecific antibodies (BsAbs: anti-HER2-IV/methoxy-polyethylene glycol (mPEG) and anti-HER2-II/methoxy-PEG) for synergistic targeting to overcome the therapeutic dilemmas of the resistance for HER2-targetable chemodrugs. DTX/PIC-loaded nanocarriers (D/P_NCs) were prepared with single emulsion methods and characterized using dynamic light scattering analysis, and the drug content was assayed by high-performance liquid chromatographic method. The integrity and function of BsABs were evaluated using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunosorbent assay (ELISA). The in vitro cell studies and in vivo breast tumor-bearing mice model were used to evaluate the anti-cancer effect and biosafety of formulations. Results: D/P_NCs optimally prepared exhibited a spherical morphology with small particle sizes (~140 nm), high drug loading (~5.5%), and good colloidal stability. The synergistic tumor cytotoxicity of loading DTX and PIC at 2:1 ratio in D/P_NCs was discovered. The BsAbs are successfully decorated on mPEGylated DTX/PIC-loaded nanocarriers via anti-mPEG moiety. In vitro studies revealed that non-covalent decoration with dual BsAbs on D_P-NCs significantly and synergistically increased cellular uptake, while with loading DTX and PIC at a synergistic ratio of 2:1 in D/P_NCs further resulted in synergistic cytotoxicity. In vivo tumor inhibition studies showed the comparable results for synergistic antitumor efficacy while minimizing systemic toxicity of chemodrugs. Conclusion: Non-covalent modification with dual distinct epitopes BsAbs on the nanocarriers loaded with dual chemodrugs at a synergistic ratio was expected to be a promising therapeutic platform to overcome the chemoresistance of various cancers and warrants further development for future therapy in the clinical.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Camundongos , Animais , Feminino , Docetaxel , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Taxoides/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Epitopos
14.
Cell Mol Biol Lett ; 27(1): 100, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401206

RESUMO

BACKGROUND: Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed. METHODS: Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness. RESULTS: Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC-3_DCX20 reacted to metformin with the Warburg effect; however, PC-3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial-mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress. CONCLUSIONS: Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.


Assuntos
Antineoplásicos , Citostáticos , Metformina , Neoplasias da Próstata , Humanos , Masculino , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Taxoides/farmacologia , Taxoides/uso terapêutico , Citostáticos/farmacologia , Citostáticos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias da Próstata/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Estresse Fisiológico
15.
Radiat Oncol ; 17(1): 189, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36397078

RESUMO

OBJECTIVE: This study introduces innovative strategies, the doublet regimen of concurrent chemoradiotherapy, to ensure longer survival for locoregionally advanced nasopharyngeal carcinoma. METHODS: We retrospectively reviewed 104 locoregionally advanced nasopharyngeal carcinoma patients who underwent taxane combined platinum-based concurrent chemoradiotherapy in our center between January 2013 and December 2018. All statistical analyses were performed using the Kaplan-Meier method (SPSS 23.0). Different groups were compared with the Wilcoxon rank-sum test. RESULTS: Ultimately, 104 patients were selected for this study, including 18 and 86 who received either concurrent chemoradiation therapy alone or concurrent chemoradiation therapy plus adjuvant chemotherapy, respectively. The median follow-up time for progression free survival was 53.0 months (IQR 48.5-57.5). The 3-years progression-free survival (PFS), overall survival (OS), local-regional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) rates of the doublet regimen of concurrent chemotherapy for locoregionally advanced nasopharyngeal carcinoma were 85.9%, 96.0%, 96.0% and 90.8%, respectively. Additionally, we analyzed the subgroups and found that the 3-years PFS, OS, LRRFS and DMFS rates for stage III versus stage IVa were 97.8% versus 75.5% (P = 0.000), 100% versus 92.5% (P = 0.004), 100% versus 92.4% (P = 0.015) and 97.8% versus 82.8% (P = 0.002), respectively. During concurrent chemotherapy, acute chemotherapy adverse events of grade 3 or 4 was only 18.3%. Leukopenia was the most common acute chemotherapy adverse event (in 10 patients [9.6%]), followed by neutropenia (in 8 patients [7.6%]). CONCLUSION: The doublet regimen of taxane plus platinum concurrent chemoradiotherapy resulted in improved long-term survival of locoregionally advanced nasopharyngeal carcinoma patients, especially for local control rate and warrants further prospective evaluation.


Assuntos
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Nasofaríngeas/patologia , Cisplatino/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Taxoides
16.
Curr Opin Support Palliat Care ; 16(4): 223-229, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36349381

RESUMO

PURPOSE OF REVIEW: Systemic chemotherapy and second-generation androgen receptor-axis targeted therapies have been in the forefront of management for metastatic castrate-resistant prostate cancer (mCRPC) patients with low or high symptom burden. However, in the recent past, due to improvement in molecular characterization, management of mCRPC has witnessed long strides of advancement. We aim to review the novel nonhormonal and nonchemotherapeutic treatment options. RECENT FINDINGS: Poly (ADP-ribose) polymerase inhibitors (PARPis) such as olaparib and rucaparib have been recently approved by the US FDA for use in mCRPC with germline or somatic mutations in homologous recombination repair. The combination of PARPi with androgen receptor axis-targeted agents (ARAT) or dual ARAT-based therapy has shown superior radiographic progression-free survival as a first-line treatment. A combination of AKT inhibitor ipatasertib and abiraterone has shown improvement in radiographic progression-free survival as a first-line treatment. Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical like 177Lu-PSMA-617, a beta particle emitter has demonstrated improvement in overall survival in mCRPC patients pretreated with ARAT or taxanes. Although immune checkpoint inhibitors are being tested in mCRPC, there is no robust evidence to support this premise. SUMMARY: These new agents have widened the treatment options for mCRPC patients. Overall treatment should be focused on improving survival while limiting the deterrent effect on the quality of life.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Masculino , Humanos , Receptores Androgênicos/genética , Receptores Androgênicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Qualidade de Vida , Taxoides , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
17.
J Am Chem Soc ; 144(46): 21398-21407, 2022 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-36346461

RESUMO

Chemical synthesis of natural products is typically inspired by the structure and function of a target molecule. When both factors are of interest, such as in the case of taxane diterpenoids, a synthesis can both serve as a platform for synthetic strategy development and enable new biological exploration. Guided by this paradigm, we present here a unified enantiospecific approach to diverse taxane cores from the feedstock monoterpenoid (S)-carvone. Key to the success of our approach was the use of a skeletal remodeling strategy which began with the divergent reorganization and convergent coupling of two carvone-derived fragments, facilitated by Pd-catalyzed C-C bond cleavage tactics. This coupling was followed by additional restructuring using a Sm(II)-mediated rearrangement and a bioinspired, visible-light induced, transannular [2 + 2] photocycloaddition. Overall, this divergent monoterpenoid remodeling/convergent fragment coupling approach to complex diterpenoid synthesis provides access to structurally disparate taxane cores which have set the stage for the preparation of a wide range of taxanes.


Assuntos
Monoterpenos , Taxoides , Estereoisomerismo
18.
Eur J Med Res ; 27(1): 239, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36352476

RESUMO

BACKGROUND: Neoadjuvant chemotherapy (NAC) for locally advanced gastric and gastroesophageal junction adenocarcinoma (LAGC) has been recommended in several guidelines. However, there is no global consensus about the optimum of NAC regimens. We aimed to determine the optimal NAC regimen for LAGC. METHODS: A systematic review and Bayesian network meta-analysis was performed. The literature search was conducted from inception to June 2022. The odds ratio (OR) value and 95% confidence interval (95% CI) were used for assessment of R0 resection rate and pathological complete response rate (pCR) as primary outcomes. The hazard ratio (HR) value and 95% CI were interpreted for the assessment of overall survival (OS) and disease-free survival (DFS) as second outcomes. The risk ratio (RR) value and 95% CI were used for safety assessment. RESULTS: Twelve randomized controlled trials were identified with 3846 eligible participants. The network plots for R0 resectability, OS, and DFS constituted closed loops. The regimens of TPF (taxane and platinum plus fluoropyrimidine), ECF (epirubicin and cisplatin plus fluorouracil), and PF (platinum plus fluoropyrimidine) showed a meaningful improvement of R0 resectability, as well as OS and/or DFS, compared with surgery (including surgery-alone and surgery plus postoperative adjuvant chemotherapy). Importantly, among these regimens, TPF regimen showed significant superiority in R0 resection rate (versus ECF regimen), OS (versus ECF regimen), DFS (versus PF and ECF regimens), and pCR (versus PF regimen). CONCLUSIONS: The taxane-based triplet regimen of TPF is likely the optimal neoadjuvant chemotherapy regimen for LAGC patients.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Terapia Neoadjuvante , Metanálise em Rede , Teorema de Bayes , Platina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Taxoides/uso terapêutico , Junção Esofagogástrica/patologia , Quimioterapia Adjuvante , Fluoruracila/uso terapêutico
19.
JAMA Netw Open ; 5(11): e2239788, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36322088

RESUMO

Importance: Understanding the detailed symptom spectrum of chemotherapy-induced peripheral neuropathy (CIPN) could facilitate shared decision-making and promote early intervention. Objective: To compare the symptom spectrum of patient-reported CIPN associated with nab-paclitaxel, paclitaxel, and docetaxel treatments among patients with breast cancer. Design, Setting, and Participants: This prospective cohort study was conducted at 9 medical centers across China from 2019 to 2021. Participants included hospitalized women diagnosed with invasive breast cancer, assessed with overlap propensity score weighting. Data were analyzed from from December 2021 to May 2022. Exposures: Treatment with nab-paclitaxel-, paclitaxel-, or docetaxel-based regimens. Main Outcomes and Measures: Patient-reported CIPN on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire: CIPN 20-item instruments, consisting of sensory, motor, and autonomic scales. Multiple regression models were adjusted for baseline patient, tumor, and treatment characteristics. Results: Of 1234 participants, the mean (SD) age was 50.9 (10.4) years, and 295 patients (23.9%) received nab-paclitaxel, 514 patients (41.7%) received paclitaxel, and 425 patients (34.4%) received docetaxel. The nab-paclitaxel group mostly reported numbness in hands or feet related to sensory symptoms (83 patients [81.4%]), while the paclitaxel and docetaxel groups reported mainly motor (eg, weakness in legs: 60 patients [47.2%] in the paclitaxel group; 52 patients [44.4%] in the docetaxel group) and autonomic (eg, blurred vision: 58 patients [45.7%] in the paclitaxel group; 51 patients [43.6%] in the docetaxel group) symptoms. Patients reported motor symptoms earlier than sensory abnormalities, with a median of 0.4 (95% CI, 0.4-2.3) weeks in the nab-paclitaxel group, 2.7 (95% CI, 1.7-3.4) weeks in the paclitaxel group, and 5.6 (95% CI, 3.1-6.1) weeks in the docetaxel group. After overlap propensity score weighting and compared with the nab-paclitaxel group, the risks of patient-reported CIPN were lower in the paclitaxel (hazard ratio [HR], 0.59 [95% CI, 0.41-0.87]; P = .008) and the docetaxel (HR, 0.65 [95% CI, 0.45-0.94]; P = .02) groups. Similarly, patients who received paclitaxel (HR, 0.44 [95% CI, 0.30-0.64]; P < .001) or docetaxel (HR, 0.52 [95% CI, 0.36-0.75]; P < .001) reported less sensory discomfort compared with those who received nab-paclitaxel. However, the risk of patients in the paclitaxel or docetaxel groups reporting motor (paclitaxel: HR, 0.76 [95% CI, 0.52-1.11]; P = .15; docetaxel: HR, 0.69 [95% CI, 0.47-1.01]; P = .05) and/or autonomic (paclitaxel: HR, 1.00 [95% CI, 0.68-1.49]; P = .98; docetaxel: HR, 0.88 [95% CI, 0.59-1.30]; P = .52) symptoms was not lower than that in the nab-paclitaxel group. Conclusions and Relevance: In this cohort study of women with invasive breast cancer, nab-paclitaxel was associated with more severe CIPN than either paclitaxel or docetaxel. In addition to sensory symptoms, the risk of motor and autonomic abnormalities was not low among these 3 taxanes, and patients-reported motor symptoms even earlier than sensory symptoms. These findings may facilitate early detection and intervention for CIPN in taxane treatments for breast cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Doenças do Sistema Nervoso Periférico , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias da Mama/patologia , Docetaxel/efeitos adversos , Qualidade de Vida , Estudos Prospectivos , Estudos de Coortes , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Taxoides/efeitos adversos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Antineoplásicos/efeitos adversos , Medidas de Resultados Relatados pelo Paciente
20.
Turk J Med Sci ; 52(5): 1559-1568, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36422493

RESUMO

BACKGROUND: The aim of our study was to compare the efficacy and the safety of the FLOT and the modified DCF (mDCF) regimens in patients with metastatic gastric (GC) and gastroesophageal junction (GEJ) adenocarcinoma as first-line treatment. METHODS: The medical records of 72 patients were retrospectively reviewed. Survivals and hematological adverse events of the patients were examined. Factors affecting survivals were analyzed in univariate analysis. A multivariate analysis was performed with the factors contributing to survivals in univariate analysis. RESULTS: The median PFS (mPFS) was 10.1 months (95% CI, 6.8-13.4) in the FLOT arm (n = 33) and 7.4 months (95% CI, 9.1-21.6) in the mDCF arm (n = 39) (p = 0.041). The median OS (mOS) was 12.9 months (95% CI, 9.7-16.1) in the FLOT arm and 15.4 months (95% CI, 9.1-21.6) in the mDCF arm (p = 0.622). It was found that all grade neutropenia was 51.3% vs. 72.7% (p = 0.063), febrile neutropenia was 8.3% vs. 6.3% (p = 0.743), and thrombocytopenia was 48.7% vs. 51.5% (p = 0.813) in the FLOT and mDCF arms, respectively. Anemia was 59% in the FLOT arm and 100% in the mDCF arm (p < 0.001). Grade 3-4 anemia was 7.7% in the FLOT arm and 24.2% in the mDCF arm (p = 0.052). DISCUSSION: It was shown that the mPFS was significantly increased in the FLOT arm compared to the mDCF arm as the first-line treatment in patients with metastatic GC and GEJC. Hematological adverse events were more favorable in the FLOT arm than in the mDCF arm.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Estudos Retrospectivos , Fluoruracila/efeitos adversos , Docetaxel/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Taxoides/efeitos adversos , Cisplatino/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia
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