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1.
Life Sci ; 246: 117428, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32057901

RESUMO

PURPOSE: Arl4c is overexpressed in several cancer tissues and is involved in cancer development. Nevertheless, the exact mechanism that regulates Arl4c expression in lung cancer has not been fully elucidated. The aim of this study was to investigate the regulatory mechanism of Arl4c and to explore potential chemotherapeutic drugs targeting Arl4c. METHODS: Immunohistochemistry was used to examine Arl4c expression levels in human lung adenocarcinoma cancer specimens. Protein expression was detected by western blot. Overexpression of Arl4c-Flag protein was used to detect the ubiquitination of Arl4c. A short interfering RNA against Arl4c was used for gene silencing. RESULTS: Arl4c was overexpressed in lung cancer tissues, and knockdown of Arl4c expression by siRNA decreased lung cancer A549 and 95-D cell proliferation. In addition, Arl4c expression was downregulated via inhibition of the AKT pathway in A549 and 95-D cells, whereas exposure to benzo (a) pyrene (a carcinogen in smoke) increased Arl4c expression in 16HBE cells via AKT activation. Finally, we found that chemotherapy drug hydroxycamptothecin (HCPT) could decrease Arl4c expression levels by inhibiting the activation of the AKT pathway in A549 and 95-D cells. Moreover, accumulation of ubiquitinated Arl4c protein was increased by HCPT and LY294002 (an AKT inhibitor) treatment whereas the proteasome inhibitor MG-132 attenuated the inhibitory effect of HCPT and LY294002 on Arl4c expression. CONCLUSION: Here, we highlighted the AKT pathway as an important regulatory pathway for Arl4c expression in lung cancer cells and identified HCPT as a promising drug for lung adenocarcinoma treatment that functioned by targeting Arl4c expression.


Assuntos
Fatores de Ribosilação do ADP/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Células A549 , Western Blotting , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Cromonas/farmacologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Leupeptinas/farmacologia , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fumar/efeitos adversos
2.
J Photochem Photobiol B ; 204: 111736, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31951858

RESUMO

The graphene-based nanomaterials have been measured as a most promising nanomaterials in the various fields. Graphene oxide having attractive and effective attention in the modified of medicine. Also, graphene oxide is one of the distinct bio-chemical properties with minimum cytotoxicity compared to the other nanomaterials. Up to till date, gastric treatments with reduced graphene oxide not studied so far. In this report, 7-ethyl- 10-hydroxycamptothecin (SN-38) coated graphene oxide synthesized (SN-rGO) effectively and are characterized using various analytical methods. The hydroxyl and carbonyl gatherings of oxidized SN38 will in general ingest onto GO by means of hydrogen bond arrangement with their leftover oxygen functionalities and offers steadiness to SN38. The morphological analyses showed the foldable fields of SN38-rGO NPs with acquire transparency, thin sheets and the crumpled structures. Further the photothermal efficiency and cytotoxicity of the SN-rGO were examined by MTT assay using two NCI-N87 and SGC-791 gastric carcinoma cells. In addition, the morphological changes were examined through the live and dead cells and nuclear staining biochemical techiniques and apoptosis were evaluated through flow cytometry analysis. Our result's suggested that the SN-38 coated reduced graphene oxide can be used for the photothermal treatment of gastric carcinoma for the future nanotechnology cancer therapies without using functionalized polymeric nanoparticles.


Assuntos
Antineoplásicos Fitogênicos/biossíntese , Camptotecina/análogos & derivados , Grafite/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/biossíntese , Camptotecina/química , Camptotecina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Raios Infravermelhos , Microscopia de Fluorescência , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
3.
Pestic Biochem Physiol ; 163: 108-116, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31973846

RESUMO

Rice blast caused by Magnaporthe oryzae B. Couch is one of the most devastating diseases on rice. Camptothecin (CPT), which was primarily isolated from Camptotheca acuminata, is well-known for its anti-tumor activities, and is also developed as a potential biological pesticide. We previously investigated the anti-microbial activities of CPT against 11 fungi, 3 oomycetes, and 4 bacteria, and found that CPT was strongly effective against M. oryzae, indicating its potential as a lead for developing fungicide against rice blast. However, the anti-fungal effects of CPT on M. oryzae need further elucidation. In this study, the anti-fungal activities of CPT against M. oryzae were further investigated, which revealed that CPT was effective against M. oryzae both in vitro and in vivo. The transcriptome of M. oryzae was analyzed after CPT treatment, which showed that CPT had a strong inhibitory effect on 'translation' and 'carbohydrate metabolism/energy metabolism' of M. oryzae. Some physiology characteristics of M. oryzae were also assayed, which confirmed that CPT inhibited RNA synthesis, protein synthesis, and carbohydrate metabolism/energy metabolism of M. oryzae, and caused membrane damage. The molecular simulation result showed that CPT binds to the interface of DNA-topoisomerase I complex of M. oryzae. In conclusion, CPT is a promising lead for developing fungicide against rice blast. CPT may bind to DNA-topoisomerase I complex of M. oryzae, thus affecting 'translation' and 'carbohydrate metabolism/energy metabolism', leading to cell death.


Assuntos
Magnaporthe , Oryza , Camptotecina , Doenças das Plantas
4.
BMC Med Genet ; 21(1): 3, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900123

RESUMO

BACKGROUND: Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients. CASE PRESENTATION: In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19-9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed. CONCLUSION: As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in a APC/TP53/KRAS triple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.


Assuntos
Proteína da Polipose Adenomatosa do Colo/sangue , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/sangue , Proteína Supressora de Tumor p53/sangue , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Ácidos Nucleicos Livres/sangue , DNA Tumoral Circulante/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas p21(ras)/genética , Indução de Remissão , Proteína Supressora de Tumor p53/genética
5.
J Cancer Res Clin Oncol ; 146(2): 493-501, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31691872

RESUMO

PURPOSE: In metastatic colorectal cancer (MCRC), mucinous histology has been associated with poor response rate and prognosis. We investigated whether bevacizumab combined with different chemotherapy regimens may have an impact on clinical outcomes of MCRC patients with mucinous histology. METHODS: 685 MCRC patients were classified in mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (NMC) and were treated with first-line bevacizumab plus fluoropyrimidine (FP)-based, oxaliplatin (OXA)-based, irinotecan (IRI)-based, or FOLFOXIRI. RESULTS: Ninety-four (13.7%) patients had MC. With a median follow-up of 50 months, MC patients had a median overall survival (OS) of 28.2 months compared with 27.7 months for the NMC group [hazard ratio (HR) = 0.92; 95% confidence interval (CI) 0.70-1.19, P = 0.530]. The overall response rates for MC and NMC were 41.5% (95% CI 31.5-51.4) and 62.4% (95% CI 58.4-66.3), respectively (Chi-square test, P <0.003). After correcting for significant prognostic factors by multivariate Cox regression analysis, age, resection of the primary tumour, and number of metastatic sites were found to be associated with poorer OS, but not mucinous histology. CONCLUSION: Compared with NMC, MCRC patients with mucinous histology treated with bevacizumab plus chemotherapy had comparable OS despite lower overall response rate.


Assuntos
Adenocarcinoma Mucinoso/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/uso terapêutico , Prognóstico , Estudos Retrospectivos
6.
Eur J Med Chem ; 187: 111971, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881457

RESUMO

For the purpose of advancing our research on diverse C-20 decorated derivatives of camptothecin (CPT), 46 new CPT acylthiourea derivatives were synthesized and evaluated in vitro for their cytotoxicity. All the compounds showed promising in vitro cytotoxicity against six tumor cell lines (Hep3B, MCF7, A549, MDA-MB-231, KB and KB-vin). Out of them, compound c20 possesses remarkable in vitro cytotoxic activity and is more potent than topotecan. Mechanistically, c20 not only induces cell cycle arrest and cell apoptosis in A549 cells, but also inhibits Topo I activity in the cell and cell-free system in a manner similar to that of topotecan. In both xenograft and primary HCC mouse models, c20 displays significant in vivo anti-cancer activity and is more potent than topotecan. In addition, the acute toxicity assay showed that c20 has no apparent toxicity to mouse liver, kidney and hemopoietic system of the FVB/N mice. Take together, these results indicated that compound c20 could be a potential anti-cancer candidate for further clinical trial.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Desenho de Drogas , Ureia/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/química
7.
Protein Pept Lett ; 27(1): 17-29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31556849

RESUMO

Currently, chemotherapy is one of the mainstays of oncologic therapies. But the efficacy of chemotherapy is often limited by drug resistance and severe side effects. Consequently, it is becoming increasingly important to investigate the underlying mechanism and overcome the problem of anticancer chemotherapy resistance. The solute carrier organic anion transporter family member 1B3 (SLCO1B3), a functional transporter normally expressed in the liver, transports a variety of endogenous and exogenous compounds, including hormones and their conjugates as well as some anticancer drugs. The extrahepatic expression of SLCO1B3 has been detected in different cancer cell lines and cancer tissues. Recently, accumulating data indicates that the abnormal expression and function of SLCO1B3 are involved in resistance to anticancer drugs, such as taxanes, camptothecin and its analogs, SN-38, and Androgen Deprivation Therapy (ADT) in breast, prostate, lung, hepatic, and colorectal cancer, respectively. Thus, more investigations have been implemented to identify the potential SLCO1B3-related mechanisms of cancer drug resistance. In this review, we focus on the emerging roles of SLCO1B3 protein in the development of cancer chemotherapy resistance and briefly discuss the mechanisms of resistance. Elucidating the function of SLCO1B3 in chemoresistance may bring out novel therapeutic strategies for cancer treatment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Antagonistas de Androgênios/metabolismo , Antineoplásicos/metabolismo , Transporte Biológico , Camptotecina/metabolismo , Humanos , Irinotecano/metabolismo , Conformação Proteica , Transdução de Sinais , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Relação Estrutura-Atividade , Taxoides/metabolismo
8.
Chem Commun (Camb) ; 56(7): 1042-1045, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868189

RESUMO

A novel enzyme-responsive supramolecular polysaccharide assembly composed of disulfide linked adamantane-naphthalimide fluorescent camptothecin prodrug (AdaCPT) and ß-CD modified hyaluronic acid (HACD) was constructed, possessing low cellular cytotoxicity and exhibiting targeted cellular imaging and controlled drug release at specific sites while providing a concurrent means for the real-time tracking of drug delivery.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Portadores de Fármacos/química , Corantes Fluorescentes/farmacologia , Pró-Fármacos/farmacologia , Adamantano/análogos & derivados , Adamantano/síntese química , Adamantano/farmacologia , Adamantano/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Camptotecina/síntese química , Camptotecina/toxicidade , Liberação Controlada de Fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HCT116 , Humanos , Ácido Hialurônico/química , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Células NIH 3T3 , Naftalimidas/síntese química , Naftalimidas/farmacologia , Naftalimidas/toxicidade , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , beta-Ciclodextrinas/química
9.
Anticancer Res ; 39(12): 6463-6470, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810910

RESUMO

BACKGROUND/AIM: The aim of the present study was to determine the efficacy of trabectedin combined with FOLFIRI (irinotecan, leucovorin and 5-fluorouracil) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (iPDOX) mouse model. MATERIALS AND METHODS: A CRC tumor from a patient previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Mice were randomized into four groups: Group 1, untreated control; group 2, FOLFIRI; group 3, trabectedin alone; group 4, trabectedin plus FOLFIRI. Tumor width, length, and mouse body weight was measured twice every week. RESULTS: All three treatment groups showed inhibited tumor growth compared to the untreated control group. Only the combination of FOLFIRI and trabectedin arrested tumor growth. No significant changes was observed in body weight in any group. CONCLUSION: These findings suggest that the combination of trabectedin plus FOLFIRI has clinical potential for patients with CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Trabectedina/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Peso Corporal/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Neoplasias Colorretais/metabolismo , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Leucovorina/administração & dosagem , Leucovorina/farmacologia , Camundongos , Camundongos Nus , Camundongos Transgênicos , Distribuição Aleatória , Trabectedina/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Anticancer Res ; 39(12): 6781-6786, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810943

RESUMO

BACKGROUND/AIM: Patients affected with Stage IV colorectal cancer and unresectable metastases represent a heterogeneous group. Resection of the primary tumor or stent positioning followed by chemotherapy and/or targeted therapies still represent a difficult choice for surgeons. PATIENTS AND METHODS: From February 2013 to September 2019, 46 patients were enrolled into a prospective randomized open label parallel trial presenting with Stage IVA and IVB rectal cancer, unresectable metastases and symptoms of subacute large bowel obstruction. Our population was divided into two groups: Group 1 included 20 patients who underwent placement of a self-expandable metal stent and Group 2 included 26 patients in whom primary tumor resection was performed. RESULTS: One-year actuarial survival rate of Group 1 was significantly lower compared to Group 2. Overall 17 patients had survival longer than 1-year (3 in Group 1 and 14 in Group 2). Cox regression analysis showed that endoscopic stent positioning and the suspension of the chemotherapy because of deterioration of liver function tests were the two most important factors negatively influencing survival. CONCLUSION: Patients affected with stage IVA and IVB rectal cancer and symptoms of bowel obstruction had a significant longer survival rate when submitted to surgical rectal resection followed by chemotherapy.


Assuntos
Adenocarcinoma/terapia , Obstrução Intestinal/terapia , Neoplasias Retais/terapia , Stents Metálicos Autoexpansíveis , Adenocarcinoma/complicações , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Terapia Combinada/métodos , Feminino , Fluoruracila/administração & dosagem , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/mortalidade , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Compostos Organoplatínicos/administração & dosagem , Estudos Prospectivos , Neoplasias Retais/complicações , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Taxa de Sobrevida
11.
Life Sci ; 239: 117074, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31751585

RESUMO

AIMS: FL118, a novel camptothecin analogue, has been extensively studied for its superior antitumor potency. The aim of this research study is to explore its potential mechanism of action in anti- colorectal cancer (CRC). MAIN METHODS: The effect of FL118 on CRC cell proliferation was assessed using CCK-8 assay, while apoptosis was detected using Hoechst staining and Flow cytometry assays. The expression levels of CIP2A were analyzed using qRT-PCR. The expression of CIP2A, PP2A-C, Bax, cleaved caspase-3 and PARP were analyzed using western blotting analysis. The expressions of related proteins in CRC tissues were detected using immunohistochemical staining. TUNEL assay was used to detect apoptosis of tissue. Toxicity of FL118 in primary organs were examined using H&E staining. KEY FINDINGS: The results show that FL118 can inhibit the proliferation and clonogenic potential of CRC cells and increase the expression of pro-apoptosis proteins, Bax, cleaved caspase-3 and PARP. Microarray analyses found that FL118 treatment significantly decreases cancerous inhibition of protein phosphatase 2A (CIP2A). Further validation found that CIP2A is aberrantly upregulated in CRC tissues, and is positively correlated with the progression of CRC. In vitro findings confirm that FL118 mediates the downregulation of CIP2A, at both protein and mRNA levels. Co-treatment with Okadaic acid (OA) (a PP2A inhibitor) partially abolishes the anti-proliferative and pro-apoptotic effect of FL118. Consistently, in vivo experiment demonstrates that FL118 can effectively suppress tumorigenesis without any obvious toxic effects. SIGNIFICANCE: Collectively, these findings exhibit the anti-neoplastic effects of FL118 against CRC through the down regulation of CIP2A, which subsequently enhances the activity of PP2A.


Assuntos
Autoantígenos/metabolismo , Benzodioxóis/farmacologia , Indolizinas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Proteína Fosfatase 2/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autoantígenos/fisiologia , Benzodioxóis/metabolismo , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , China , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Indolizinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Masculino , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína Fosfatase 2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Gan To Kagaku Ryoho ; 46(11): 1791-1793, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31748495

RESUMO

A 65-year-old woman was diagnosed with simultaneous hepatic metastasis of rectal cancer with portal venous tumor thrombi(Vp3)that developed in the bifurcation of the portal vein. Four days from the first visit, abdominal dynamic contrastenhanced CT image on the portal venous phase shows that the tumor thrombi progressed in the main trunk of the portal vein (Vp4). We decided that it was a condition of oncologic emergency and initiated FOLFOXIRI plus BV therapy. After 12 courses, tumor shrinkage and regression of the portal venous tumor thrombi were achieved, but conversion surgery was impossible because the collateral circulation of the hepatic portal region remained. The treatment target was changed to the extension of the survival period. The initiation and reinitiation of FOLFOXIRI plus BV therapy and maintenance of 5-FU/l-LV plus BV therapy contributed to disease control in 24 months and survival period of 36months.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas , Neoplasias Retais , Trombose Venosa , Idoso , Camptotecina/análogos & derivados , Feminino , Fluoruracila , Hepatectomia , Humanos , Leucovorina , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organoplatínicos , Veia Porta , Neoplasias Retais/complicações , Neoplasias Retais/tratamento farmacológico , Trombose Venosa/etiologia
13.
Drug Deliv ; 26(1): 1068-1079, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31735094

RESUMO

Therapeutic application of unmodified camptothecin (CPT) is severely restricted by its extremely low water solubility and the instability of active lactone ring. In this study, a redox-sensitive CPT-OA conjugate containing the disulfide bond (CPT-SS-OA) was used to deliver the lactone-stabilized CPT for the improved antitumor efficacy. A non-sensitive CPT-OA was used as control to illuminate the role of disulfide bond. Both CPT-SS-OA and CPT-OA formulated in cremophor EL micelles (CM) displayed multiple therapeutic advantages: small diameter (∼14 nm), efficient cellular internalization, prolonged blood circulation, and favorable biodistribution. However, only CPT-SS-OA/CM achieved the superior chemotherapeutic efficacy over CPT solution in the Lewis lung carcinoma (LLC) cancer xenograft, which was ascribed to the accelerated release of the active lactone CPT responding to the elevated reductive glutathione in tumor cells. Such redox-sensitive lipophilic prodrugs represent an effective alternative strategy for the delivery of CPT in the active lactone form. This strategy can be used for other chemically unstable chemotherapeutant for the improved therapeutic efficacies.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Animais , Antineoplásicos/metabolismo , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Glutationa/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Micelas , Oxirredução , Tamanho da Partícula , Pró-Fármacos/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
14.
Drugs Today (Barc) ; 55(9): 575-585, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584574

RESUMO

Patients with metastatic triple-negative breast cancer (mTNBC) that has progressed on first-line therapy have a poor prognosis with limited therapeutic options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate (ADC) that has shown promising efficacy in mTNBC. SG is comprised of SN-38, the active metabolite of irinotecan, conjugated via a hydrolyzable linker to the humanized RS7 antibody targeting trophoblast cell surface antigen 2 (Trop-2), a glycoprotein that is expressed at high levels in many epithelial solid tumors. It has received breakthrough therapy status by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pretreated mTNBC. In this review, we summarize available data regarding the pharmacology, pharmacokinetics, safety and efficacy of SG and describe ongoing and future clinical studies investigating this agent.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antígenos de Neoplasias , Camptotecina/uso terapêutico , Moléculas de Adesão Celular , Feminino , Humanos , Estados Unidos , United States Food and Drug Administration
15.
J Biomed Sci ; 26(1): 85, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31647037

RESUMO

INTRODUCTION: Efficacy and safety are critical concerns when designing drug carriers. Nanoparticles are a particular type of carrier that has gained recent attention in cancer therapeutics. METHODS: In this study, we assess the safety profile of IT-101, a nanoparticle formed by self-assembly of camptothecin (CPT) conjugated cyclodextrin-based polymers. IT-101 delivers CPT to target cancer cells in animal models of numerous human cancers and in humans. Previous data from preclinical and clinical trials indicate that IT-101 has no notable immunological side effects. However, there have been no published studies focused on evaluating the effects of IT-101 on host immune systems. RESULTS: In this work, we demonstrate that IT-101 diminished initial host immune response following first injection of the nanopharmaceutical and induced NK cell activation and T cell proliferation upon further IT-101 exposure. Additionally, IT-101 could attenuate tumor growth more efficiently than CPT treatment only. CONCLUSIONS: Drugs administration in whole-body circulation may lead to poorly bioavailable in central nervous system and often has toxic effects on peripheral tissues. Conjugated with cyclodextrin-based polymers not only reduce adverse effects but also modulate the immune responses to elevate drug efficacy. These immune responses may potentially facilitate actions of immune blockage, such as PD1/PDL1 in cancer treatment.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Camptotecina/administração & dosagem , Celulose/administração & dosagem , Ciclodextrinas/administração & dosagem , Imunidade Inata/efeitos dos fármacos , Nanopartículas/administração & dosagem , Animais , Camundongos , Organismos Livres de Patógenos Específicos
16.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 527-532, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642230

RESUMO

OBJECTIVE: To investigate the effect of 2-deoxy-d-glucose (2-DG) combined with hydroxycamptothecin (HCPT) on anti-tumor activity of breast cancer cells and its mechanism. METHODS: MDA-MB-231 and MCF-7 breast cancer cells were incubated with varying concentrations of 2-DG (0, 1.25, 2.5, 5, 10, 20 mmol/L), HCPT(0, 5, 10, 20, 40 µmol/L) and 2-DG (5 mmol/L) combined with HCPT. Cell viability was measured using the MTT assay; Propidium iodide (PI) detected the apoptosis of MDA-MB-231 cells by 5 mmol/L 2-DG, 10 µmol/L HCPT alone or in combination; MDA-MB-231 cells were treated with 2-DG (0, 2.5, 5, 10, 20 mmol/L) and the level of ATP was detected by ATP kit; the expression of Akt, p-Akt, Bcl-2/Bax, PARP, Caspase-8 and Caspase-3 proteins in MDA-MB-231 cells were measured by Western blot assay. RESULTS: The combination of 2-DG (5 mmol/L) and HCPT had a synergistic effect. The 48 h combination index (CI < 1) was higher than that of the single-use group (P < 0.05). At the same time, the combination of the two drugs inhibits the phosphorylation of Akt protein and increases the activation of Caspase-3 protein, thereby increasing the cleavage of PARP proteins. CONCLUSION: The combination of 2-DG and HCPT can synergistically induce the apoptosis of breast cancer cells, which may be caused by inhibiting the energy generation of tumor cells, inhibiting the phosphorylation of Akt protein and enhancing the activity of caspase-3 protein.


Assuntos
Apoptose , Neoplasias da Mama/patologia , Camptotecina/análogos & derivados , Desoxiglucose/farmacologia , Camptotecina/farmacologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Células MCF-7
17.
Gan To Kagaku Ryoho ; 46(10): 1632-1634, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31631158

RESUMO

We report a case of altered consciousness related to hyperammonemia due to FOLFIRI plus bevacizumab therapy in a patient with recurrent colorectal cancer and renal dysfunction.A 76-year-old man received third-line chemotherapy for left mediastinal lymph node metastasis.He complained of diarrhea on the evening of the same day, and mental confusion on day 3 of the first FOLFIRI therapy.He had a JCS of Ⅲ(200).The laboratory results revealed a marked hyperammonemia.5 - fluorouracil(5-FU)-induced hyperammonemia was diagnosed and the patient was ventilated and managed with branchedchain amino acid solutions, lactulose, and hemodialysis in the ICU.After hemodialysis, the blood ammonia level reduced to the normal limits, and the symptoms of encephalopathy resolved on the following day.He was discharged home on the 19th day of hospitalization.5 -FU-containing therapy should be carefully administered in patients with renal dysfunction.Herein, we report a case of 5-FU-induced hyperammonemia with literature considerations.


Assuntos
Neoplasias Colorretais , Fluoruracila/efeitos adversos , Hiperamonemia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Estado de Consciência , Humanos , Hiperamonemia/induzido quimicamente , Leucovorina , Masculino , Recidiva Local de Neoplasia
18.
Eur J Med Chem ; 183: 111682, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563805

RESUMO

Targeted drug delivery has improved cancer treatment significantly in recent years, although it is difficult to achieve. Different approaches have been developed to apply targeted drug delivery. Among which, antibody-drug conjugate (ADC) provides a potentially ideal solution to such a challenge. ADC is an innovative drug treatment model with three key components: payload, monoclonal antibody, and linker. The monoclonal antibody targets the antigen-expressing tumor cells and internalizes the payload linked by the linker to the target cells to reduce the side effects of the traditional chemotherapy drugs. The off-target effect has an excellent therapeutic prospect. Among them, ado-trastuzumab emtansine (T-DM1) is a successful example of targeting human epidermal growth factor receptor-2 (HER2). Its antibody (trastuzumab) is derived from Herceptin with annual sales of more than $6 billion. It has excellent targeting and specific anti-tumor activity against HER2. Its linker is not cleavable and releases the Lys-linker-payload to kill the cells. The two ADCs described here use the same antibody as T-DM1, but the cleavable linker and the more toxic payload allow them to have the not only targeting of T-DM1, but also the reduce T-DM1 resistance and improve efficacy in heterogeneous tumors. This paper describes the mechanism of action and the biochemical characteristics of different parts and preclinical and clinical progress of trastuzumab deruxtecan(DS-8201a) and (vic-)trastuzumab duocarmazine (SYD985).


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Imunoconjugados/farmacologia , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , /farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/uso terapêutico
19.
Chem Commun (Camb) ; 55(78): 11679-11682, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31524892

RESUMO

We show herein the highly effective inhibition of tumor cell growth using a gel consisting of a fibrin polymer formed with the in situ condensation of a camptothecin (CPT) derivative as an anti-cancer drug, which is efficiently conveyed with a carrier aptamer from a solution to the gel in a phenomenon, called selective oligonucleotide entrapment in fibrin polymers (SOEF).


Assuntos
Antineoplásicos/química , Fibrina/química , Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/química , Camptotecina/química , Camptotecina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Géis/química , Humanos , Microscopia de Fluorescência , Polímeros/química
20.
Cancer Sci ; 110(11): 3565-3572, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520559

RESUMO

Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Grupo com Ancestrais do Continente Asiático , Camptotecina/uso terapêutico , Neoplasias do Colo/sangue , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Fluoruracila/uso terapêutico , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Interleucina-8/sangue , Japão , Calicreínas/sangue , Leucovorina/uso terapêutico , Fator de Crescimento Placentário/sangue , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Proteína D Associada a Surfactante Pulmonar/sangue , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Neoplasias Retais/sangue , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Análise de Regressão , Tenascina/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
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