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1.
Mol Cancer Ther ; 23(2): 174-186, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37906695

RESUMO

The MAPK and PI3K pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or reexpression of receptor-type tyrosine kinases (RTK). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations. Additional RSK inhibitory activity may differentiate the sensitivity profile of TAS0612 from that of signaling inhibitors that target only the PI3K pathway. Moreover, TAS0612 demonstrated broad-spectrum activity against tumor models wherein inhibition of MAPK or PI3K pathways was insufficient to exert antitumor effects. TAS0612 exhibited a stronger growth-inhibitory activity against the cancer cell lines and tumor models with dysregulated signaling with the genetic abnormalities described above than treatment with inhibitors against AKT, PI3K, MEK, BRAF, and EGFR/HER2. In addition, TAS0612 demonstrated the persistence of blockade of downstream growth and antiapoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent reexpression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for patients with cancer to improve clinical responses and overcome resistance mechanisms.


Assuntos
Antineoplásicos , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Quinases S6 Ribossômicas 70-kDa , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/farmacologia , Receptores Proteína Tirosina Quinases/farmacologia
2.
Chemotherapy ; 68(2): 102-110, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36623495

RESUMO

INTRODUCTION: Trifluridine/tipiracil hydrochloride (FTD/TPI, Lonsurf®) is an oral antineoplastic agent that has been approved as late-stage chemotherapy for colorectal cancer. Its major mechanism of action is the dysfunction of tumoral DNA including DNA strand breaks and decreased replication. Fruquintinib (ELUNATE®) is a novel kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-1, -2, and -3. In this study, we evaluated the antitumor activity of combination therapy with FTD/TPI and fruquintinib in vivo. METHODS: The enhancement of the antitumor effects with FTD/TPI and fruquintinib combination, compared to the single drugs given alone was evaluated using two human colorectal cancer xenografts in nude mouse models. FTD/TPI (200 mg/kg) was orally administered for 5 consecutive days followed by 2 days of rest in a 7-day period. Fruquintinib (10 mg/kg) was orally administered consecutively for 2 and 3 weeks in SW48 and HCT 116 tumor-bearing models, respectively. After treatment with these agents, the microvessel density was evaluated by CD31 immunohistochemical analyses. RESULTS: In both models, FTD/TPI and fruquintinib significantly inhibited tumor growth, and the activity of the combined treatment was significantly superior to that of either monotherapy. Body weight loss of greater than 20% was not observed in any group. A histochemical analysis showed nuclei enlargement, abnormal mitosis, and karyorrhexis in the FTD/TPI treatment group. The microvessel density in the HCT 116 tumors treated with FTD/TPI and fruquintinib was significantly lower than that in the control group. CONCLUSION: The combination of FTD/TPI and fruquintinib could be a promising treatment option for colorectal cancer.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Demência Frontotemporal , Animais , Camundongos , Humanos , Trifluridina/farmacologia , Trifluridina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Demência Frontotemporal/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Combinação de Medicamentos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
3.
Mol Cancer Ther ; 18(5): 920-928, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872380

RESUMO

TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common EGFR mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T790M), and uncommon mutations (G719X and L861Q) with those of other EGFR-TKIs. We also commenced investigation of the clinical benefits of TAS-121. The IC50 for intracellular EGFR phosphorylation was determined by using Jump-In GripTite HEK293 cells transiently transfected with EGFR expression vectors. Mouse xenograft models were used to evaluate the antitumor activity of TAS-121. TAS-121 potently inhibited common activating and resistance EGFR mutations to the same extent as another third-generation EGFR-TKI (osimertinib). In addition, TAS-121 showed equivalent inhibitory activity against some uncommon mutations such as G719X and L861Q. Furthermore, TAS-121 demonstrated greater selectivity for mutant EGFRs versus the wild-type EGFR compared with other EGFR-TKIs. Moreover, TAS-121 displayed antitumor activity in SW48 (EGFR G719S) and NCI-H1975 (EGFR L858R/T790M) xenograft models, and achieved an objective response in patients with NSCLC with EGFR mutations including G719A mutation. In conclusion, TAS-121 is a novel third-generation EGFR-TKI and demonstrates antitumor activities in patients with NSCLC expressing either common or uncommon EGFR mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Mutação/genética
4.
Genes Cancer ; 7(1-2): 27-35, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27014419

RESUMO

Receptor tyrosine kinase (RTK)-related genes, including HER2, EGFR, MET, FGFR2 and KRAS, are target molecules that are clinically beneficial in gastric cancer (GC). We investigated the correlation between RTK-related genes and the curative effect of first-line S-1 plus cisplatin (SP) combination chemotherapy in metastatic and recurrent GC. We enrolled 150 patients with histopathologically confirmed metastatic and recurrent GC treated with SP. KRAS mutation was detected using direct sequencing. DNA copy number was measured by real-time PCR. Formalin-fixed paraffin-embedded specimens were examined immunohistochemically for HER2, EGFR, FGFR2 and MET. Among 144 patients, KRAS mutation was detected in five (3.5%) at codon 12 and one (0.7%) at codon 13. FGFR2, EGFR, HER2, MET and KRAS gene amplification was suggested in 4.4%, 5.9%, 9%, 3.7% and 10.3% of patients, respectively. KRAS mutation, but not KRAS amplification, was associated with significantly shorter overall and progression-free survival. MET membranous overexpression was associated with a significantly higher tumor response. MET amplification was associated with significantly shorter overall survival. We show for the first time that KRAS mutation and MET amplification are promising predictive markers in metastatic and recurrent GC patients treated with SP. KRAS status may be a useful prognostic marker in patients treated with SP.

5.
Toxicol Sci ; 110(2): 341-52, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19465456

RESUMO

The genotoxicity testing battery is highly sensitive for detection of chemical carcinogens. However, it features a low specificity and provides only limited mechanistic information required for risk assessment of positive findings. This is especially important in case of positive findings in the in vitro chromosome damage assays, because chromosome damage may be also induced secondarily to cell death. An increasing body of evidence indicates that toxicogenomic analysis of cellular stress responses provides an insight into mechanisms of action of genotoxicants. To evaluate the utility of such a toxicogenomic analysis we evaluated gene expression profiles of TK6 cells treated with four model genotoxic agents using a targeted high density real-time PCR approach in a multilaboratory project coordinated by the Health and Environmental Sciences Institute Committee on the Application of Genomics in Mechanism-based Risk Assessment. We show that this gene profiling technology produced reproducible data across laboratories allowing us to conclude that expression analysis of a relevant gene set is capable of distinguishing compounds that cause DNA adducts or double strand breaks from those that interfere with mitotic spindle function or that cause chromosome damage as a consequence of cytotoxicity. Furthermore, our data suggest that the gene expression profiles at early time points are most likely to provide information relevant to mechanisms of genotoxic damage and that larger gene expression arrays will likely provide richer information for differentiating molecular mechanisms of action of genotoxicants. Although more compounds need to be tested to identify a robust molecular signature, this study confirms the potential of toxicogenomic analysis for investigation of genotoxic mechanisms.


Assuntos
Dano ao DNA , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Laboratórios , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Reação em Cadeia da Polimerase , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Aberrações Cromossômicas/induzido quimicamente , Cisplatino/toxicidade , Análise por Conglomerados , Adutos de DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Relação Dose-Resposta a Droga , Etoposídeo/toxicidade , Perfilação da Expressão Gênica/normas , Humanos , Laboratórios/normas , Testes de Mutagenicidade/normas , Variações Dependentes do Observador , Paclitaxel/toxicidade , Reação em Cadeia da Polimerase/normas , Reprodutibilidade dos Testes , Medição de Risco , Cloreto de Sódio/toxicidade , Fuso Acromático/efeitos dos fármacos , Fatores de Tempo
6.
Mutat Res ; 673(1): 9-20, 2009 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-19100860

RESUMO

We examined the dose-dependency of gene expression changes for 51 genes in mouse liver treated with two N-nitroso genotoxic hepatocarcinogens, diethylnitrosamine (DEN) and ethylnitrosourea (ENU) by quantitative real-time PCR (qPCR). DEN (3, 9, 27 and 80mg/kg bw) or ENU (6, 17, 50 and 150mg/kg bw) was injected intraperitoneally into groups of five male 9-week-old B6C3F(1) mice and the livers were dissected after 4h and 28 days. Total RNA from pooled livers was reverse-transcribed to cDNA and the amount of each gene was quantified by qPCR. Results were analyzed by hierarchical and k-means clustering and ingenuity pathway analysis (IPA). The most characteristic result was a similar dose-dependency of gene expression changes with DEN and ENU. Twenty-one genes exhibited a distinct dose-dependent increase in expression at 4h for both carcinogens [Bax, Btg2, Ccng1, Cdkn1a, Cyp4a10, Cyp21a1, Fos, Gadd45b, Gdf15, Hmox1, Hspb1, Isg20l1, Jun, Mbd1, Mdm2, Myc, Net1, Plk2, Ppp1r3c, Rcan1 and Tubb2c], although the increase in gene expression due to ENU was generally weaker than that due to DEN. Only Gdf15 showed a dose-dependent increase in expression at 28 days for both carcinogens. The differences between DEN and ENU were in the expression of additional genes (7 for DEN and 8 for ENU). IPA extracted five gene networks: Network-1 included genes related to cancer and cell cycle arrest and associated with Bax, Btg2, Ccng1, Cdkn1a, Gadd45b, Gdf15, Hspb1, Mdm2 and Plk2 and Network-2 was related to DNA replication, recombination, repair and cell death and associated with Cyp21a1, Gdf15, Ppp1r3c, Rcan1 and Tubb2c. The present results show a distinct dose-dependency of gene expression changes induced by DEN and ENU. These changes were associated with cancer, cell cycle arrest, DNA replication, recombination, repair and cell death and were seen not only at 4h but also, for some, at 28 days after administration.


Assuntos
Carcinógenos/toxicidade , Dietilnitrosamina/toxicidade , Etilnitrosoureia/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Algoritmos , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Reação em Cadeia da Polimerase
7.
Gan To Kagaku Ryoho ; 33(3): 345-8, 2006 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-16531715

RESUMO

Drug-induced allergic adverse events including rash, interstitial pneumonia and hepatic injury are often observed in a few patients treated with anticancer drugs that are 5-FU derivatives, including TS-1. In patients suspected to be liable to develop allergic reactions, the drug-induced lymphocyte stimulation test (DLST), based on the (3)H-thymidine incorporation ratio into the DNA of lymphocytes derived from the patients, is generally employed to identify drugs that could induce allergy. In this case report, we conducted the DLST on 20 healthy volunteers without TS-1 treatment in order to obtain reference data on the evaluation of TS-1-induced allergy. Even though all 20 volunteers were healthy, there were 6 positive responses to the DLST. In view of the positive response to TS-1 in healthy volunteers undergoing the DLST, it is suggested that the DLST could show a false positive response through an intracellular function that accelerates incorporation of thymidine in the lymphocytes by the salvage pathway after inhibition of DNA de novo synthesis caused by 5-FU derivative anticancer, including TS-1. Therefore, such a positive response to the drugs is considered, in fact, to be false-positive in the DLST. In view of the occurrence of false-positive results, the possibility of drug-induced allergy in patients receiving TS-1 should be carefully evaluated using a combination of other clinical examinations.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Testes Imunológicos/métodos , Ativação Linfocitária , Ácido Oxônico/efeitos adversos , Piridinas/efeitos adversos , Tegafur/efeitos adversos , Adulto , Combinação de Medicamentos , Reações Falso-Positivas , Humanos , Masculino , Timidina/metabolismo
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