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1.
Cancer ; 129(7): 1041-1050, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36718624

RESUMO

BACKGROUND: Senaparib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor with strong antitumor activity in preclinical studies. This first-in-human, phase 1, dose-escalation study examined the safety and preliminary efficacy of senaparib in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were enrolled from three centers in Australia, using a conventional 3 + 3 design. Dose-escalation cohorts continued until the maximum tolerated dose or a recommended phase 2 dose was determined. Patients received one dose of oral senaparib and, if no dose-limiting toxicity occurred within 7 days, they received senaparib once daily in 3-week cycles. The primary end points were safety and tolerability. RESULTS: Thirty-nine patients were enrolled at 10 dose levels ranging from 2 to 150 mg. No dose-limiting toxicities were observed in any cohort. Most treatment-emergent adverse events were grade 1-2 (91%). Seven patients (17.9%) reported hematologic treatment-emergent adverse events. Treatment-related adverse events occurred in eight patients (20.5%), and the most frequent was nausea (7.7%). Two deaths were reported after the end of study treatment, one of which was considered a complication from senaparib-related bone marrow failure. Pharmacokinetic analysis indicated that senaparib the accumulation index was 1.06-1.67, and absorption saturation was 80-150 mg daily. In 22 patients with evaluable disease, the overall response rate was 13.6%, and the disease control rate was 81.8%. The overall response rate was 33.3% for the BRCA mutation-positive subgroup and 6.3% for the nonmutated subgroup. CONCLUSIONS: Senaparib was well tolerated in Australian patients with advanced solid tumors, with encouraging signals of antitumor activity. The recommended phase 2 dose for senaparib was determined to be 100 mg daily. GOV ID: NCT03507543.


Assuntos
Antineoplásicos , Neoplasias , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Austrália , Dose Máxima Tolerável , Neoplasias/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
2.
Int J Clin Pract ; 2022: 9592969, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685604

RESUMO

Background: Previous observational studies and meta-analysis suggested a possible association between metformin use and reduced mortality in women with ovarian cancer (OC). However, clinical factors that may influence the relationship remain poorly evaluated. We performed an updated meta-analysis to systematically evaluate the above association and to observe the potential influences of study characteristics on the association. Methods: Relevant studies reporting the association between metformin use and mortality in women with OC in the multivariate adjusted model were identified by search of electronic databases that included PubMed, Embase, and Web of Science. The random-effects model was adopted to combine the results. Results: Nine studies including 10030 women with OC were included. Overall, metformin use was independently associated with reduced overall mortality (hazard ratio (HR): 0.72, 95% confidence interval (CI): 0.55-0.93, P=0.01; I 2 = 62%). Consistent results were observed for studies comparing metformin users with nondiabetic women and studies comparing metformin users with diabetic women who did not use metformin (P for subgroup analysis = 0.70). Further subgroup analyses showed consistent results in studies with metformin use before or after the diagnosis of OC, with or without adjustment of body mass index (BMI) and with or without adjustment of concurrent medications (P for subgroup analyses all >0.10). Conclusion: Metformin use is associated with reduced mortality in women with OC, which may be independent of the diabetic status of the controls, timing of metformin use, or adjustment of BMI and concurrent medications. Clinical trials are needed to validate the potential benefits of metformin on survival of OC.


Assuntos
Diabetes Mellitus , Metformina , Neoplasias Ovarianas , Índice de Massa Corporal , Feminino , Humanos , Metformina/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Modelos de Riscos Proporcionais
3.
Mol Cancer Ther ; 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38920409

RESUMO

Poly (ADP-ribose) polymerases 1 (PARP1) is a critical enzyme involved in DNA damage repair. It belongs to a super family of proteins and catalyzes poly (ADP-ribosyl)ation (PARylation). PARP1 inhibitors are effective to treat tumors that have homologous recombination deficiency (HRD) such as the ones with BRCA1/2 mutations. The PARP1 inhibitors that have been approved by FDA inhibit both PARP1 and PARP2. PARP2 has also been suggested to have similar function in DNA repair as PARP1. In addition to inhibiting PARP1 enzymatic activities, PARP1 inhibitors also cause PARP1 enzyme to be "trapped" on DNA which leads to DNA replication fork to stall and eventually double-strand DNA breaks and cell death. Here, we report a PARP1 inhibitor, Senaparib, which has a novel chemical structure and high potency inhibiting PARP1/2 enzymes. Senaparib was highly potent in cell viability tests against tumor cells with BRCA1/2 mutations. It was efficacious in CDX and PDX xenograft models in tumor harboring BRCA1/2 mutations. In combination studies, Senaparib used with temozolomide (TMZ) had shown strong synergistic cytotoxicity in both in vitro and in vivo experiments. Senaparib represents a novel class of PARP1 inhibitors that can be used for the treatment of cancer. A phase III clinical study of Senaparib for maintenance treatment following first-line chemotherapy in patients with advanced ovarian cancer has met its primary endpoint, and a new drug application of Senaparib has been accepted by National Medical Products Administration (NMPA) of China for review.

4.
Pharmacol Rep ; 59(5): 573-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18048958

RESUMO

Epidemiological studies suggest that nerve growth factor (NGF) is associated with a reduced risk of acute or chronic neuropathies. We studied the synergistic protective effect of picroside II and NGF against the oxidative stress in PC12 cells induced by hydrogen peroxide (H2O2). The fluorescent probe CDCFH was used to assess the intracellular reactive oxygen species (ROS) level, and MTT assay, morphological observation as well as LDH leakage test were conducted to measure cellular injury. The H2O2-induced cytotoxicity was significantly attenuated in the presence of picroside II (25 microg/ml ) and NGF (2 ng/ml). Cultures with this combined treatment possessed decreased level of ROS while increased cell survival, as compared to that of picroside II or NGF alone-treated cells. Accordingly, it was concluded that their synergistic protective activities against oxidative stress in vitro were demonstrated in various aspects, including reversing morphological changes, enhancing the ability of cell proliferation and ROS scavenging. Such action supports the therapeutic potential of picroside II and NGF in treating nervous disorders based on their synergistic effect.


Assuntos
Cinamatos/farmacologia , Glucosídeos/farmacologia , Peróxido de Hidrogênio/farmacologia , Fator de Crescimento Neural/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Glucosídeos Iridoides , L-Lactato Desidrogenase/metabolismo , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo
5.
Am J Chin Med ; 35(4): 681-91, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17708634

RESUMO

Picroside II is an active constituent extracted from the traditional Chinese medicine (TCM) hu-huang-lian. To evaluate the neuroprotective effect of picroside II, PC12 cells were treated with glutamate in vitro and male ICR mice were treated with AlCl(3) in vivo. Pre-treatment of PC12 cells with picroside II could enhance the cell viability and decrease the level of intracellular reactive oxygen species (ROS) induced by glutamate. By DNA fragmentation and flow cytometry assay, picroside II (1.2 mg/ml) significantly prevented glutamate-induced cell apoptosis. In the animal study, amnesia was induced in mice by AlCl(3) (100 mg/kg/d, i.v.). Pricroside II, at the dose of 20 and 40 mg/kg/d (i.g.), markedly ameliorated AlCl(3)-induced learning and memory dysfunctions and attenuated AlCl(3)-induced histological changes. This was associated with the significant increased superoxide dismutase (SOD) activity in the brain of experimental mice. All these results indicated that picroside II possessed the therapeutic potential in protecting against neurological injuries damaged by oxidative stress.


Assuntos
Cinamatos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Glucosídeos/farmacologia , Medicina Tradicional Chinesa , Transtornos da Memória/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Neoplasias das Glândulas Suprarrenais/patologia , Cloreto de Alumínio , Compostos de Alumínio , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloretos , Cinamatos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Glucosídeos/uso terapêutico , Glutamatos , Glucosídeos Iridoides , Aprendizagem/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos ICR , Células PC12 , Feocromocitoma/patologia , Fitoterapia/métodos , Distribuição Aleatória , Ratos
6.
Cancer Biol Ther ; 15(12): 1635-45, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25482937

RESUMO

VEGF/VEGFR signal axis has been proven to be an important target for development of novel cancer therapies. One challenging aspect in small molecular VEGFR inhibitors is to achieve sustained target inhibition at tolerable doses previously seen only with the long-acting biologics. It would require high potency (low effective drug concentrations) and sufficient drug exposures at tolerated doses so that the drug concentration can be maintained above effective drug concentration for target inhibition within the dosing period. Fruquintinib (HMPL-013) is a small molecule inhibitor with strong potency and high selectivity against VEGFR family currently in Phase II clinical studies. Analysis of Phase I pharmacokinetic data revealed that at the maximum tolerated dose of once daily oral administration fruquintinib achieved complete VEGFR2 suppression (drug concentrations were maintained above that required to produce >85% inhibition of VEGFR2 phosphorylation in mouse) for 24 hours/day. In this article, the preclinical data for fruquintinib will be described, including kinase enzyme activity and selectivity, cellular VEGFR inhibition and VEGFR-driven functional activity, in vivo VEGFR phosphorylation inhibition in the lung tissue in mouse and tumor growth inhibition in a panel of tumor xenograft and patient derive xenograft models in mouse. Pharmacokinetic and target inhibition data are also presented to provide a correlation between target inhibition and tumor growth inhibition.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/administração & dosagem , Benzofuranos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Phytother Res ; 21(3): 262-8, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17186493

RESUMO

In this report, the mechanism of the antitumor activities of Kushen flavonoids (KS-Fs) were explored. KS-Fs and kurarinone (Kur), a single flavonoid compound, were able to induce apoptosis of H460 and Eca-109 cells in vitro and H460 cells in vivo. The apoptosis inducing effect was enhanced in the presence of Taxol. In H460 xenograft mice treated with Kur, down-regulation of Bcl-2 and up-regulation of caspase 8 and caspase 3 in tumors were observed by immunohistochemical staining. In addition, KS-Fs and Kur were able to inhibit TNFalpha-induced NF-kappaB activation in 293 cells mediated by the decreased IkappaBalpha phosphorylation. Further the effects of KS-Fs and Kur on multiple receptor tyrosine kinase activities were explored. In cell-based assays, KS-Fs and Kur inhibited the EGF-induced EGF receptor phosphorylation in A431 cells and a constitutively activated Her-2 in MDA-MB-453s cells. In enzymatic assays, KS-Fs and Kur inhibited KDR, but not PDGF BR activities. In A431 xenograft mice treated with Kur, an inhibition of EGF receptor phosphorylation in tumors was observed. These results reveal a novel mechanism by which KS-Fs induces apoptosis in tumors by acting on multiple cellular targets including the inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Fitoterapia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Flavonoides/administração & dosagem , Flavonoides/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transplante Heterólogo
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