Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Infecções por Coronavirus/prevenção & controle , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/virologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Administração Oral , Betacoronavirus/isolamento & purificação , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Infusões Intravenosas , Compostos Organoplatínicos/administração & dosagem , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , SARS-CoV-2RESUMO
OBJECTIVE: This study is aimed to analyze the clinical outcome of recurrent ovarian cancer patients bearing isolated lymph-node recurrence (ILNR) who underwent salvage lymphadenectomy (SL). The prognostic role of clinicopathological variables and the mutational status of BRCA1/2 have also been investigated. METHODS: This retrospective, single-institutional study included women with platinum-sensitive lymph node recurrence underwent to SL between June 2008 and June 2018. Univariate and multivariate analysis was performed to evaluate the impact of clinical parameters, and BRCA1/2 mutational status on post salvage lymphadenectomy progression-free survival (PSL-PFS). RESULTS: As of June 2019, the median follow-up after SL was 30 months, and the relapse has been documented in 48 (56.5%) patients. In the whole series, the median PSL-PFS was 21 months, and the 3-year PSL-PFS was 36.7%. The median PSL-PFS, according to patients with ILNR (N = 71) versus patients with lymph-nodes and other sites of disease (N = 14), was 27 months versus 12 months, respectively. Univariate analysis of variables conditioning PSL-PFS showed that platinum-free interval (PFI) ≥12 months, normal Ca125 serum levels, and number of metastatic lymph-nodes ≤3 played a statistically significant favorable role. In multivariate analysis, PFI duration ≥12 months and the number of metastatic lymph nodes ≤3 were shown to keep their favorable, independent prognostic value on PSL-PFS. CONCLUSIONS: In the context of SL, the patients with long PFI and low metastatic lymph node numbers at ILNR diagnosis have the best outcome. The BRCA mutational status seems not associated with clinical variables and PSL-PFS, differently from other sites of disease in ROC patients.
Assuntos
Carcinoma Epitelial do Ovário/cirurgia , Genes BRCA1 , Genes BRCA2 , Excisão de Linfonodo , Recidiva Local de Neoplasia/cirurgia , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Ca-125/sangue , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/secundário , Quimioterapia Adjuvante , Procedimentos Cirúrgicos de Citorredução , Feminino , Seguimentos , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Compostos de Platina/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Intervalo Livre de Progressão , Estudos Retrospectivos , Terapia de Salvação , Fatores de Tempo , Carga TumoralRESUMO
BACKGROUND: With the well established shift to neoadjuvant treatment for locally advanced rectal cancer, there is increasing focus on the use of radiosensitizers to improve the efficacy and tolerability of radiotherapy. There currently exist few randomized data exploring novel radiosensitizers to improve response and it is unclear what the clinical endpoints of such trials should be. METHODS: A qualitative systematic review was performed according to the PRISMA guidelines using preset search criteria across the PubMed, Cochrane and Scopus databases from 1990 to 2017. Additional results were generated from the reference lists of included papers. RESULTS: A total of 123 papers were identified, of which 37 were included; a further 60 articles were obtained from additional referencing to give a total of 97 articles. Neoadjuvant radiosensitization for locally advanced rectal cancer using fluoropyrimidine-based chemotherapy remains the standard of treatment. The oral derivative capecitabine has practical advantages over 5-fluorouracil, with equal efficacy, but the addition of a second chemotherapeutic agent has yet to show a consistent significant efficacy benefit in randomized clinical assessment. Preclinical and early-phase trials are progressing with promising novel agents, such as small molecular inhibitors and nanoparticles. CONCLUSION: Despite extensive research and promising preclinical studies, a definite further agent in addition to fluoropyrimidines that consistently improves response rate has yet to be found.
Assuntos
Quimiorradioterapia/métodos , Neoplasias Retais/terapia , Inibidores da Angiogênese/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Capecitabina/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Receptores ErbB/antagonistas & inibidores , Fluoruracila/administração & dosagem , Humanos , Imunoterapia/métodos , Irinotecano/administração & dosagem , Terapia Neoadjuvante , Oxaliplatina/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Radiossensibilizantes/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorafenibe/administração & dosagemRESUMO
Neuropathic pain, a debilitating pain condition and the underlying pathogenic mechanisms are complex and interwoven amongst each other and still there is scant information available regarding therapies which promise to treat the condition. Evidence indicate that oxidative/nitrosative stress induced poly (ADP-ribose) polymerase (PARP) overactivation initiate neuroinflammation and bioenergetic crisis culminating into neurodegenerative changes following nerve injury. Hence, we investigated the therapeutic effect of combining an antioxidant, quercetin and a PARP inhibitor, 4-amino 1, 8-naphthalimide (4-ANI) on the hallmark deficits induced by chronic constriction injury (CCI) of sciatic nerve in rats. Quercetin (25 mg/kg, p.o.) and 4-ANI (3 mg/kg, p.o.) were administered either alone or in combination for 14 days to examine sciatic functional index, allodynia and hyperalgesia using walking track analysis, Von Frey, acetone spray and hot plate tests respectively. Malondialdehyde, nitrite and glutathione levels were estimated to detect oxidative/nitrosative stress; mitochondrial membrane potential and cytochrome c oxidase activity to assess mitochondrial function; NAD & ATP levels to examine the bioenergetic status and levels of inflammatory markers were evaluated in ipsilateral sciatic nerve. Quercetin and 4-ANI alone improved the pain behaviour and biochemical alterations but the combination therapy demonstrated an appreciable reversal of CCI-induced changes. Nitrotyrosine and Poly ADP-Ribose (PAR) immunopositivity was decreased and nuclear factor erythroid 2-related factor (Nrf-2) levels were increased significantly in micro-sections of the sciatic nerve and dorsal root ganglion (DRG) of treatment group. These results suggest that simultaneous inhibition of oxidative stress-PARP activation cascade may potentially be useful strategies for management of trauma induced neuropathic pain.
Assuntos
1-Naftilamina/análogos & derivados , Antioxidantes/administração & dosagem , Encefalite/prevenção & controle , Naftalimidas/administração & dosagem , Neuralgia/prevenção & controle , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Poli(ADP-Ribose) Polimerases/metabolismo , Quercetina/administração & dosagem , Quinolonas/administração & dosagem , 1-Naftilamina/administração & dosagem , 1-Naftilamina/uso terapêutico , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/uso terapêutico , Encefalite/complicações , Encefalite/enzimologia , Hiperalgesia/prevenção & controle , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NAD/metabolismo , Naftalimidas/uso terapêutico , Neuralgia/complicações , Neuralgia/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Quercetina/uso terapêutico , Quinolonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesõesRESUMO
The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle structure and function and may play a role in suppressing multi-polar spindle formation in cells with supernumerary centrosomes, we initiated a phenotypic screen to look for small molecule poly (ADP-ribose) polymerase (PARP) enzyme family inhibitors that could produce a multi-polar spindle phenotype via declustering of centrosomes. Screening of AstraZeneca's collection of phthalazinone PARP inhibitors in HeLa cells using high-content screening techniques identified several compounds that produced a multi-polar spindle phenotype at low nanomolar concentrations. Characterization of these compounds across a broad panel of PARP family enzyme assays indicated that they had activity against several PARP family enzymes, including PARP1, 2, 3, 5a, 5b, and 6. Further optimization of these initial hits for improved declustering potency, solubility, permeability, and oral bioavailability resulted in AZ0108, a PARP1, 2, 6 inhibitor that potently inhibits centrosome clustering and is suitable for in vivo efficacy and tolerability studies.
Assuntos
Centrossomo/metabolismo , Ftalazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Administração Oral , Animais , Sítios de Ligação , Células CACO-2 , Centrossomo/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Humanos , Microssomos/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Ftalazinas/administração & dosagem , Ftalazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Estrutura Terciária de Proteína , Ratos , Tanquirases/antagonistas & inibidores , Tanquirases/metabolismoRESUMO
PURPOSE: To determine the antitumor efficacy and tolerability of combination temozolomide (TMZ) and veliparib (ABT-888) in patients with advanced, sorafenib-refractory hepatocellular carcinoma (HCC). METHODS: This single-arm phase II trial enrolled patients with pathologically confirmed, sorafenib-refractory HCC. All patients received 40 mg ABT-888 PO daily on days 1-7 and 150 mg/m(2) TMZ PO daily on days 1-5 of a 28-day cycle. The primary endpoint was objective response rate (ORR) at 2 months. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile. Tumor response was assessed every 2 cycles using RECIST criteria, and toxicities were assessed using CTCAE v4.03. RESULTS: We enrolled 16 patients in the first phase of the trial, but the study was discontinued due to a poor ORR; only four patients (25 %) had SD after 2 cycles. Twelve patients (75 %) were taken off study after 2 months of treatment; 10 of these had disease progression. Two patients (13 %) were taken off study due to severe toxicity, and one patient (6 %) died from non-treatment-related liver failure. One patient had SD for 16 months, receiving 11 cycles of therapy before being taken off study. The most common grade 3 treatment-related toxicities included vomiting (n = 2), thrombocytopenia (n = 2), nausea (n = 1), and anemia (n = 1). The median PFS was 1.9 months, and median OS was 13.1 months. CONCLUSION: The combination of TMZ and ABT-888 is well tolerated in patients with advanced HCC. However, the regimen failed to show survival benefit. CLINICALTRIALS. GOV IDENTIFIER: NCT01205828.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Carcinoma Hepatocelular/genética , Metilação de DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Fadiga/induzido quimicamente , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Terapia de Salvação , Sorafenibe , Temozolomida , Falha de TratamentoRESUMO
Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA(-) ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1(-) cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1(-) cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1(-) tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer.