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1.
Anticancer Res ; 41(7): 3253-3260, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230119

RESUMO

Epithelial ovarian cancer is the second most common malignancy of the female genital tract, with approximately 7,400 new cases annually in Germany. With 5,500 deaths per year, ovarian cancer is the leading gynecologic cause of death. Epithelial ovarian cancer is characterized by morphologic heterogeneity with 4 molecular biological subtypes (immunoreactive-like, differentiated-like, proliferative-like, mesenchymal-like) with different prognosis. Significantly improved survival is achieved by optimal debulking with no residual disease (R0). Systematic lymphonodectomy of clinical negative lymph nodes has no effect on overall survival in advanced ovarian cancer. Interval debulking in advanced ovarian cancer after three cycles of neoadjuvant chemotherapy with carboplatin/paclitaxel is controversial. Standard chemotherapy for advanced ovarian cancer consists of six cycles of carboplatin AUC5 and paclitaxel 175 mg/m2, in a three-week cycle. Intraperitoneal chemotherapy is not a standard therapy. Anti-hormonal therapy with an aromatase inhibitor plays a minor role in therapy of both low grade serous ovarian cancer (LGSOC) and high grade serous ovarian cancer (HGSOC). A major achievement in ovarian cancer therapy has been the results of the SOLO-1 trial, in which olaparib as a first line maintenance monotherapy resulted in an overall 70% lower risk of disease progression in patients with advanced Breast Cancer Gene (BRCA)-mutated ovarian cancer.


Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada/métodos , Feminino , Alemanha , Humanos , Terapia Neoadjuvante/métodos
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(6): 644-652, 2021 Jun 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34275934

RESUMO

Ovarian cancer is a common malignant tumor in gynaecology and its mortality rate is the highest in gynecological cancer. Ovarian cancer patients should face platinum resistance, caused by multiple recurrences. According to the platinum-free interval (PFI), recurrent ovarian cancer can be divided into platinum-resistant (PFI<6 months) and platinum-sensitive (PFI≥6 months). When PFI is 6-12 months, it belongs to the partial platinum-sensitive ovarian cancer. At present, how to prolong the survival of patients with partial platinum-sensitive recurrent ovarian cancer is difficult. Secondary cytoreductive surgery, non-platinum chemotherapy, anti-angiogenesis drugs, and molecular targeted therapy of poly (ADP ribose) polymerase (PARP) inhibitors can improve the prognosis of patients with partial platinum-sensitive recurrent ovarian cancer.


Assuntos
Recidiva Local de Neoplasia , Neoplasias Ovarianas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Doença , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico
3.
Int J Hyperthermia ; 38(1): 1013-1022, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34192990

RESUMO

PURPOSE: We aimed to determine the effects and possible mechanisms of hyperthermic intraperitoneal chemotherapy (HIPEC) in targeting ovarian cancer stem-like cells (CSCs). METHODS: Murine ovarian cancer cell lines presenting CSC surface markers were grown intraperitoneally in both immunocompetent and immunodeficient mice, which were then treated by intraperitoneal hyperthermia with the chemotherapeutic agents: paclitaxel and cisplatin. Tumor growth was measured by non-invasive luminescent imaging. Intraperitoneal immune cells, such as CD4+, CD8+ T cells, macrophages, and dendritic cells, were evaluated through flow cytometry analysis. RESULTS: Combined hyperthermia and chemotherapy exhibited an efficient therapeutic effect in the immunocompetent mice. However, a similar effect was not observed in the immunodeficient mice. Intraperitoneal hyperthermia increased the number of Intraperitoneal macrophages and dendritic cells that were lost due to chemotherapy. Compared with ovarian cancer bulk cells, CSCs were more susceptible to phagocytosis by macrophages. CONCLUSION: We demonstrated that the superior therapeutic efficacy and reduced proportion of CSCs associated with intraperitoneal hyperthermic chemotherapy were immune-related. Hyperthermia recruits the phagocytes that target surviving CSCs after chemotherapy. These results provide a novel mechanism for the efficacy of HIPEC in treating ovarian cancer.


Assuntos
Hipertermia Induzida , Neoplasias Ovarianas , Animais , Linfócitos T CD8-Positivos , Terapia Combinada , Feminino , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Camundongos , Células-Tronco Neoplásicas , Neoplasias Ovarianas/tratamento farmacológico
4.
BMJ Case Rep ; 14(5)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059546

RESUMO

We report a case of a previously healthy woman in her early 70s who presented with 2 weeks of episodic abdominal pain and significant weight loss. Imaging of her abdomen revealed acute right ovarian torsion associated with bilateral ovarian enlargement and an indeterminant pelvic mass. An urgent laparoscopic bilateral oophorectomy was performed with pathological results consistent with triple-hit high-grade B-cell lymphoma. She was successfully treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab, intrathecal methotrexate and venetoclax with complete remission after three cycles. Ovarian lymphoma is a rare entity and its genetic features have not been well described. We performed a literature review, describe the current knowledge regarding ovarian lymphoma and its therapeutic implication in the genomic age.


Assuntos
Linfoma de Células B , Neoplasias Ovarianas , Feminino , Humanos , Linfoma de Células B/complicações , Linfoma de Células B/diagnóstico , Linfoma de Células B/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Torção Ovariana , Rituximab/uso terapêutico , Vincristina
5.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(5): 736-746, 2021 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-34134962

RESUMO

OBJECTIVE: To develop a nano-delivery system for targeted delivery of miR-16/polypeptide for enhancing cisplatin sensitivity of ovarian cancer. OBJECTIVE: R9-SS-R9 and cRGD-R9-SS-R9 peptides were synthesized and self-assembled with miR-16 molecules to form a nano-delivery system. The stability, particle size, potential and morphology of the nanoparticles were determined by agarose gel electrophoresis, particle size potentiometer and transmission electron microscopy. CCK-8 assay was used to assess the toxicity of the polypeptides in ovarian cancer cells. Stem loop qRT-PCR and living cell imaging were used to verify the uptake efficiency and intracellular distribution of the nanoparticles. Flow cytometry and Western blotting were performed to verify the effect of the nanoparticles for enhancing cisplatin sensitivity of ovarian cancer cells and explore the possible mechanism. OBJECTIVE: R9-SS-R9/miR-16 and cRGD-R9-SS-R9/miR-16 nanoparticles were successfully prepared. The nanoparticles, with a particle size below 150 nm, a dispersity index less than 0.1 and a potential of about 40 mV, showed a good serum stability. The polypeptide material had no obvious cytotoxicity. The miR-16/polypeptide nanoparticles could be efficiently absorbed by human ovarian cancer cells and were distributed in the cytoplasm. The nanoparticles significantly increased the intracellular expression level of miR-16 (P < 0.001) and decreased the expression of Bcl-2 and Chk-1 proteins in ovarian cancer cells, thus enabling miR-16 to promote apoptosis and enhance cisplatin sensitivity of the cells. OBJECTIVE: We successfully prepared a miR-16/polypeptide nano-delivery system for targeted delivery of miR-16 to ovarian cancer cells for enhancing cisplatin sensitivity of the cancer cells.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , MicroRNAs/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Peptídeos
6.
Lancet Oncol ; 22(7): 1034-1046, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143970

RESUMO

BACKGROUND: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints. FINDINGS: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). INTERPRETATION: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Platina/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Compostos de Platina/efeitos adversos , Polietilenoglicóis/uso terapêutico , Fatores de Tempo
7.
Gan To Kagaku Ryoho ; 48(6): 821-824, 2021 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-34139731

RESUMO

In the present report, the patient was a 55-year-old woman who had undergone an oophorectomy in October 2016 as surgical intervention for ovarian cancer, followed by 6 courses of TC therapy as postoperative adjuvant therapy. She was diagnosed with recurrent ovarian cancer in August 2017, and we planned anticancer drug treatment considering that the tumor exhibited platinum resistance. However, the platelet count decreased significantly to 2.4×104/µL. Accordingly, she was referred to the hematology department and was diagnosed with idiopathic thrombocytopenic purpura. She was started on oral eltrombopag, and her platelet level recovered to 5.8×104/µL on day 68. Next, gemcitabine plus bevacizumab therapy was initiated. However, as the platelet level again decreased to 1.6×104/µL on day 8, the eltrombopag dose was increased only for 5 days before and after the anticancer drug administration on day 1. Accordingly, after increasing the eltrombopag dose, the anticancer drug treatment was performed without interruptions. Moreover, the gemcitabine dose could be increased. Herein, we report that in patients with platinum-resistant recurrent ovarian cancer complicated with idiopathic thrombocytopenic purpura, increasing the oral hematopoietic stimulant dose for 5 days before and after day 1 had beneficial results in continuing anticancer drug treatment.


Assuntos
Neoplasias Ovarianas , Púrpura Trombocitopênica Idiopática , Carcinoma Epitelial do Ovário , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/tratamento farmacológico
8.
J Biomed Nanotechnol ; 17(5): 960-970, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082881

RESUMO

Graphene oxide (GO) is one of the most popular nanomaterials that widely used to achieve effective cancer treatment. In this study, a novel, folic acid-decorated graphene oxide (FA-GO)-mediated drug delivery system was synthesized by loading the chemotherapy drug cisplatin (CDDP) or paclitaxel (PTX) to the large surface area of GO for ovarian cancer target therapy. In vitro study showed that the therapeutic effects of FA-GO-CDDP or FA-GO-PTX were increased with folate-binding protein (FBP) expression levels. The GO-CDDP or GO-PTX modified with FA enhanced cancer cell death by promoting DNA damage, ROS production, and apoptotic pathway activation. In vivo anticancer study demonstrated that FA-GO-CDDP nanosheets showed excellent therapeutic performance and attenuated the body weight loss evoked by CDDP treatment. Our results indicate that the chemotherapy agent-loaded FA-GO nanosheets have high potential therapeutic effects against FBP high expressing ovarian cancer.


Assuntos
Neoplasias Ovarianas , Preparações Farmacêuticas , Linhagem Celular Tumoral , Portadores de Fármacos , Feminino , Ácido Fólico , Grafite , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel
9.
Medicina (Kaunas) ; 57(5)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063455

RESUMO

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.


Assuntos
Motivação , Neoplasias Ovarianas , Bevacizumab/uso terapêutico , Feminino , Humanos , Estudos Multicêntricos como Assunto , Neoplasias Ovarianas/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
J Pak Med Assoc ; 71(4): 1258-1259, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34125784

RESUMO

We report a case of mixed germ cell tumour, which presented with acute kidney injury in an unmarried 22-year-old Asian girl. The case demonstrated that an aggressive approach with multidisciplinary teamwork ascertained outstanding clinical outcome. The patient was successfully managed fertility-sparing surgery and three cycles of Bleomycin, Etoposide and Cisplatin (BEP) therapy. The patient's pathophysiology returned to normal within weeks and she was declared tumour-free. Furthermore, three-year follow up scans and biomarkers were evident for tumour negativity.


Assuntos
Injúria Renal Aguda , Anestésicos , Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Injúria Renal Aguda/etiologia , Adulto , Anestésicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Resultado do Tratamento , Adulto Jovem
11.
Medicina (Kaunas) ; 57(5)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066975

RESUMO

Background andObjective: Epigenetic modifications are believed to play a significant role in the development of cancer progression, growth, differentiation, and cell death. One of the most popular histone deacetylases inhibitors (HDACIs), suberoylanilide hydroxamic acid (SAHA), also known as Vorinostat, can directly activate p21WAF1/CIP1 gene transcription through hyperacetylation of histones by a p53 independent mechanism. In the present investigation, we evaluated the correlation between histone modifications and DNA methyltransferase enzyme levels following SAHA treatments in A2780 ovarian cancer cells. Materials and Methods: Acetylation of histones and methyltransferases levels were analyzed using RT2 profiler PCR array, immunoblotting, and immunofluorescence methods in 2D and 3D cell culture systems. Results: The inhibition of histone deacetylases (HDAC) activities by SAHA can reduce DNA methyl transferases / histone methyl transferases (DNMTs/HMTs) levels through induction of hyperacetylation of histones. Immunofluorescence analysis of cells growing in monolayers and spheroids revealed significant up-regulation of histone acetylation preceding the above-described changes. Conclusions: Our results depict an interesting interplay between histone hyperacetylation and a decrease in methyltransferase levels in ovarian cancer cells, which may have a positive impact on the overall outcomes of cancer treatment.


Assuntos
Inibidores de Histona Desacetilases , Neoplasias Ovarianas , Acetilação , Linhagem Celular Tumoral , Feminino , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histonas/metabolismo , Humanos , Metiltransferases , Neoplasias Ovarianas/tratamento farmacológico
12.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071702

RESUMO

Cisplatin is a chemotherapy drug that kills cancer cells by damaging their DNA. In human cells, this damage is repaired primarily by nucleotide excision repair. While cisplatin is generally effective, many cancers exhibit initial or acquired resistance to it. Here, we studied cisplatin resistance in a defined cell line system. We conducted a comprehensive genomic characterization of the cisplatin-sensitive A2780 ovarian cancer cell line compared to A2780cis, its resistant derivative. The resistant cells acquired less damage, but had similar repair kinetics. Genome-wide mapping of nucleotide excision repair showed a shift in the resistant cells from global genome towards transcription-coupled repair. By mapping gene expression changes following cisplatin treatment, we identified 56 upregulated genes that have higher basal expression in the resistant cell line, suggesting they are primed for a cisplatin response. More than half of these genes are novel to cisplatin- or damage-response. Six out of seven primed genes tested were upregulated in response to cisplatin in additional cell lines, making them attractive candidates for future investigation. These novel candidates for cisplatin resistance could prove to be important prognostic markers or targets for tailored combined therapy in the future.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Genoma/efeitos dos fármacos , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo
13.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072728

RESUMO

Ovarian cancer is often detected at the advanced stages at the time of initial diagnosis. Early-stage diagnosis is difficult due to its asymptomatic nature, where less than 30% of 5-year survival has been noticed. The underlying molecular events associated with the disease's pathogenesis have yet to be fully elucidated. Thus, the identification of prognostic biomarkers as well as developing novel therapeutic agents for targeting these markers become relevant. Herein, we identified 264 differentially expressed genes (DEGs) common in four ovarian cancer datasets (GSE14407, GSE18520, GSE26712, GSE54388), respectively. We constructed a protein-protein interaction (PPI) interaction network with the overexpressed genes (72 genes) and performed gene enrichment analysis. In the PPI networks, three proteins; TTK Protein Kinase (TTK), NIMA Related Kinase 2 (NEK2), and cyclin-dependent kinase (CDK1) with higher node degrees were further evaluated as therapeutic targets for our novel multi-target small molecule NSC777201. We found that the upregulated DEGs were enriched in KEGG and gene ontologies associated with ovarian cancer progression, female gamete association, otic vesicle development, regulation of chromosome segregation, and therapeutic failure. In addition to the PPI network, ingenuity pathway analysis also implicate TTK, NEK2, and CDK1 in the elevated salvage pyrimidine and pyridoxal pathways in ovarian cancer. The TTK, NEK2, and CDK1 are over-expressed, demonstrating a high frequency of genetic alterations, and are associated with poor prognosis of ovarian cancer cohorts. Interestingly, NSC777201 demonstrated anti-proliferative and cytotoxic activities (GI50 = 1.6 µM~1.82 µM and TGI50 = 3.5 µM~3.63 µM) against the NCI panels of ovarian cancer cell lines and exhibited a robust interaction with stronger affinities for TTK, NEK2, and CDK1, than do the standard drug, paclitaxel. NSC777201 displayed desirable properties of a drug-like candidate and thus could be considered as a novel small molecule for treating ovarian carcinoma.


Assuntos
Biologia Computacional , Descoberta de Drogas , Perfilação da Expressão Gênica , Variação Genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Inibidores de Proteínas Quinases/química , Biomarcadores Tumorais , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Biologia Computacional/métodos , Descoberta de Drogas/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/química , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Relação Estrutura-Atividade , Transcriptoma
14.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064635

RESUMO

Ovarian cancer is a fatal gynecological malignancy. Although first-line chemotherapy and surgical operation are effective treatments for ovarian cancer, its clinical management remains a challenge owing to intrinsic or acquired drug resistance and relapse at local or distal lesions. Cancer stem cells (CSCs) are a small subpopulation of cells inside tumor tissues, and they can self-renew and differentiate. CSCs are responsible for the cancer malignancy involved in relapses as well as resistance to chemotherapy and radiation. These malignant properties of CSCs are regulated by cell surface receptors and intracellular pluripotency-associated factors triggered by internal or external stimuli from the tumor microenvironment. The malignancy of CSCs can be attenuated by individual or combined restraining of cell surface receptors and intracellular pluripotency-associated factors. Therefore, targeted therapy against CSCs is a feasible therapeutic tool against ovarian cancer. In this paper, we review the prominent roles of cell surface receptors and intracellular pluripotency-associated factors in mediating the stemness and malignancy of ovarian CSCs.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Animais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Microambiente Tumoral
15.
J Registry Manag ; 48(1): 28-35, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34170893

RESUMO

BACKGROUND: Overall survival associated with National Comprehensive Cancer Network (NCCN) adjuvant chemotherapy treatment guideline using population-based surveillance data is limited. This study examined overall survival and compliance to the NCCN guideline for adjuvant chemotherapy. METHODS: The Midwest Ovarian Cancer Study was a collaborative project between 3 state cancer registries (Iowa, Kansas, and Missouri), Westat, and the Centers for Disease Control and Prevention. A standardized protocol was used to ascertain International Federation of Gynecology and Obstetrics (FIGO) stage-specific adjuvant chemotherapy. Primary epithelial ovarian cancers with FIGO stages IA/IB grade 3, IC, and II-IV with histologies 8000-8576 and 8930-9110 were included in this study. The Kaplan-Meier method was used to calculate survival functions. Adjusted hazard ratio (HR) was analyzed for all-cause mortality associated with NCCN compliance with adjuvant chemotherapy after adjusting for stage at diagnosis and comorbidity. RESULTS: Sixtynine percent (523 of 756 eligible) were compliant with NCCN guidelines. Compliance was significantly different by age at diagnosis and insurance type (both P < .0001). The overall survival was significantly different by age group, census tract median income, histologic subtype, and tumor grade (all P < .0001). The adjusted HR of noncompliance with adjuvant chemotherapy guideline was 3.2 (95% CI, 2.600-3.911). CONCLUSIONS: Better overall survival in patients who had received NCCN-recommended adjuvant chemotherapy was confirmed. IMPACT: The survival benefit was 7% higher over 4 years after diagnosis when considering FIGO stage-specific chemotherapy and the corresponding number of cycles. Using the chemotherapy data field that is collected by statewide cancer registries underestimated the overall survival.


Assuntos
Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Quimioterapia Adjuvante , Feminino , Humanos , Iowa , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Sistema de Registros
17.
Zhonghua Fu Chan Ke Za Zhi ; 56(6): 385-392, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34154313

RESUMO

Objective: To explore the prognostic factors of patients with advanced epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). Methods: The clinical and pathological data of patients with stage Ⅲc-Ⅳ EOC underwent surgical treatment in Sichuan Cancer Center from January 1st, 2014 to December 31th, 2018 were retrospectively analyzed, and the prognosis was followed up. Results: (1) A total of 216 EOC patients were included in the study, whose age was (52.1±8.7) years old, the median follow-up time was 44.6 months (17.2-80.1 months), the median progression free survival (PFS) was 11.1 months (8.5-13.8 months), and the median overall survival (OS) was 40.0 months (32.7-47.3 months). (2) Among 216 patients with advanced EOC, there were 75 cases in the primary debulking surgery (PDS) group and 141 cases in the NACT+IDS group. Compared with the PDS group, the serum CA125 level before treatment (median: 859.4 vs 1 371.0 kU/L), proportion of stage Ⅳ patients [5.3% (4/75) vs 23.4% (33/144)] and no visible residual disease (R0) cytoreduction rate in the NACT+IDS group were significantly higher [(41.3% (31/75) vs 61.7% (87/144); all P<0.05]. The median PFS in the NACT+IDS group was significantly shorter than that of the PDS group (9.1 vs 15.2 months; χ2=7.014, P=0.008), but there was no significant difference in the median OS between the two groups (42.6 vs 38.0 months; χ2=1.325, P=0.250). (3) Univariate analysis showed that body mass index (BMI), preoperative serum CA125 level, surgical-pathological stage, NACT effect, postoperative residual tumor size, time to initiation of postoperative chemotherapy and chemotherapy regimen were significantly correlated with PFS in the NACT+IDS group (all P<0.05); preoperative serum CA125 level, surgical-pathological stage, NACT effect, postoperative residual tumor size, postoperative chemotherapy regimen were significantly related with OS in the NACT+IDS group (all P<0.05). Multivariate analysis showed that BMI, postoperative residual tumor size, time to initiation of postoperative chemotherapy were independent factors of PFS in the NACT+IDS group (all P<0.05); preoperative serum CA125 level, surgical-pathological stage, postoperative residual tumor size were independent factors of OS in the NACT+IDS group (all P<0.05). The results showed that the PFS of patients with normal preoperative serum CA125 level and (or) chemotherapy ≤7 days after IDS was longer, while no significant difference comparable with those in the PDS group (P>0.05), and OS was also showing an prolonged trend, but the difference was also not statistically significant (P>0.05). Conclusions: Normal CA125 before IDS and time received chemotherapy no longer than 7 days after IDS are two related factors of prognosis benefit in advance EOC patients treated with NACT+IDS. Therefore, timely adjustment of the dose and regimen of NACT to reduce CA125 level to normal range in about three cycles before IDS, and strengthen IDS perioperative management to promote postoperative recovery and perform chemotherapy as soon as possible might help to improve the prognosis of patients.


Assuntos
Procedimentos Cirúrgicos de Citorredução , Neoplasias Ovarianas , Adulto , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Prognóstico , Estudos Retrospectivos
18.
Zhonghua Fu Chan Ke Za Zhi ; 56(6): 393-400, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34154314

RESUMO

Objective: To identify the factors associated with long-term survival and guide the decision for primary surgery in patients with advanced high-grade serous ovarian cancer(HGSOC). Methods: In this case-control study, clinical parameters, including surgical and non-surgical associated factors, were collected and compared between the patients with short-term (<2 years) and long-term (>5 years) survival who all underwent primary debulking surgery (PDS) followed by carboplatin and paclitaxel chemotherapy from January 2004 to December 2016. Univariate analysis was examined by chi-square test and multivariate analysis was performed by logistic regression analysis. Results: There were 95 cases long-term survival (LTS group) and 77 cases short-term survival (STS group) in 698 newly diagnosed HGSOC patients with International Federation of Gynecology and Obstetrics (FIGO) stage Ⅲc and Ⅳ who met include and exclude criteria. (1) Univariate analysis showed that the proportion of complete cytoreduction with no visible residual disease (R0) at PDS and platinum sensitivity in LTS group were significantly higher than those in STS group (P<0.01). The surgical complexity score (SCS), the preoperative serum CA125 level and the ascites volume in the LTS group were significantly lower than those of the STS group (all P<0.05). In the LTS group, the preoperative incidence of lesions in retrograde peritoneum of the bladder, serosal and mesangial membrane of the small intestine, upper abdominal peritoneum and liver parenchyma were significantly lower than those in the STS group (all P<0.05). Multivariate logistic regression analysis showed that platinum sensitivity (OR=0.016, 95%CI: 0.004-0.063, P<0.01), ascites volume >500 ml (OR=3.193, 95%CI: 1.285-7.930, P=0.012), and SCS ≥8 (OR=17.433, 95%CI: 2.281-133.25, P=0.003) were independent factors affecting long-term survival (P>0.05). (2) Totally 37 of 95 in long-term survival and 16 of 77 in short-term survival achieved R0 cytoreduction at PDS. Univariate analysis showed that preoperative serum CA125 level, preoperative lesion score, preoperative lesion (DS) score, ascites volume, platinum sensitivity,and SCS were significantly correlated with the R0 PDS (all P<0.05). Multivariate analysis showed that ascites volume >500 ml (OR=5.199, 95%CI: 2.015-13.409, P=0.001), DS >2 (OR=15.264, 95%CI: 5.843-39.874, P<0.01) and SCS ≥4 (OR=4.176, 95%CI: 1.618-10.777, P=0.003) were independent factors associated with R0 cytoreduction. In patients with DS ≤2 or SCS <4, but not those with DS >2 or SCS ≥4, R0 cytoreduction was significantly associated with long-term survival. Conclusion: The intrinsic biology of tumor is the factor influencing long-term survival of advanced HGSOC patients, and those who present with wide intraperitoneal metastases and need to remove multiple organs may not benefit from R0 cytoreduction.


Assuntos
Neoplasias Ovarianas , Carboplatina , Estudos de Casos e Controles , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Paclitaxel , Estudos Retrospectivos
19.
Zhonghua Fu Chan Ke Za Zhi ; 56(6): 401-407, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34154315

RESUMO

Objective: To explore the clinical features of poly ADP-ribose polymerase (PARP) inhibitor-related anemia in advanced and relapsed epithelial ovarian cancer (EOC). Methods: Patients diagnosed with advanced or relapsed EOC and treated with PARP inhibitor at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2015 to October 2020 were accrued. The data included PARP inhibitors, treatment details, and lab tests before treatment and during treatment were collected and the clinical characteristics of PARP inhibitor-related anemia were analyzed. Results: (1) A total of 98 patients with a median age of 56.5 years old (30-82 years old) were enrolled in this study. All patients were treated with PARP inhibitor (65 cases of olaparib, 17 cases of niraparib, and 16 cases of fluzoparib). The median treatment duration was 37.5 weeks (4-119 weeks). (2) The anemia rate was 40% (39/98), including 5% (5/98) of grade Ⅰ, 14% (14/98) of grade Ⅱ, 11% (11/98) of grade Ⅲ, and 9% (9/98) of grade Ⅳ. Fourteen patients with pre-treatment grade Ⅰ anemia had a higher rate of anemia events than the 80 patients without pre-treatment anemia, 7/14 vs 35% (28/80; χ2=4.281, P=0.039). (3) The median anemia occurrence time was 7.0 weeks (1-52 weeks), including 41% (16/39) of anemia cases occurred in 1-4 weeks, 26% (10/39) occurred in 5-8 weeks, 13% (5/39) occurred in 9-12 weeks, 3% (1/39) occurred in 13-16 weeks, 10% (4/39) occurred in 17-20 weeks, 8% (3/39) occurred ≥21 weeks. At the time of the lowest hemoglobulin tested, the median value of mean corpuscular volume (MCV) was 106 fl,which was higher than the up limit of normal range (100 fl), 74% (29/39) of anemia patients had an elevated MCV level; the median value of mean corpuscular hemoglobin (MCH) was 36 pg, 54% (21/39) of anemia patients had an elevated MCH level; the median value of mean corpuscular hemoglobin concentration (MCHC) was 320 g/L, 69% (27/39) of anemia patients had a higher MCHC level; 92% (36/39) of anemia patients had a normal level of serum iron; 79% (31/39) of anemia patients had a normal level of transferrin. 74% (29/39) of the anemia patients were macrocytic orthochromatic anemia. (4) Among the 39 patients with anemia, 20 patients (51%, 20/39) withhold the treatment of PARP inhibitor due to grade Ⅲ or Ⅳ anemia, including 10 patients (50%, 10/20) who resumed the PARP inhibitor treatment by suppling iron, folate, and vitamin B12. The median stopping time of PARP inhibitor was 5.5 weeks (2-10 weeks), while the other 10 patients terminated the PARP inhibitor treatment for not recovering from severe anemia. Conclusions: One of the common adverse effects of PARP inhibitors is anemia, which mostly happened in the first 3 months of treatment. In the treatment of EOC, PARP inhibitor-related anemia mainly manifest as macrocytic orthochromatic anemia, and most patients with normal serum iron and transferrin.


Assuntos
Anemia , Neoplasias Ovarianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Anemia/epidemiologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos
20.
Adv Exp Med Biol ; 1187: 159-179, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33983578

RESUMO

Cancer has been defined as a genetic disorder caused by the accumulation of genetic alterations, which result from various internal and external DNA damage that is left unrepaired. One of the main characteristics of cancer is a partial loss of DNA damage repair (DDR) pathway, resulting in increased DNA damage levels and replication stress. DDR inhibitors have been suggested as a new anticancer strategy, under the concept of synthetic lethality. The poly-(ADP-ribose) polymerase (PARP) inhibitor is the first DDR inhibitor to be used in clinical practice. PARP inhibitors have been tested in patients with BRCA1/2 germline mutations (gBRCA1/2mt) and shown robust clinical benefits in breast cancer with gBRCA1/2mt and serous ovarian cancer patients. The concept of synthetic lethality is not limited to gBRCAmt for PARP inhibitor, and discovering homologous recombination deficiency (HRD) markers beyond BRCA1/2 and identifying best candidates for DDR inhibitors are the active research areas. At the same time, various combinations of DDR inhibitors and other anticancer drugs are being tested in both preclinical and clinical studies. In addition, based on recent evidence of the immune-modulatory effect of PARP inhibitors, the combination of DDR inhibitors and immune checkpoint inhibitors is being actively investigated. Acquired resistance mechanism of DDR inhibitors, as well as defining best candidates and best combinations, would be future research topics for DDR inhibitors. Furthermore, it would also be crucial to establish a clinically relevant standardized method to detect HRD for future clinical use.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Dano ao DNA , Reparo do DNA , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
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