RESUMO
RESEARCH QUESTION: What are the real-life oncofertility practices in young women diagnosed with breast cancer? DESIGN: The FEERIC (FErtility, prEgnancy, contRaceptIon after breast Cancer in France) study is a web-based cohort study launched with the French collaborative research platform Seintinelles. The current work is based on the enrolment self-administered questionnaire of 517 patients with prior breast cancer diagnosis, free from relapse and aged 18 to 43 years at inclusion (from 12 March 2018 to 27 June 2019). RESULTS: Median age at breast cancer diagnosis was 33.6 years and 424 patients (82.0%) received chemotherapy. Overall, 236 (45.6%) patients were offered specialized oncofertility counselling, 181 patients underwent at least one fertility preservation procedure (FPP); 125 (24.2%) underwent one or more FPP with material preservation (oocytes n = 108, 20.9%; embryos n = 31, 6.0%; ovarian cryopreservation n = 6, 1.2%) and 78 patients received gonadotrophin-releasing hormone agonists (15.1%). With a median follow-up of 26.9 months after the end of treatments, 133 pregnancies had occurred in 85 patients (16.4%), including 20 unplanned pregnancies (15.0%). Most of the pregnancies were natural conceptions (n = 113, 87.6%), while 16 (12.4%) required medical interventions. For the planned pregnancies, median time to the occurrence of an ongoing pregnancy was 3 months. Patients who had an unplanned pregnancy reported lower rates of information on the consequences of the treatments on fertility (P = 0.036) at diagnosis. CONCLUSIONS: Most of the patients were not offered proper specialized oncofertility counselling at the time of breast cancer diagnosis. Naturally conceived pregnancies after breast cancer were much more frequent than pregnancies resulting from the use of cryopreserved gametes. Adequate contraceptive counselling seems as important as information about fertility and might prevent unplanned pregnancies.
Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Preservação da Fertilidade , Neoplasias da Mama/tratamento farmacológico , Estudos de Coortes , Criopreservação , Feminino , Preservação da Fertilidade/métodos , Humanos , Recidiva Local de Neoplasia , GravidezRESUMO
Recent investigations showed that anandamide, the main endogenous ligand of CB1 and CB2 cannabinoid receptors, possesses analgesic, antidepressant and anti-inflammatory effects. In the perspective to treat inflammatory bowel disease (IBD), our approach was to develop new selective CB2 receptor agonists without psychotropic side effects associated to CB1 receptors. In this purpose, a new series of 3-carboxamido-5-aryl-isoxazoles, never described previously as CB2 receptor agonists, was designed, synthesized and evaluated for their biological activity. The pharmacological results have identified great selective CB2 agonists with in vivo anti-inflammatory activity in a DSS-induced acute colitis mouse model.
Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Isoxazóis/química , Receptor CB2 de Canabinoide/agonistas , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/toxicidade , Proliferação de Células/efeitos dos fármacos , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana/toxicidade , Células HT29 , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Isoxazóis/uso terapêutico , Isoxazóis/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Breast cancer (BC) is the most common cancer in women worldwide. Neoadjuvant chemotherapy (NAC) makes it possible to monitor in vivo response to treatment. Several studies have investigated the impact of the seasons on the incidence and detection of BC, on tumor composition, and on the prognosis of BC. However, no evidence is available on their association with immune infiltration and the response to treatment. The objective of this study was to analyze pre- and post-NAC immune infiltration as assessed by TIL levels, the response to treatment as assessed by pathological complete response (pCR) rates, and oncological outcomes as assessed by relapse-free survival (RFS) or overall survival (OS) according to the seasonality of BC diagnoses in a clinical cohort of patients treated with neoadjuvant chemotherapy. Out of 1199 patients, the repartition of the season at BC diagnosis showed that 27.2% were diagnosed in fall, 25.4% in winter, 24% in spring, and 23.4% in summer. Baseline patient and tumor characteristics, including notable pre-NAC TIL levels, were not significantly different in terms of the season of BC diagnosis. Similarly, the pCR rates were not different. No association for oncological outcome was identified. Our data do not support the idea that the seasonality of diagnoses has a major impact on the natural history of BC treated with NAC.
RESUMO
Adapted physical activity (APA) improves quality of life and cancer outcomes. The aim of this study was to assess the feasibility of an APA program in outpatients beginning medical anticancer treatment. The secondary objective was to assess the impact of APA on fatigue, anxiety, depression, and handgrip strength (HGS). This prospective study was conducted between January and July 2017. Among 226 patients beginning treatment in the unit for a digestive, lung, hematological, or dermatological cancer, 163 were included. Adherence to the APA program was defined as more than or equal to one one-hour session per week for 3 months. The first evaluation was conducted at 3 months (M3), and the second evaluation at 6 months (M6). A total of 163 patients were included (mean age 62.5 ± 14.3); 139 (85.3%) agreed to follow the APA program. At M3, 106 of them were evaluated, of which 86 (81.1%) declared that they had followed the program. Improvement in anxiety was observed at M3 (-1.0 ± 3.2; p = 0.002) but there was no significant change in fatigue or depression. HGS decreased significantly (-1.2 ± 5.5; p = 0.04). The APA program was feasible in cancer outpatients beginning medical anticancer treatment. APA should be part of standard support care.
RESUMO
Three series of 6,7-dimethoxyquinazoline derivatives substituted in the 4-position by aniline, N-methylaniline and aryloxy entities, targeting EGFR and VEGFR-2 tyrosine kinases, were designed and synthesized. Pharmacological activities of these compounds have been evaluated for their enzymatic inhibition of VEGFR-2 and EGFR and for their antiproliferative activities on various cancer cell lines. We have studied the impact of the variation in the 4-position substitution of the quinazoline core. Substitution by aryloxy groups led to new compounds which are selective inhibitors of VEGFR-2 enzyme with IC(50) values in the nanomolar range in vitro.
Assuntos
Quinazolinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Modelos Moleculares , Quinazolinas/química , Relação Estrutura-AtividadeRESUMO
Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), two protein tyrosine kinases, are involved in pathological disorders and the progression of different types of carcinomas. Concomitant inhibition of both tyrosine kinase activities appears to be an attractive target for cancer chemotherapy. A series of new quinazoline derivatives substituted by amide, urea, or carbamic acid ester groups have been synthesized. The biological activities of these new compounds have been evaluated for their enzyme inhibition and antiproliferative activities.
Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases , Quinazolinas , Ureia/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbamatos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Neoplasias da Próstata/enzimologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologiaRESUMO
INTRODUCTION: Adapted physical activity (APA) is recognized as an effective supportive care for asthenia and quality of life in oncology. Before an APA program was organized, the feasibility of such a program was evaluated among the patients. METHODS: Descriptive, prospective, semi-qualitative, single-center study over a 3-month period in patients treated with ambulatory chemotherapy for digestive cancer. A self-questionnaire was offered to all patients to evaluate their practice and knowledge about APA. In ten patients, fatigue, anxiety and depression were assessed, before and after 9 weeks of hospital-based APA. The scores were compared by matched Student test. RESULTS: Of the 123 patients treated, 80 questionnaires (65%) were exploitable. Before the diagnosis of cancer, 40 patients (50%) were physically active, 20% after (n=16). The reasons for not practicing were: lack of interest/not the idea (42%), lack of time (34%), do not believe in profit (9%), too expensive (8%). Fifty-three patients (66%) were interested in the program. In 10 patients, the APA program significantly reduced the depression score (P=0.024) and a non-significant improvement in anxiety and fatigue. DISCUSSION: This study shows that patients treated with chemotherapy are unaware of the usefulness of APA and that medical information can improve adherence to such a program. The establishment of an intra-hospital APA program proved to be possible and relevant.
Assuntos
Assistência Ambulatorial/métodos , Neoplasias do Sistema Digestório/tratamento farmacológico , Exercício Físico , Desenvolvimento de Programas , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/diagnóstico , Depressão/diagnóstico , Neoplasias do Sistema Digestório/psicologia , Fadiga/diagnóstico , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
FTase inhibitors constitute a new class of potential cancer therapeutics, especially in colorectal cancer where K-ras-selective mutations exist and have a role in tumorigenesis. The synthesis and biological evaluation of two nonpeptidic molecules (13 and 16) designed on the basis of a zinc chelator imidazole linked to two aromatic fragments able to fit in the "exit groove" and in the "A2 binding site" of FTase are described. These molecules are characterized respectively by a flexible phenylmethyl chain and a more constrained scaffold so as to evaluate their respective influences on site recognition. They have been evaluated in vitro and in vivo against human colon cancer cell lines and 13 not only inhibited tumor growth but also showed no toxic effects at the dose used.
Assuntos
Antineoplásicos/síntese química , Química Farmacêutica/métodos , Neoplasias do Colo/tratamento farmacológico , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Inibidores Enzimáticos/síntese química , Farnesiltranstransferase/antagonistas & inibidores , Animais , Células HT29 , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de NeoplasiasRESUMO
Bioassay-guided fractionation using antimicrobial assay of the crude acetonic extract of Garcinia goudotiana leaves and of its five partitions led to the isolation of two new prenylated benzoylphloroglucinol derivatives, goudotianone 1 (1) and goudotianone 2 (2), in addition to two known compounds including one xanthone, 1,3,7-trihydroxy-2-isoprenylxanthone (3), and one triterpenoid, friedelin (4). Their structures were elucidated on the basis of different spectroscopic methods, including extensive 1D- and 2D-NMR spectroscopy and mass spectrometry. The crude acetonic extract, the methylene chloride and ethyl acetate partitions, and some tested compounds isolated from this species (1-3) demonstrated selective significant antimicrobial activities against Gram-positive bacteria, in particular Staphylococcus lugdunensis, Enterococcus faecalis and Mycobacterium smegmatis. The potential cytotoxic activities of these extracts and compounds were evaluated against human colon carcinoma HT29 and human fetal lung fibroblast MRC5 cells.
Assuntos
Antibacterianos/farmacologia , Clusiaceae/química , Bactérias Gram-Positivas/efeitos dos fármacos , Floroglucinol/farmacologia , Folhas de Planta/química , Xantonas/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HT29 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Floroglucinol/análogos & derivados , Floroglucinol/química , Relação Estrutura-Atividade , Xantonas/química , Xantonas/isolamento & purificaçãoRESUMO
The synthesis of new acridinone and dioxophenothiazine derivatives along with their tubulin polymerization inhibitory and antiproliferative activities is reported. The analysis of correlation for cytotoxic and antitubulin potential of tested compounds showed that 4-methoxyphenylethyl derivatives 18a and 19a were highly cytotoxic but were regarded to have no significant antitubulin activity. However, the introduction of a 3-hydroxy substituent leading to compounds 18e and 19e, strongly increased the antitubulin potential but was associated with a loss of the antiproliferative activity. Modeling studies, topoisomerase inhibition assays and cell cycle analysis have been performed to better investigate the mechanism of action of such compounds.
Assuntos
Acridonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Tubulina (Proteína)/metabolismo , Acridonas/síntese química , Acridonas/química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
In our continuing search for medicinal agents to treat proliferative diseases, quinazoline derivatives were synthesized and evaluated pharmacologically as epithelial growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitors. A quantitative structure-activity relationship analysis was conducted to rationalize the structure-activity relationship and to predict how similar the inhibitor-binding profiles of two protein kinases are likely to be on the basis of the docking of lead coumpounds into the ATP-binding site. This model was used to direct the synthesis of new compounds. A series of N-(aromatic)-N'-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]phenyl}urea were identified as potent and selective inhibitors of the tyrosine kinase activity of VEGFR-2 (fetal liver kinase 1, kinase insert domain-containing receptor). An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. Substitution of diarylurea, competitive with ATP, afforded several analogues with low nanomolar inhibition of enzymatic activity of VEGFR-2. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of the series.
Assuntos
Antineoplásicos/síntese química , Relação Quantitativa Estrutura-Atividade , Quinazolinas/síntese química , Ureia/análogos & derivados , Ureia/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Quinazolinas/farmacologia , Ureia/farmacologiaRESUMO
A new class of potent farnesyltransferase inhibitors based on a 1,4-diazepane scaffold was synthesized with protein farnesyltransferase inhibition potencies in the low nanomolar range. The compounds block the growth on two hormone-resistant tumor prostatic cell lines (DU145 and PC3). The advanced cellular evaluation of the more potent farnesyltransferase inhibitors was explored and revealed a disorganization of tubulin in PC3 cells.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Azepinas/síntese química , Farnesiltranstransferase/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Moduladores de Tubulina/síntese química , Azepinas/farmacocinética , Azepinas/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Modelos Moleculares , Relação Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/ultraestrutura , Moduladores de Tubulina/farmacocinética , Moduladores de Tubulina/farmacologiaRESUMO
New N-alkylanilinoquinazoline derivatives 5, 12, 20, and 22 have been prepared from 4-chloro-6,7-dimethoxyquinazoline 3, 4-chloro-6,7-methylenedioxyquinazoline 19, and commercially available anilines. Differents classes of compounds substituted by an aryloxygroup (6a-c, 16a,b, and 17a,b), (aminophenyl)ureas (12a,b and 13a-f), anilines (4a-m, 20a,b), N-alkyl(aniline) (5a-m, 21a,b, 22a,d), and N-aminoalkyl(aniline) (22e-g) have been synthesized. These molecules were evaluated for their cytotoxic activities and as potential DNA intercalating agents. We studied the strength and mode of binding to DNA of these molecules by DNA melting temperature measurements, fluorescence emission, and circular dichroism. The results of various spectral and gel electrophoresis techniques obtained with the different compounds, in particular compounds 5g and 22f, revealed significant DNA interaction. These experiments confirm that the N-aminoalkyl(anilino)-6,7-dimethoxyquinazoline nucleus is an efficient pharmacophore to trigger binding to DNA, via an intercalative binding process.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , DNA/química , Substâncias Intercalantes/síntese química , Quinazolinas/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Ensaios de Seleção de Medicamentos Antitumorais , Fluorescência , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Conformação de Ácido Nucleico , Quinazolinas/química , Quinazolinas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Temperatura de TransiçãoRESUMO
The tyrosine kinase activity of the epidermal growth factor receptor (EGFR) is widely involved in signaling pathways and often deregulated in cancer. Its role in the development of prostate cancer is well established, and therapeutic strategies such as blockade of the intracellular tyrosine kinase domain with small-molecule tyrosine kinase inhibitors have been proposed. Herein we describe the synthesis and in vitro pharmacological properties of C6- and C7-substituted 4-anilinoquinazolines, analogues of Iressa and powerful proapoptotic inducers in hormone-independent prostate cancer PC3 cell lines.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Apoptose/fisiologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Gefitinibe , Humanos , Masculino , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/síntese química , Quinazolinas/síntese químicaRESUMO
A new series of FTase inhibitors containing a tricyclic moiety--dioxodibenzothiazepine or dibenzocycloheptane--has been designed and synthesized. Among them, dioxodibenzothiazepine 18d displayed significant inhibitory FTase activity (IC(50)=17.3 nM) and antiproliferative properties.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Humanos , Leucemia L1210 , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade , Sais de Tetrazólio , TiazóisRESUMO
Protein farnesyltransferase of Plasmodium falciparum is a potential target in the treatment of malaria for which increased drug resistance is observed. The design, synthesis and evaluation of a series of N-(4-piperidinyl)benzamides is reported. The most potent compounds showed in vitro activity against the parasite at submicromolar concentrations.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antimaláricos/síntese química , Antimaláricos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Animais , Antimaláricos/química , Benzamidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Relação Estrutura-AtividadeRESUMO
An assessment of structure-activity relationships associated with the new benzo[5,6]pyrrolizino[1,2-b]quinoline system displaying potent in vitro cytotoxic activity against the MCF7 cell line is described.