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1.
Oxf Med Case Reports ; 2017(2): omx002, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28473915

RESUMO

Common sites for metastatic spreading from breast cancer are bones, lungs and liver, the skeletal muscle being an unusual site. Although rare, when skeletal muscle metastases occur they are associated with a poor prognosis. These metastases are clinically difficult to diagnose since they can be found without pain symptoms. Radiologically, magnetic resonance imaging has been considered better than computed tomography for imaging of the muscles and has been the first procedure to use in case of muscle metastasis suspicion. In the last years, positron emission tomography (PET) with 18Fluorine-2-fluoro-2-deoxy-d-glucose (18F-FDG) has emerged as the main imaging tool. We here report a case of a hormone receptor-positive/human epidermal growth factor receptor 2-negative patient who presented with a recurrent infiltrating ductal carcinoma and diffuse skeletal muscle metastases detected by 18F-FDG-PET. The treatment of the patient with exemestane and everolimus led to a durable complete response.

2.
Urol Case Rep ; 9: 1-3, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27617210

RESUMO

Human heterophile antibodies may develop after infection or contact with animal tissues or animal serum products. These antibodies have the capacity to bind to the animal immunoglobulins used in immunoassays leading to erroneous results. We here report a case of a testicular germ cell tumor patient who developed heterophile antibodies during the surveillance period of his disease. Following false-positive results of human chorionic gonadotropin (hCG) he received unneeded chemotherapy. This article also stresses the problem of using serum tumor markers without no major imaging abnormalities to diagnose a patients' relapse.

3.
Curr Pharm Des ; 22(44): 6625-6644, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27587198

RESUMO

Despite the efficacy of most cancer therapies, drug resistance remains a major problem in the clinic. The eradication of the entire tumor and the cure of the patient by chemotherapy alone are rare, in particular for advanced disease. From an evolutionary perspective, the selective pressure exerted by chemotherapy leads to the emergence of resistant clones where resistance can be associated with many different functional mechanisms at the single cell level or can involve changes in the tumor micro-environment. In the last decade, tumor genomics has contributed to the improvement of our understanding of tumorigenesis and has led to the identification of numerous cellular targets for the development of novel therapies. However, since tumors are by nature extremely heterogeneous, the drug efficacy and economical sustainability of this approach is now debatable. Importantly, tumor cell heterogeneity depends not only on genetic modifications but also on non-genetic processes involving either stochastic events or epigenetic modifications making genetic biomarkers of uncertain utility. In this review, we wish to highlight how evolutionary biology can impact our understanding of carcinogenesis and resistance to therapies. We will discuss new approaches based on applied ecology and evolution dynamics that can be used to convert the cancer into a chronic disease where the drugs would control tumor growth. Finally, we will discuss the way metabolic dysfunction or phenotypic changes can help developing new delivery systems or phenotypetargeted drugs and how exploring new sources of active compounds can conduct to the development of drugs with original mechanisms of action.


Assuntos
Antineoplásicos/uso terapêutico , Evolução Biológica , Sistemas de Liberação de Medicamentos , Genótipo , Neoplasias/tratamento farmacológico , Fenótipo , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/genética , Neoplasias/patologia , Microambiente Tumoral
4.
Bull Cancer ; 103(10): 861-868, 2016 Oct.
Artigo em Francês | MEDLINE | ID: mdl-27641463

RESUMO

The concept of high-doses chemotherapy was developed in the 1980s based on in vitro scientific observations. Exposure of tumor cells to increasing concentrations of alkylating agents resulted in increased cell death in a strong dose-response manner. Moreover, the acquired resistance of tumor cells could be overcome by dose intensification. In clinic, dose intensification of alkylating agents resulted in increased therapeutic responses, however associated with significant hematological toxicity. Following the development of autologous stem cells transplantation harvesting from peripheral blood, the high-doses of chemotherapy, initially associated with marked toxic effects, could be more easily tolerated. As a result, the approach was evaluated in different types of solid tumors, including breast, ovarian and germ cell tumors, small cell lung carcinoma, soft tissue sarcomas and Ewing sarcoma. To date, high-doses chemotherapy with hematopoietic stem cells support is only used as a salvage therapy to treat poor prognosis germ cell tumors patients with chemo-sensitive disease. Regarding breast and ovarian cancer, high-doses chemotherapy should be considered only in the context of clinical trials. However, intensive therapy as an approach to overcome resistance to standard treatments is still relevant. Numerous efforts are still ongoing to identify novel therapeutic combinations and active treatments to improve patients' responses.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Neoplasias/tratamento farmacológico , Terapia de Salvação , Sarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
5.
J Chemother ; 28(6): 494-499, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27535294

RESUMO

INTRODUCTION: The active clinical research programme of trabectedin continues to improve knowledge on the therapeutic activity and toxicity of the drug in the treatment of soft tissue sarcomas (STS). In contrast, limited number of data is available on its use outside of clinical trials. PATIENTS AND METHODS: We retrospectively analysed efficacy and safety of trabectedin when given in daily practice to patients with advanced/recurrent STS. Outcomes were compared with previously published works including clinical and retrospective studies. RESULTS: Forty-five patients received trabectedin between January 2005 and May 2014. Sarcomas were histologically heterogeneous in our cohort (37.9% of other types of sarcomas than L-sarcomas). Our patients had poor baseline health status (ECOG ≥ 2 [17.8%]) and had received multiple previous lines of chemotherapy. Patients received a median of five cycles of treatment (1-22). The objective response rate was statistically superior in our study (37.8%) compared to the other works. However, median PFS was similar. Trabectedin-related serious adverse events (AEs) induced hospitalizations and treatment discontinuation in 22 and 15% of patients. CONCLUSION: This analysis confirms the efficacy of trabectedin in clinical practice (with a third of patients experiencing prolonged disease control) and highlighted the importance of its administration as early line therapy to allow the best management of serious AEs.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Intervalo Livre de Doença , França , Humanos , Estudos Retrospectivos , Sarcoma/diagnóstico , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina
6.
An Acad Bras Cienc ; 88 Suppl 1: 565-77, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27275646

RESUMO

It has now been 15 years since the HER2-targeted monoclonal antibody trastuzumab was introduced in clinical and revolutionized the treatment of HER2-positive breast cancer patients. Despite this achievement, most patients with HER2-positive metastatic breast cancer still show progression of their disease, highlighting the need for new therapies. The continuous interest in novel targeted agents led to the development of pertuzumab, the first in a new class of agents, the HER dimerization inhibitors. Pertuzumab is a novel recombinant humanized antibody directed against extracellular domain II of HER2 protein that is required for the heterodimerization of HER2 with other HER receptors, leading to the activation of downstream signalling pathways. Pertuzumab combined with trastuzumab plus docetaxel was approved for the first-line treatment of patients with HER2-positive metastatic breast cancer and is currently used as a standard of care in this indication. In the neoadjuvant setting, the drug was granted FDA-accelerated approval in 2013. Pertuzumab is also being evaluated in the adjuvant setting. The potential of pertuzumab relies in the dual complete blockade of the HER2/3 axis when administered with trastuzumab. This paper synthetises preclinical and clinical data on pertuzumab and highlights the mechanisms underlying the synergistic activity of the combination pertuzumab-trastuzumab which are essentially due to their complementary mode of action.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Trastuzumab/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Docetaxel , Feminino , Humanos , Receptor ErbB-2/antagonistas & inibidores , Taxoides/uso terapêutico
7.
Oncotarget ; 7(18): 25885-901, 2016 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-27029031

RESUMO

Trabectedin (Yondelis®, ecteinascidin-743, ET-743) is a marine-derived natural product approved for treatment of advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer. Lurbinectedin is a novel anticancer agent structurally related to trabectedin. Both ecteinascidins generate DNA double-strand breaks that are processed through homologous recombination repair (HRR), thereby rendering HRR-deficient cells particularly sensitive. We here characterize the DNA damage response (DDR) to trabectedin and lurbinectedin in HeLa cells. Our results show that both compounds activate the ATM/Chk2 (ataxia-telangiectasia mutated/checkpoint kinase 2) and ATR/Chk1 (ATM and RAD3-related/checkpoint kinase 1) pathways. Interestingly, pharmacological inhibition of Chk1/2, ATR or ATM is not accompanied by any significant improvement of the cytotoxic activity of the ecteinascidins while dual inhibition of ATM and ATR strongly potentiates it. Accordingly, concomitant inhibition of both ATR and ATM is an absolute requirement to efficiently block the formation of γ-H2AX, MDC1, BRCA1 and Rad51 foci following exposure to the ecteinascidins. These results are not restricted to HeLa cells, but are shared by cisplatin-sensitive and -resistant ovarian carcinoma cells. Together, our data identify ATR and ATM as central coordinators of the DDR to ecteinascidins and provide a mechanistic rationale for combining these compounds with ATR and ATM inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Carbolinas/farmacologia , Dioxóis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Antineoplásicos Alquilantes/farmacologia , Dano ao DNA/efeitos dos fármacos , Células HeLa , Humanos , Reparo de DNA por Recombinação/efeitos dos fármacos , Trabectedina
8.
Oncol Lett ; 11(3): 1859-1865, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26998090

RESUMO

The poor outcome of patients with recurrent ovarian cancer constitutes a continuous challenge for decision-making in clinical practice. In this setting, molecular targets have recently been identified, and novel compounds are now available. Bevacizumab has been introduced for the treatment of patients with ovarian cancer and is, to date, the most extensively investigated targeted therapy in this setting. However, potential toxicities are associated with the use of this monoclonal antibody. These toxicities have been reported in clinical trials, and can also be observed outside of trials. As limited data is currently available regarding the safety of bevacizumab treatment in daily clinical practice, the current retrospective study was designed to evaluate this. Data from 156 patients with recurrent ovarian cancer who had received bevacizumab treatment between January 2006 and June 2009 were retrospectively identified from the institutional records of five French centers. In contrast to clinical trials, the patients in the present study were not selected and had a heterogeneous profile according to their prior medical history, lines of treatment prior to bevacizumab introduction and number of relapses. The results first confirm the effect of heavy pretreatment on the occurrence of serious and fatal adverse events in clinical practice, as previously reported for clinical trials and for other retrospective cohort studies. Importantly, the data also demonstrates, for the first time, that medical history of hypertension is an independent predictive risk factor for the development of high-grade hypertension during bevacizumab treatment. These results thus suggest that treating physicians must consider all risk factors for managing bevacizumab toxicity prior to its introduction. Such risk factors include the time of bevacizumab introduction, a patient's history of hypertension and a low incidence of pre-existing obstructive disease.

9.
Chemotherapy ; 61(1): 15-22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26528705

RESUMO

BACKGROUND: Dose-intensive chemotherapy with hematopoietic stem cell transplantation has been evaluated as a salvage treatment for recurrent ovarian cancer, but its benefit has not yet been demonstrated. In a previous phase I trial, we reported the feasibility of administering topotecan as a salvage regimen. METHODS: Twenty-one patients were treated with escalating doses of topotecan associated with a fixed dose of cyclophosphamide. RESULTS: The maximum tolerated dose was established at 9.0 mg/m2 on a 5-day regimen, analogously to what was reported for topotecan monotherapy. One toxic death from septic shock and multiorgan failure occurred. Although hematopoietic toxicities were overcome by peripheral blood stem cell transplantation, superior nonhematological toxicities were observed as compared to the initial trial. CONCLUSION: Response rates were generally short and survival rates were poor. Results of the ITOV 01bis study demonstrate that, in the setting of recurrent ovarian cancer, intensive chemotherapy based on topotecan-cyclophosphamide association is not currently clinically indicated.


Assuntos
Adenocarcinoma de Células Claras/terapia , Adenocarcinoma Mucinoso/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cistadenocarcinoma Seroso/terapia , Neoplasias do Endométrio/terapia , Transplante de Células-Tronco Hematopoéticas , Neoplasias Ovarianas/terapia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Terapia Combinada , Ciclofosfamida/administração & dosagem , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Terapia de Salvação , Taxa de Sobrevida , Topotecan/administração & dosagem , Adulto Jovem
10.
Cell Cycle ; 14(13): 2080-90, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25945522

RESUMO

Repair of DNA-targeted anticancer agents is an active area of investigation of both fundamental and clinical interest. However, most studies have focused on a small number of compounds limiting our understanding of both DNA repair and the DNA damage response. S23906 is an acronycine derivative that shows strong activity toward solid tumors in experimental models. S23906 forms bulky monofunctional DNA adducts in the minor groove which leads to destabilization of the double-stranded helix. We now report that S23906 induces formation of DNA double strand breaks that are processed through homologous recombination (HR) but not Non-Homologous End-Joining (NHEJ) repair. Interestingly, S23906 exposure was accompanied by a higher sensitivity of BRCA2-deficient cells compared to other HR deficient cell lines and by an S-phase accumulation in wild-type (wt), but not in BRCA2-deficient cells. Recently, we have shown that S23906-induced S phase arrest was mediated by the checkpoint kinase Chk1. However, its activated phosphorylated form is equally induced by S23906 in wt and BRCA2-deficient cells, likely indicating a role for BRCA2 downstream of Chk1. Accordingly, override of the S phase arrest by either 7-hydroxystaurosporine (UCN-01) or AZD7762 potentiates the cytotoxic activity of S23906 in wt, but not in BRCA2-deficient cells. Together, our findings suggest that the pronounced sensitivity of BRCA2-deficient cells to S23906 is due to both a defective S-phase arrest and the absence of HR repair. Tumors with deficiencies for proteins involved in HR, and BRCA2 in particular, may thus show increased sensitivity to S23906, thereby providing a rationale for patient selection in clinical trials.


Assuntos
Acronina/análogos & derivados , Antineoplásicos Alquilantes/metabolismo , Proteína BRCA2/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Reparo do DNA/fisiologia , Acronina/metabolismo , Acronina/farmacologia , Animais , Antineoplásicos Alquilantes/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cricetinae , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/fisiologia , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos
11.
Mutat Res ; 753(2): 91-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23872363

RESUMO

Many alkylating agents are used as chemotherapeutic drugs and have a long history of clinical application. These agents inflict a wide range of DNA damage resulting in a complex cellular response. After DNA damage, cells trigger a series of signaling cascades promoting cellular survival and cell cycle blockage which enables time for DNA repair to occur. More recently, induction of autophagy has been observed in cancer cells after treatment with different DNA-targeted anticancer drugs, including alkylating agents. Several studies have demonstrated that induction of autophagy after DNA damage delays apoptotic cell death and may therefore lead to chemoresistance, which is the limiting factor for successful chemotherapy. On the other hand, depending on the extent of damage and the cellular context, the induction of autophagy may also contribute to cell death. Given these conflicting results, many studies have been conducted to better define the role of autophagy in cancer cells in response to chemotherapy. In this review, we describe the main alkylating agents used in clinical oncology as well as the cellular response they evoke with emphasis on autophagy.


Assuntos
Alquilantes/farmacologia , Autofagia/genética , Dano ao DNA , Alquilação , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos
12.
Cancer Chemother Pharmacol ; 70(4): 491-502, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22851206

RESUMO

The development of new strategies for cancer therapeutics is indispensable for the improvement of standard protocols and the creation of other possibilities in cancer treatment. Yeast models have been employed to study numerous molecular aspects directly related to cancer development, as well as to determine the genetic contexts associated with anticancer drug sensitivity or resistance. The budding yeast Saccharomyces cerevisiae presents conserved cellular processes with high homology to humans, and it is a rapid, inexpensive and efficient compound screening tool. However, yeast models are still underused in cancer research and for screening of antineoplastic agents. Here, the employment of S. cerevisiae as a model system to anticancer research is discussed and exemplified. Focusing on the important determinants in genomic maintenance and cancer development, including DNA repair, cell cycle control and epigenetics, this review proposes the use of mutant yeast panels to mimic cancer phenotypes, screen and study tumor features and synthetic lethal interactions. Finally, the benefits and limitations of the yeast model are highlighted, as well as the strategies to overcome S. cerevisiae model limitations.


Assuntos
Antineoplásicos/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Resistência a Medicamentos , Epigênese Genética , Humanos , Mutação , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética
13.
Carcinogenesis ; 33(8): 1433-40, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22431722

RESUMO

Adenosine diphosphate (ADP)-ribosylation is an important posttranslational modification catalyzed by a variety of enzymes, including poly (ADP ribose) polymerases (PARPs), which use nicotinamide adenine dinucleotide (NAD(+)) as a substrate to synthesize and transfer ADP-ribose units to acceptor proteins. The PARP family members possess a variety of structural domains, span a wide range of functions and localize to various cellular compartments. Among the molecular actions attributed to PARPs, their role in the DNA damage response (DDR) has been widely documented. In particular, PARPs 1-3 are involved in several cellular processes that respond to DNA lesions, which include DNA damage recognition, signaling and repair as well as local transcriptional blockage, chromatin remodeling and cell death induction. However, how these enzymes are able to participate in such numerous and diverse mechanisms in response to DNA damage is not fully understood. Herein, the DDR functions of PARPs 1-3 and the emerging roles of poly (ADP ribose) polymers in DNA damage are reviewed. The development of PARP inhibitors, their applications and mechanisms of action are also discussed in the context of the DDR.


Assuntos
Dano ao DNA , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/química , Conformação Proteica
14.
Mol Cancer Ther ; 10(8): 1481-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21622731

RESUMO

PM01183 is a novel marine-derived covalent DNA binder in clinical development. PM01183 is structurally similar to trabectedin (yondelis, ecteinascidin-743) except for the C subunit, and this modification is accompanied by different pharmacokinetics in cancer patients. We here characterize the interaction of PM01183 with the nucleotide excision repair (NER) pathway in comparison with trabectedin. Our results show for the first time that although neither PM01183 nor trabectedin is repaired by NER, both compounds are able to interfere with the NER machinery thereby attenuating the repair of specific NER substrates. We further show that the NER activity is increased in 3 of 4 cellular models with acquired resistance to cisplatin or oxaliplatin, confirming the involvement of NER in the resistance to platinum derivatives. Importantly, both PM01183 and trabectedin show unchanged or even enhanced activity toward all 4 cisplatin- and oxaliplatin-resistant cell lines. We finally show that combinations of PM01183 and cisplatin were mostly synergistic toward both parental and cisplatin-resistant ovarian carcinoma cells as indicated by Chou and Talalay analysis. These data show that the C subunit of trabectedin can be subjected to at least some structural modifications without loss of activity or NER interaction. While PM01183 and trabectedin appear functionally similar in cellular models, it is likely that the differences in pharmacokinetics may allow different dosing and scheduling of PM01183 in the clinic that could lead to novel and/or increased antitumor activity. Taken together, our results provide a mechanistic basis to support clinical trials of PM01183 alone or in combination with cisplatin.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Carbolinas/farmacologia , Cisplatino/farmacologia , Reparo do DNA/efeitos dos fármacos , Dioxóis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/metabolismo , Carbolinas/química , Linhagem Celular Tumoral , Cromatina/metabolismo , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Dioxóis/química , Dioxóis/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Células HCT116 , Células HT29 , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/metabolismo , Trabectedina , Raios Ultravioleta/efeitos adversos
15.
Biochem J ; 437(1): 63-73, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21470188

RESUMO

Numerous anticancer agents and environmental mutagens target DNA. Although all such compounds interfere with the progression of the replication fork and inhibit DNA synthesis, there are marked differences in the DNA-damage response pathways they trigger, and the relative impact of the proximal or the distal signal transducers on cell survival is mainly lesion-specific. Accordingly, checkpoint kinase inhibitors in current clinical development show synergistic activity with some DNA-targeting agents, but not with others. In the present study, we characterize the DNA-damage response to the antitumour acronycine derivative S23906, which forms monofunctional adducts with guanine residues in the minor groove of DNA. S23906 exposure is accompanied by specific recruitment of RPA (replication protein A) at replication sites and rapid Chk1 activation. In contrast, neither MRN (Mre11-Rad50-Nbs1) nor ATM (ataxia-telangiectasia mutated), contributes to the initial response to S23906. Interestingly, genetic attenuation of ATR (ATM- and Ras3-related) activity inhibits not only the early phosphorylation of histone H2AX and Chk1, but also interferes with the late phosphorylation of Chk2. Moreover, loss of ATR function or pharmacological inhibition of the checkpoint kinases by AZD7762 is accompanied by abrogation of the S-phase arrest and increased sensitivity towards S23906. These findings identify ATR as a central co-ordinator of the DNA-damage response to S23906, and provide a mechanistic rationale for combinations of S23906 and similar agents with checkpoint abrogators.


Assuntos
Acronina/análogos & derivados , Antineoplásicos Alquilantes/farmacologia , Proteínas de Ciclo Celular/fisiologia , Dano ao DNA , Mutação , Proteínas Serina-Treonina Quinases/fisiologia , Acronina/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinase 1 do Ponto de Checagem , Quinase do Ponto de Checagem 2 , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HeLa , Histonas/metabolismo , Humanos , Proteína Homóloga a MRE11 , Microscopia de Fluorescência , Proteínas Nucleares/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteína de Replicação A/metabolismo , Tiofenos/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia
16.
Biochem Pharmacol ; 80(3): 335-43, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20399198

RESUMO

S23906 belongs to a novel class of alkylating anticancer agents forming bulky monofunctional DNA adducts. A unique feature of S23906 is its "helicase-like" activity leading to the destabilization of the surrounding duplex DNA. We here characterize the recognition and repair of S23906 adducts by the nucleotide excision repair (NER) machinery. All NER-deficient human cell lines tested showed increased sensitivity to S23906, which was particularly pronounced for cells deficient in XPC, CSB and XPA. In comparison, deficiencies in ERCC1 or XPF had lesser impact on the sensitivity to S23906. The sensitivity was, at least in part, linked to the conversion of unrepaired adducts into toxic DNA strand breaks as shown by single cell electrophoresis and gamma-H2AX formation. The pharmacological relevance of these findings was confirmed by the characterization of KB carcinoma cells with acquired S23906 resistance. These cells showed increased NER activity in vivo as well as toward damaged plasmid DNA in vitro. In particular, both global genome NER, as shown by unscheduled DNA synthesis, and transcription-coupled NER, as shown by transcriptional recovery, were up-regulated in the S23906-resistant cells. The increased NER activity was accompanied by up to 5-fold up-regulation of XPC, CSB and XPA proteins without detectable alterations of ERCC1 on the DNA, RNA or protein levels. Our results suggest that S23906 adducts are recognized and repaired by both NER sub-pathways in contrast to other members of this class, that are only recognized by transcription-coupled NER. We further show that NER activity can be up-regulated without changes in ERCC1 expression.


Assuntos
Acronina/farmacologia , Antineoplásicos Alquilantes/metabolismo , DNA Helicases/fisiologia , Enzimas Reparadoras do DNA/fisiologia , Proteínas de Ligação a DNA/fisiologia , DNA/metabolismo , Endonucleases/fisiologia , Acronina/metabolismo , Alquilantes/química , Alquilantes/metabolismo , Antineoplásicos Alquilantes/química , Sítios de Ligação/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Adutos de DNA/metabolismo , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos/deficiência , Receptores Nucleares Órfãos/fisiologia , Proteínas de Ligação a Poli-ADP-Ribose , Xeroderma Pigmentoso/metabolismo
17.
Biochem Pharmacol ; 79(2): 147-53, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19712668

RESUMO

5-Fluorouracil (5-FU) is an antitumor antimetabolite that can be converted into fluoronucleotides and FdUMP. Fluoronucleotides are incorporated into DNA and RNA, while FdUMP results in nucleotide pool imbalance. Saccharomyces cerevisiae is unable to convert 5-FU into FdUMP, making yeast a unique model system to study the cellular effects of 5-FU and FdUMP independently. A panel of repair-deficient yeast strains was used to identify the DNA repair pathways needed for repair of lesions generated by 5-FU or FdUMP. This included yeast deficient in base excision repair (BER), nucleotide excision repair (NER), translesion synthesis (TLS), mismatch repair (MMR), post-replication repair (PRR), homologous recombination (HR) and non-homologous end-joining (NHEJ). The results revealed an important role of BER, since BER-mutants (ntg1, ntg2, apn1, apn2) showed pronounced sensitivity to both 5-FU and FdUMP. MMR mutants also showed high sensitivity to both compounds. In contrast, deficiencies in NER, NHEJ and TLS repair had only minor influence on the sensitivity to FU and FdUMP. Interestingly, deficiencies in HR (rad52) and PPR (rad6, rad18) were associated with increased sensitivity to 5-FU, but not to FdUMP. Taken together, our study reveals an important contribution of DNA repair pathways on the sensitivity to 5-FU and its active metabolite FdUMP. Importantly, the repair mechanisms differed for the 2 antimetabolites since lesions induced by 5-FU were repaired by BER, MMR, HR and PRR, while only BER and MMR were required for repair of FdUMP-induced lesions.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Reparo do DNA , Fluoruracila/efeitos adversos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento
18.
J Agric Food Chem ; 51(4): 1077-80, 2003 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-12568575

RESUMO

The antioxidant capacity of butylated hydroxytoluene (BHT; 2,6-di-tert-butyl-p-cresol), propyl gallate (3,4,5-trihydroxybenzoic acid n-propyl ester), resveratrol (trans-3,4',5-trihydroxystilbene), and vitamins C (l-ascorbic acid) and E [(+)-alpha-tocopherol] was studied in chemical and biological systems. The chemical assays evaluated the capacity of these antioxidants to sequester 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS.) and 1,1 diphenyl-2-picrylhydrazyl (DPPH.). A new colorimetric method to determine hydroxyl radical scavenging is also described. The biological tests use the eucaryotic cells of Saccharomyces cerevisiae treated with the antioxidants in the presence of the stressing agents apomorphine, hydrogen peroxide, and paraquat dichloride (methylviologen; 1,1'-dimethyl-4,4'-bipyridinium dichloride). The results in chemical systems showed that all of the antioxidants were able to significantly inhibit the oxidation of beta-carotene by hydroxyl free radicals. The assays in yeast showed that the antioxidant activity of the tested compounds depended on the stressing agent used and the mechanism of action of the antioxidant.


Assuntos
Antioxidantes/química , Ácido Ascórbico/química , Hidroxitolueno Butilado/química , Galato de Propila/química , Estilbenos/química , Vitamina E/química , Antioxidantes/farmacologia , Apomorfina/farmacologia , Benzotiazóis , Compostos de Bifenilo , Peróxido de Hidrogênio/farmacologia , Radical Hidroxila/química , Oxirredução , Paraquat/farmacologia , Picratos/química , Resveratrol , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Ácidos Sulfônicos/química , beta Caroteno/química
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