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1.
Reproduction ; 146(6): 615-23, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24062569

RESUMO

Potassium voltage-gated channel, subfamily H (eag-related), member 1 (KCNH1) potassium channels are potential tumour markers and cancer therapeutic targets and are up-regulated by oestrogens and human papilloma virus (HPV) oncogenes. However, the role of KCNH1 in normal tissues is poorly understood, and its expression in pregnancy is unknown. We wondered whether KCNH1 channels are expressed in cervical cells from pregnant patients and whether progesterone (P4) regulates KCNH1. The association with HPV was also investigated. KCNH1 protein expression was studied by immunocytochemistry in liquid-based cervical cytologies; 93 samples were obtained from pregnant patients at different trimesters, and 15 samples were obtained from non-pregnant women (controls). The presence of HPV was studied by PCR with direct sequencing and nested multiplex PCR. HeLa cervical cancer cells were transfected with human progesterone receptor-B (PR-B) and treated with P4. KCNH1 mRNA expression in these cultures was studied by real-time PCR. KCNH1 protein was detected in 100% of the pregnancy samples and in 26% of the controls. We found 18 pregnant patients infected with HPV and detected 14 types of HPV. There was no association between the percentage of cells expressing KCNH1 and either the presence or type of HPV. P4 induced KCNH1 mRNA and protein expression in cells transfected with human PR-B. No regulation of KCNH1 by P4 was observed in non-transfected cells. We show for the first time the expression of an ion channel during human pregnancy at different trimesters and KCNH1 regulation by P4 in human cells. These data raise a new research field for KCNH1 channels in human tissues.


Assuntos
Colo do Útero/metabolismo , Canais de Potássio Éter-A-Go-Go/genética , Gravidez/genética , Progesterona/farmacologia , Adolescente , Adulto , Colo do Útero/efeitos dos fármacos , Colo do Útero/patologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Papillomaviridae/isolamento & purificação , Gravidez/metabolismo , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/genética , Complicações Infecciosas na Gravidez/metabolismo , Receptores de Progesterona/genética , Esfregaço Vaginal , Adulto Jovem
2.
Ann Oncol ; 12(4): 541-7, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11398890

RESUMO

BACKGROUND: Cisplatin-based chemoradiation for locally advanced cervical carcinoma is now the standard of care for most patients with cervical carcinoma. However, induction chemotherapy followed by surgery, particularly with newer agents or combinations remains to be explored. This study was undertaken to evaluate the antitumor activity and toxicity of gemcitabine in combination with cisplatin for untreated locally advanced cervical carcinoma. PATIENTS AND METHODS: Open-label, single center, phase II, non-randomized study of neoadjuvant gemcitabine plus cisplatin. Forty-one patients with histologic diagnosis of cervical carcinoma, with no previous treatment and staged as IB2 to IIIB, were treated with three 21-day courses of cisplatin 100 mg/m2 day I and gemcitabine 1000 mg/m2 days 1 and 8, followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated before each course and at the end of chemotherapy. RESULTS: All patients were evaluated for toxicity and 40 for response. The overall objective response rate was 95% (95% confidence interval (CI): 88%-100%) being complete in 3 patients (7.5%) and partial in 35 (87.5%). A complete pathological response was found in 6 (26%) of the 23 patients that underwent surgery. Granulocytopenia grades 3-4 occurred in 13.8% and 3.4% of the courses, respectively, whereas non-hematological toxicity was mild. CONCLUSIONS: Induction chemotherapy with the combination of gemcitabine and cisplatin is highly active for untreated cervical cancer patients and has an acceptable toxicity profile.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Carcinoma Adenoescamoso/mortalidade , Carcinoma Adenoescamoso/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Gencitabina
3.
Drug Metab Dispos ; 22(4): 503-10, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7956722

RESUMO

2-Br-(diglutathion-S-yl)hydroquinone (2-Br-(diGSyl)HQ) is a potent nephrotoxicant, causing glucosuria, enzymuria, proteinuria, elevations in blood urea nitrogen, and severe histological alterations to renal proximal tubules at doses of 10-15 mumol/kg. In contrast, 2-Br-3-(glutathion-S-yl)hydroquinone (2-Br-3-(GSyl)HQ) is substantially less nephrotoxic than 2-Br-(diGSyl)HQ and requires a dose of at least 50 mumol/kg to cause modest elevations in blood urea nitrogen concentrations. The reason or reasons for this difference in potency is unclear, but since inhibition of renal gamma-glutamyl transpeptidase (gamma-GT) prevents 2-Br-(diGSyl)HQ-mediated nephrotoxicity, metabolism of these conjugates by the kidney must play an important role. To address this question we have compared the metabolism and toxicity of 2-Br-(diGSyl)HQ and 2-Br-3-(GSyl)HQ in the in situ perfused rat kidney (ISPRK). Following infusion of 20 mumol 2-Br-3-(GSyl)HQ into the right renal artery of male Sprague Dawley rats, a total of 23.5 +/- 1.9% (mean +/- SE) of the dose was accounted for in urine and bile over a period of 180 min. 2-Bromo-3-(cystein-S-yl)hydroquinone and 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone were identified in urine, and unchanged 2-Br-3-(GSyl)HQ was identified in urine and bile. The product arising from the oxidative cyclization of 2-bromo-3-(cystein-S-glycine)hydroquinone, 2H-(3-glycine)-7-hydroxy-8-bromo-1,4-benzothiazine, was also identified in urine.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Glutationa/análogos & derivados , Hidroquinonas/metabolismo , Hidroquinonas/toxicidade , Nefropatias/induzido quimicamente , Rim/metabolismo , Animais , Glutationa/metabolismo , Glutationa/toxicidade , Rim/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Perfusão , Ratos , Ratos Sprague-Dawley
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