RESUMEN
: The treatment of advanced non-small cell lung cancer (NSCLC) has been revolutionized by immune checkpoint inhibitors (ICIs). The identification of prognostic and predictive factors in ICIs-treated patients is presently challenging. Circulating tumor cells (CTCs) and cell-free DNA (cfDNA) were evaluated in 89 previously treated NSCLC patients receiving nivolumab. Blood samples were collected before therapy and at the first and second radiological response assessments. CTCs were isolated by a filtration-based method. cfDNA was extracted from plasma and estimated by quantitative PCR. Patients with baseline CTC number and cfDNA below their median values (2 and 836.5 ng from 3 mL of blood and plasma, respectively) survived significantly longer than those with higher values (p = 0.05 and p = 0.04, respectively). The two biomarkers were then used separately and jointly as time-dependent covariates in a regression model confirming their prognostic role. Additionally, a four-fold risk of death for the subgroup presenting both circulating biomarkers above the median values was observed (p < 0.001). No significant differences were found between circulating biomarkers and best response. However, progressing patients with concomitant lower CTCs and cfDNA performed clinically well (p = 0.007), suggesting that jointed CTCs and cfDNA might help discriminate a low-risk population which might benefit from continuing ICIs beyond progression.
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Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk.
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Nicotine exerts its oncogenic effects through the binding to nicotinic acetylcholine receptors (nAChRs) and the activation of downstream pathways that block apoptosis and promote neo-angiogenesis. The nAChRs of the α7 subtype are present on a wide variety of cancer cells and their inhibition by cobra venom neurotoxins has been proposed in several articles and reviews as a potential innovative lung cancer therapy. However, since part of the published results was recently retracted, we believe that the antitumoral activity of cobra venom neurotoxins needs to be independently re-evaluated.We determined the activity of α-neurotoxins from Naja atra (short-chain neurotoxin, α-cobrotoxin) and Naja kaouthia (long-chain neurotoxin, α-cobratoxin) in vitro by cytotoxicity measurements in 5 lung cancer cell lines, by colony formation assay with α7nAChRs expressing and non-expressing cell lines and in vivo by assessing tumor growth in an orthotopic Non-Obese Diabetic/Severe Combined Immunodeficient (NOD/SCID) mouse model system utilizing different treatment schedules and dosages.No statistically significant reduction in tumor growth was observed in the treatment arms in comparison to the control for both toxins. Paradoxically α-cobrotoxin from Naja atra showed the tendency to enhance tumor growth although, even in this case, the statistical significance was not reached.In conclusion our results show that, in contrast with other reports, the nAChR inhibitors α-cobratoxin from N. kaouthia and α-cobrotoxin from N. atra neither suppressed tumor growth nor prolonged the survival of the treated animals.
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Proteínas Neurotóxicas de Elápidos/toxicidad , Venenos Elapídicos/toxicidad , Neoplasias Pulmonares/tratamiento farmacológico , Receptores Nicotínicos/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Células Clonales , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Mediciones Luminiscentes , Ratones , Pruebas de Toxicidad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
The cytotoxicity in vitro and antitumor activity in vivo of the organotin compound tri-n-butyltin(IV)lupinylsulfide hydrogen fumarate (IST-FS 35) have been investigated. The IC50 values obtained in a panel of tumor cell lines were compared to those of the parental compound IST-FS 29 in the same cells. IST-FS 35 resulted significantly more active than IST-FS 29 with IC50 values in the range 0.16-1.8 microM. Toxicity studies in vivo, after intravenous administration of escalating concentrations of IST-FS 35, provided the identification of the maximal tolerated dose (3.5 mg/kg) which was employed as therapeutic dose in the antitumor activity experiments. Preliminary results, in transplanted murine tumor models, revealed that both the P388 myelomonocytic leukaemia and the B16-F10 melanoma, implanted subcutaneously in BDF1 mice, were inhibited about 96% in their tumor volume at day 11, following a single intravenous injection of the compound. Additional studies are mandatory to unravel the mechanism of action for the development of IST-FS 35 as potential antitumor drug.
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Antineoplásicos/uso terapéutico , Compuestos Orgánicos de Estaño/uso terapéutico , Animales , Línea Celular Tumoral , Femenino , Humanos , Concentración 50 Inhibidora , Leucemia P388 , Dosis Máxima Tolerada , Melanoma Experimental , Ratones , Compuestos Orgánicos de Estaño/efectos adversos , Compuestos Orgánicos de Estaño/química , Compuestos de Trietilestaño/química , Compuestos de Trietilestaño/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Forty-four evaluable patients with intracranial meningiomas were assessed for the expression of the cell-cycle regulator cyclin D1 and of proteins involved in proliferation and apoptosis such as PCNA, MIB-1, p53 and bcl-2. Analyses were carried out by western blot and immunohistochemistry after immediate processing of fresh tumor specimens. By western blot, expression of cyclin D1 significantly correlated with p53 (p=0.02) and with proliferative activity, as assessed by PCNA expression (p=0.0009). By immunohistochemistry, a significant relationship between cyclin D1 and the proliferation marker MIB-1 was confirmed (p=0.05), whereas significance with bcl-2 expression was not found (p=0.01). Moreover, although the association with tumor grade appeared of borderline statistical significance (p=0.07), all the grade II/III meningiomas showed increased expression of cyclin D1 and high proliferative activity. In conclusion, data from this preliminary study seem to suggest a potential value of the combined expression of cyclin D1 and proliferation indicators in defining subgroups of meningiomas with a more aggressive biological behavior.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Ciclina D1/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Meningioma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Índice de Severidad de la Enfermedad , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
OBJECTIVE: In order to assess the prognostic role of the cell-cycle regulator cyclin D1 in epithelial ovarian cancer, 70 patients have been studied during an observation period of 8 years. METHODS: The cyclin D1 protein content was analyzed by Western blotting, and classed as negative, positive and highly positive by densitometric scanning. The relationship between cyclin D1 expression and clinicopathological variables was determined. Univariate and multivariate survival analyses were also carried out. RESULTS: Patients with highly positive cyclin D1 tumors had shorter overall survival than patients with positive cyclin D1 (median survival 31 vs. 49 months; p = 0.058). Furthermore, in patients with stage III/IV tumors and residual disease greater than 2 cm, cyclin D1 expression significantly influenced clinical outcome (p = 0.047 and 0.040, respectively). In the Cox's regression model, cyclin D1 expression and residual disease were identified as the most important predictors of survival (p = 0.016 and 0.002, respectively). In patients with high cyclin D1 expression and residual disease after debulking surgery greater than 2 cm, the relative risks of death were to 2.48 and 3.7, respectively, compared to their correspondent counterparts. CONCLUSION: The overexpression of cyclin D1 is significantly related to a more aggressive tumor phenotype and poor prognosis in ovarian carcinoma.
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Biomarcadores de Tumor/análisis , Carcinoma/química , Carcinoma/mortalidad , Ciclina D1/análisis , Neoplasias Ováricas/química , Neoplasias Ováricas/mortalidad , Análisis de Varianza , Western Blotting , Carcinoma/patología , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/patología , Valor Predictivo de las Pruebas , Pronóstico , Análisis de Supervivencia , Regulación hacia ArribaRESUMEN
The development of multidrug-resistance (MDR) in neoplastic cells is often responsible for the therapy failure and poor outcome of a number of human cancers. MDR may be associated with the expression of the multidrug transporter glycoprotein p170, encoded by the MDR1 gene, which acts as an ATP-dependent efflux pump by reducing the intracellular accumulation of some cytotoxic agents. A variety of iminodibenzyl and phenothiazine derivatives, characterized by the presence of a bicyclic, strongly basic, and highly lipophilic quinolizidine nucleus, were synthesized to investigate their ability to modulate the MDR phenotype. A set of 10 of them (named 1-10), bearing quinolizidine moiety linked through different connecting chains, were tested as chemoresistance-reversing agents on doxorubicin-resistant ovarian cancer cells (A2780-DX3). A 51-fold resistance to doxorubicin was reported in the A2780-DX3 compared to the parental sensitive A2780 WT with mean IC(50) values of 0.02 and 1.02 muM, respectively. Moreover, overexpression of the glycoprotein p170 in the resistant cell line was detected by Western blot analysis. By cytotoxicity assays and time-course experiments, different treatment schedules with resistance modulators (including clomipramine as reference drug) and doxorubicin were taken into account. The 16 h exposure of cells to 1 muM of modulator before doxorubicin demonstrated to be superior in sensitizing the resistant cell line. In particular, compounds 8, 7, 10, and 4 increasingly potentiated doxorubicin cytotoxicity, up to 5.6-fold in A2780-DX3 cells. The present results suggest promising indications for further development of these compounds as chemosensitizing drugs.
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Bencilaminas/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Fenotiazinas/farmacología , Quinolizinas/farmacología , Bencilaminas/química , Bencilaminas/uso terapéutico , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Resistencia a Múltiples Medicamentos/fisiología , Femenino , Humanos , Neoplasias Ováricas/metabolismo , Fenotiazinas/química , Fenotiazinas/uso terapéutico , Quinolizinas/química , Quinolizinas/uso terapéuticoRESUMEN
Sigma receptors, namely sigma1 and sigma2, have been shown to be expressed in a variety of human cell lines playing a role in cell growth. In the human breast, they are absent in normal mammary tissue but expressed in tumors, particularly in the proliferating stage. The study presented here concerns nine newly synthesized ligands for sigma receptors. The compounds are of general structure consisting of: five (1alpha/1beta-arylalkyl)quinolizidines including two thioisosteres and four spiro-[3,4-dihydro-1,2,4-benzotriazino-3,4'-(1'-substituted) piperidines]. These compounds exhibited varying degrees of affinity for sigma receptors and were able to inhibit the growth of MCF-7 and MDA-MB 231 human breast cancer cell lines, in vitro. Good to moderate binding to at receptors occurred with all tested ligands. However, affinity for sigma2 appeared more evident with compounds FN/C-2 and FN/C-4 (spiro-[3,4-dihydro-1,2,4-benzotriazino-3,4'-(1'-substituted) piperidines] derivatives). In addition, higher cytotoxic activity of FN/C-2 and FN/C-4 with IC50 values below 100 microM in MCF-7 and lower than 40 microM in MDA-MB 231 was revealed. The data from the current study show that these novel sigma receptor ligands exhibit interesting cytotoxic activity and suggest their potential for development as antitumor agents.
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Neoplasias de la Mama/metabolismo , Inhibidores de Crecimiento/metabolismo , Receptores sigma/metabolismo , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores de Crecimiento/farmacología , Inhibidores de Crecimiento/uso terapéutico , Humanos , LigandosRESUMEN
The toxicity and antitumor activity of the novel organotin compound triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29), administered by the oral route, have been evaluated against three transplantable murine tumor models: P388 lymphocytic leukemia, B16F10 melanoma and 3LL Lewis lung carcinoma. Mild and reversible signs of acute toxicity such as behavioral symptoms, weight loss and histological alterations were mainly reported at the highest single dose of 28 mg/kg. Conversely, lower concentrations of compound ranging from 7 to 21 mg/kg did not result in major toxic effects, even after repeated dosing. The antitumor activity studies showed that fractionation dosing, rather than single bolus administration, over 1 week, might prove more active and better tolerated by allowing the achievement of the highest therapeutic total dose of IST-FS 29 (42 mg/kg). Indeed, repeated administrations of IST-FS 29 resulted in marked significant improvement of antitumor activity against B16F10 (50% of tumor volume inhibition, p = 0.0003) and, to a greater extent, 3LL (90% of tumor volume inhibition, p = 0.0001) tumors. These results indicate that IST-FS 29 might be a suitable candidate as an orally administrable anticancer drug and support its further development in human tumor xenografts.
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Antineoplásicos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Compuestos Orgánicos de Estaño/farmacología , Compuestos de Trietilestaño/farmacología , Animales , Antineoplásicos/toxicidad , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Femenino , Leucemia P388/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Trasplante de Neoplasias , Neoplasias Experimentales/patología , Compuestos Orgánicos de Estaño/toxicidad , Compuestos de Trietilestaño/toxicidad , Células Tumorales CultivadasRESUMEN
Malignant gliomas are the most common primary brain tumors in humans. However, poor response to conventional therapeutic approaches, including chemotherapy, leads invariably to disease recurrence and progression. The organo-tin derivative triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29) was identified and developed as potential antiproliferative agent in human cancer cell lines. However, for its peculiar chemical structure and good lipophilicity, this compound also appeared an eligible candidate for the treatment of gliobastoma cells. The present experiments were designed to explore the in vitro effects of IST-FS 29 on four human glioblastoma cell lines: A-172, DBTRG.05MG, U-87MG and CAS-1. The average IC50 values were obtained by MTT assay and ranged between 3 and 10 microM. Time-course assays with cell recovery after drug withdrawal, demonstrated marked cytotoxicity following exposure to IST-FS 29 for 8, 24 and 72 h. Cultures treated for 8 h were able to partially re-grow by 144 h; on the contrary, longer times of exposure did not allow surviving cells to recover from the damage and actively proliferate. Cell morphology of cultures exposed to IST-FS 29 was assessed by inverted light microscopy after 24 and 72 h and was more consistent with cell death by necrosis which included cell size reduction, vacuolation of cytoplasm, round dying cells. The present results and our previous data, in vitro and in vivo, indicate the relevant cytotoxic activity of this organo-tin compound and suggest that IST-FS 29 might be a promising novel agent to be developed for the treatment of malignant brain neoplasms.
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Antineoplásicos/farmacología , Neoplasias Encefálicas , Glioblastoma , Compuestos de Trietilestaño/farmacología , Calcio/metabolismo , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas/citología , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismoAsunto(s)
Humanos , Masculino , Femenino , Historia de la Medicina , Higiene/educación , Higiene/historia , Higiene/normasAsunto(s)
Masculino , Femenino , Humanos , Historia de la Medicina , Higiene/educación , Higiene/historia , Higiene/normasRESUMEN
O presente documento apresenta os resultados da Avaliaçäo do Curso de Nutriçäo da PUCCAMP, realizada por meio de aplicaçäo de questionário aos alunos do 4- ano e discussäo desses resultados com o grupo pesquisado, e as propostas levantadas para a Reestruturaçäo do Currículo. Em anexo há o documento elaborado pelos alunos a partir das discussöes