RESUMEN
OBJECTIVE: Although highly successful, the medical R&D model is failing at improving people's health due to a series of flaws and defects inherent to the model itself. A new collective intelligence, incorporating human and artificial intelligence (AI) could overcome these obstacles. Because AI will play a key role in this new collective intelligence, it is necessary that those involved in healthcare have a general knowledge of how these technologies work. With this comprehensive review, we intend to provide it. MATERIALS AND METHODS: A broad-ranging search has been undertaken on institutional and non-institutional websites in order to identify relevant papers, comments and reports. RESULTS: We firstly describe the flaws and defects of the current R&D biomedical model and how the generation of a new collective intelligence will result in a better and wiser medicine through a truly personalized and holistic approach. We, then, discuss the new forms of data collection and data processing and the different types of artificial learning and their specific algorithms. Finally, we review the current uses and applications of AI in the biomedical field and how these can be expanded, as well as the limitations and challenges of applying these new technologies in the medical field. CONCLUSIONS: This colossal common effort based on a new collective intelligence will exponentially improve the quality of medical research, resulting in a radical change for the better in the healthcare model. AI, without replacing us, is here to help us achieve the ambitious goal set by the WHO in the Alma Ata declaration of 1978: "Health for All".
Asunto(s)
Inteligencia Artificial/tendencias , Diagnóstico por Computador/tendencias , Desarrollo de Medicamentos/tendencias , Descubrimiento de Drogas/tendencias , Terapia Asistida por Computador/tendencias , Toma de Decisiones Clínicas , Técnicas de Apoyo para la Decisión , Difusión de Innovaciones , Predicción , HumanosRESUMEN
BACKGROUND: PM01183 is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. PM01183 showed strong antitumor activity in preclinical models of cisplatin-resistant epithelial ovarian cancer. PATIENTS AND METHODS: Patients with platinum-resistant/refractory ovarian cancer were included in a two-stage, controlled, randomized (in a second stage), multicenter, phase II study. Primary endpoint was overall response rate (ORR) by RECIST and/or GCIG criteria. The exploratory first stage (n = 22) confirmed the activity of PM01183 as a single agent at 7.0 mg flat dose every 3 weeks (q3wk). The second stage (n = 59) was randomized and controlled with topotecan on days 1-5 q3wk or weekly (every 4 weeks, q4wk). RESULTS: ORR was 23% (95% CI, 13%-37%) for 52 PM01183-treated patients. Median duration of response was 4.6 months (95% CI, 2.5-6.9 months), and 23% (95% CI, 0%-51%) of responses lasted 6 months or more. Ten of the 12 confirmed responses were reported for 33 patients with platinum-resistant disease [ORR = 30% (95% CI, 16%-49%)]; for the 29 patients treated with topotecan in the second stage, no responses were found. Median PFS for all PM01183-treated patients was 4.0 months (95% CI, 2.7-5.6 months), and 5.0 months (95% CI, 2.7-6.9 months) for patients with platinum-resistant disease. Grade 3/4 neutropenia in 85% of patients; febrile neutropenia in 21% and fatigue (grade 3 in 35%) were the principal safety findings for PM01183. CONCLUSION: PM01183 is an active drug in platinum-resistant/refractory ovarian cancer and warrants further development. The highest activity was observed in platinum-resistant disease. Its safety profile indicates the dose should be adjusted to body surface area (mg/m2). TRIAL CODE: EudraCT 2011-002172-16.
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Antineoplásicos/uso terapéutico , Carbolinas/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Topotecan/uso terapéutico , Anciano , Femenino , HumanosRESUMEN
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive disease, that can be described as a member of the family of small round blue cell tumors. The molecular diagnostic marker is the t(11;22)(p13;q12) translocation, which creates an aberrant transcription factor, EWS-WT1, that underlies the oncogenesis of DSRCT. Current treatments are not very effective so new active drugs are needed. Trabectedin, now used as a single agent for the treatment of soft tissue sarcoma, was reported to be active in some pre-treated DSRCT patients. Using JN-DSRCT-1, a cell line derived from DSRCT expressing the EWS-WT1 fusion protein, we investigated the ability of trabectedin to modify the function of the chimeric protein, as in other sarcomas expressing fusion proteins. After detailed characterization of the EWS-WT1 transcripts structure, we investigated the mode of action of trabectedin, looking at the expression and function of the oncogenic chimera. METHODS: We characterized JN-DSRCT-1 cells using cellular approaches (FISH, Clonogenicity assay) and molecular approaches (Sanger sequencing, ChIP, GEP). RESULTS: JN-DSRCT-1 cells were sensitive to trabectedin at nanomolar concentrations. The cell line expresses different variants of EWS-WT1, some already identified in patients. EWS-WT1 mRNA expression was affected by trabectedin and chimeric protein binding on its target gene promoters was reduced. Expression profiling indicated that trabectedin affects the expression of genes involved in cell proliferation and apoptosis. CONCLUSIONS: The JN-DSRCT-1 cell line, in vitro, is sensitive to trabectedin: after drug exposure, EWS-WT1 chimera expression decreases as well as binding on its target promoters. Probably the heterogeneity of chimera transcripts is an obstacle to precisely defining the molecular mode of action of drugs, calling for further cellular models of DSRCT, possibly growing in vivo too, to mimic the biological complexity of this disease.
Asunto(s)
Tumor Desmoplásico de Células Pequeñas Redondas/tratamiento farmacológico , Dioxoles/farmacología , Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Tumor Desmoplásico de Células Pequeñas Redondas/metabolismo , Tumor Desmoplásico de Células Pequeñas Redondas/fisiopatología , Dioxoles/uso terapéutico , Humanos , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN , Tetrahidroisoquinolinas/uso terapéutico , Trabectedina , Proteínas WT1RESUMEN
BACKGROUND: In order to investigate the mechanisms of acquired resistance to trabectedin, trabectedin-resistant human myxoid liposarcoma (402-91/T) and ovarian carcinoma (A2780/T) cell lines were derived and characterised in vitro and in vivo. METHODS: Resistant cell lines were obtained by repeated exposures to trabectedin. Characterisation was performed by evaluating drug sensitivity, cell cycle perturbations, DNA damage and DNA repair protein expression. In vivo experiments were performed on A2780 and A2780/T xenografts. RESULTS: 402-91/T and A2780/T cells were six-fold resistant to trabectedin compared with parental cells. Resistant cells were found to be hypersensitive to UV light and did not express specific proteins involved in the nucleotide excision repair (NER) pathway: XPF and ERCC1 in 402-91/T and XPG in A2780/T. NER deficiency in trabectedin-resistant cells was associated with the absence of a G2/M arrest induced by trabectedin and with enhanced sensitivity (two-fold) to platinum drugs. In A2780/T, this collateral sensitivity, confirmed in vivo, was associated with an increased formation of DNA interstrand crosslinks. CONCLUSIONS: Our finding that resistance to trabectedin is associated with the loss of NER function, with a consequent increased sensitivity to platinum drugs, provides the rational for sequential use of these drugs in patients who have acquired resistance to trabectedin.
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Antineoplásicos/farmacología , Dioxoles/farmacología , Compuestos Organoplatinos/farmacología , Tetrahidroisoquinolinas/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN , Resistencia a Antineoplásicos , Femenino , Histonas/metabolismo , Humanos , Ratones , Ratones Desnudos , Trabectedina , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum-sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti-cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of trabectedin, which appears to represent a new class of anti-neoplastic drugs acting both on cancer cells and on the tumour microenvironment.
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Antineoplásicos Alquilantes/farmacología , Dioxoles/farmacología , Liposarcoma Mixoide/tratamiento farmacológico , Tetrahidroisoquinolinas/farmacología , Microambiente Tumoral/efectos de los fármacos , Animales , Antineoplásicos Alquilantes/uso terapéutico , Dioxoles/uso terapéutico , Humanos , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/patología , Tetrahidroisoquinolinas/uso terapéutico , Trabectedina , Translocación GenéticaRESUMEN
To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes, we have developed and characterized three MRCL xenografts, namely ML017, ML015 and ML004 differing for the break point of the fusion gene FUS-CHOP, respectively of type I, II and III. FUS-CHOP binding to the promoters of some target genes such as Pentraxin 3 or Fibronectin 1, assessed by chromatin immunoprecipitation, was strongly reduced in the tumor 24 h after the first or the third weekly dose of trabectedin, indicating that the drug at therapeutic doses causes a detachment of the FUS-CHOP chimera from its target promoters as previously shown in vitro. Moreover, the higher sensitivity of MRCL types I and II appears to be related to a more prolonged block of the transactivating activity of the fusion protein. Doxorubicin did not affect the binding of FUS-CHOP to target promoters. Histologically, the response to trabectedin in ML017 and ML015 was associated with a marked depletion of non-lipogenic tumoral cells and vascular component, as well as lipidic maturation as confirmed by PPARγ2 expression in western Blot. By contrast, in ML004 no major changes either in the cellularity or in the amount of mature were found, and consistently PPARγ2 was null. In conclusion, the data support the view that the selective mechanism of action of trabectedin in MRCL is specific and related to its ability to cause a functional inactivation of the oncogenic chimera with consequent derepression of the adypocytic differentiation.
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Antineoplásicos Alquilantes/farmacología , Dioxoles/farmacología , Liposarcoma Mixoide/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Proteína FUS de Unión a ARN/genética , Tetrahidroisoquinolinas/farmacología , Factor de Transcripción CHOP/genética , Adulto , Animales , Biopsia , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Doxorrubicina/farmacología , Femenino , Humanos , Liposarcoma Mixoide/genética , Ratones Desnudos , Proteínas de Fusión Oncogénica/metabolismo , Proteína FUS de Unión a ARN/metabolismo , Trabectedina , Factor de Transcripción CHOP/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cabazitaxel is a new taxane characterized by convenient administration, a favorable pharmacokinetic and safety profile and a decreased propensity for P-glycoprotein (Pgp)-mediated drug resistance. In preclinical studies cabazitaxel inhibited cell growth in a wide range of human cancer cell lines, including tumor models expressing Pgp. Phase I clinical trials established that the cabazitaxel side effect profile is similar to that reported for taxanes, with neutropenia and neuropathy being the most commonly reported toxicities. Further clinical studies have revealed that cabazitaxel is clinically active in women with taxaneresistant metastatic breast cancer and in men with metastatic castration-resistant prostate cancer previously treated with docetaxel. The TROPIC phase III trial concluded that, compared to mitoxantrone/prednisone, the combination cabazitaxel/prednisone conferred a statistically significantly longer overall survival in patients after treatment with a docetaxel-containing regimen, providing the basis for its FDA approval in 2010.
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Antineoplásicos/uso terapéutico , Taxoides/uso terapéutico , Animales , Femenino , Humanos , Masculino , Neoplasias/tratamiento farmacológico , Taxoides/efectos adversos , Taxoides/metabolismo , Taxoides/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that is currently in phase I clinical development for the treatment of solid tumours. In this study we have characterized the interactions of PM01183 with selected DNA molecules of defined sequence and its in vitro and in vivo cytotoxicity. EXPERIMENTAL APPROACH: DNA binding characteristics of PM01183 were studied using electrophoretic mobility shift assays, fluorescence-based melting kinetic experiments and computational modelling methods. Its mechanism of action was investigated using flow cytometry, Western blot analysis and fluorescent microscopy. In vitro anti-tumour activity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the in vivo activity utilized several human cancer models. KEY RESULTS: Electrophoretic mobility shift assays demonstrated that PM01183 bound to DNA. Fluorescence-based thermal denaturation experiments showed that the most favourable DNA triplets providing a central guanine for covalent adduct formation are AGC, CGG, AGG and TGG. These binding preferences could be rationalized using molecular modelling. PM01183-DNA adducts in living cells give rise to double-strand breaks, triggering S-phase accumulation and apoptosis. The potent cytotoxic activity of PM01183 was ascertained in a 23-cell line panel with a mean GI(50) value of 2.7 nM. In four murine xenograft models of human cancer, PM01183 inhibited tumour growth significantly with no weight loss of treated animals. CONCLUSIONS AND IMPLICATIONS: PM01183 is shown to bind to selected DNA sequences and promoted apoptosis by inducing double-strand breaks at nanomolar concentrations. The potent anti-tumour activity of PM01183 in several murine models of human cancer supports its development as a novel anti-neoplastic agent.
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Antineoplásicos/farmacología , ADN/metabolismo , Neoplasias/tratamiento farmacológico , Tetrahidroisoquinolinas/farmacología , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Secuencia de Bases , Línea Celular Tumoral , Aductos de ADN/metabolismo , Roturas del ADN de Doble Cadena/efectos de los fármacos , Ensayo de Cambio de Movilidad Electroforética , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Modelos Moleculares , Neoplasias/patología , Tetrahidroisoquinolinas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cytotoxic nucleoside analogues are clinically important anticancer drugs. These agents behave as antimetabolites, compete with physiologic nucleosides, and, consequently, interact with a large number of intracellular targets to induce cytotoxicity. Nucleoside analogues share some general common characteristics, namely in terms of requiring transport by specific membrane transporters and intracellular metabolism. However these compounds differ in regard to the preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumours and others on neoplasia with a more protracted evolution. Purine and pyrimidine analogues are widely used not only as antileukaemic agents, but also as cytotoxic agents to treat solid tumours. However, the clinical use of these compounds is limited by important side-effects and primary or acquired drug resistance. Thus, there is an unmet medical need for the development of new antimetabolites and for technologies allowing a more suitable and effective administration of nucleoside analogues for the treatment of cancer patients. Here, we will review literature data concerning the recent development of novel purine nucleoside analogues (clofarabine, nelarabine and forodesine) and pyrimidine nucleoside analogues (troxacitabine, sapacitabine, CP-4055, 3'-C-ethynylcytidine and 5-azapyrimidines) that are in evaluation at the clinical level.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Nucleósidos/uso terapéutico , Animales , Antimetabolitos Antineoplásicos/química , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Nucleósidos/química , Resultado del TratamientoRESUMEN
Despite its increasing clinical use, almost no data are currently available about paclitaxel effects on non-cancerous mammary epithelial cells. We have previously established paclitaxel-resistant sub-cell lines (paclitaxel-surviving populations, PSPs; n=20), and sensitive controls (control clones, CCs; n=10), from the untransformed human mammary epithelial cell line HME1. In this study, we aimed to establish whether paclitaxel resistance was associated with a modified sensitivity to paclitaxel-induced aneuploidy. For this purpose, we analysed basal and paclitaxel-induced chromosome missegregation, apoptosis and aberrant spindle multipolarisation as well as microtubular network composition for each subline. PSP sublines showed higher basal and paclitaxel-induced chromosome missegregation than the CC sublines. This phenomenon was associated with resistance to paclitaxel-induced apoptosis. No significant difference in paclitaxel-induced spindle pole abnormalities between CC and PSP sublines was found. Besides, we showed that a majority of PSPs display a constitutively disrupted microtubular network composition due to aberrant tubulin expression and post-translational modifications. These results clearly indicate that paclitaxel resistance in untransformed human mammary epithelial cells is related to an increased susceptibility to acquire aneuploidy in response to this agent. The consequences of these paclitaxel-associated alterations could be deleterious as they can potentially trigger tumorigenesis.
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Aneuploidia , Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos , Glándulas Mamarias Humanas/efectos de los fármacos , Paclitaxel/farmacología , Apoptosis , Western Blotting , Segregación Cromosómica , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Femenino , Humanos , Glándulas Mamarias Humanas/patología , FenotipoRESUMEN
This study assessed the antiproliferative activity of sapacitabine (CYC682, CS-682) in a panel of 10 human cancer cell lines with varying degrees of resistance or sensitivity to the commonly used nucleoside analogues ara-C and gemcitabine. Growth inhibition studies using sapacitabine and CNDAC were performed in the panel of cell lines and compared with both nucleoside analogues and other anticancer compounds including oxaliplatin, doxorubicin, docetaxel and seliciclib. Sapacitabine displayed antiproliferative activity across a range of concentrations in a variety of cell lines, including those shown to be resistant to several anticancer drugs. Sapacitabine is biotransformed by plasma, gut and liver amidases into CNDAC and causes cell cycle arrest predominantly in the G(2)/M phase. No clear correlation was observed between sensitivity to sapacitabine and the expression of critical factors involved in resistance to nucleoside analogues such as deoxycytidine kinase (dCK), human equilibrative nucleoside transporter 1, cytosolic 5'-nucleotidase and DNA polymerase-alpha. However, sapacitabine showed cytotoxic activity against dCK-deficient L1210 cells indicating that in some cells, a dCK-independent mechanism of action may be involved. In addition, sapacitabine showed a synergistic effect when combined with gemcitabine and sequence-specific synergy with doxorubicin and oxaliplatin. Sapacitabine is therefore a good candidate for further evaluation in combination with currently used anticancer agents in tumour types with unmet needs.
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Arabinonucleósidos/farmacología , Proliferación Celular/efectos de los fármacos , Citosina/análogos & derivados , 5'-Nucleotidasa/genética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Arabinonucleósidos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Citarabina/análogos & derivados , Citarabina/química , Citarabina/farmacología , Citosina/química , Citosina/farmacología , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacología , Docetaxel , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Tranportador Equilibrativo 1 de Nucleósido/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Células HT29 , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Taxoides/farmacología , GemcitabinaRESUMEN
As microtubules are essential in many cell functions, they have been used as a target of a variety of anticancer drugs that are grouped as stabilizing (taxanes) and destabilizing (vinca-alkaloids, colchicinoids) microtubule agents. It appears clearly now that the dynamic behaviour more than modifications of microtubule mass are altered by antitubulin agents in the range of serum concentrations obtained after administration in humans. While the role of microtubule associated proteins in the regulation of microtubule dynamics has been extensively studied, there is a growing body of data suggesting that tubulin folding could also play an important role in microtubule dynamics. We review the current knowledge regarding tubulin folding pathways, their relation to disease, and their possible influence on microtubule dynamics.
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Microtúbulos/metabolismo , Pliegue de Proteína , Tubulina (Proteína)/química , Antineoplásicos/farmacología , Humanos , Moduladores de TubulinaRESUMEN
Nucleoside analogues are widely used for the treament of hematological malignancies and solid tumors. Their activity is based on the interference with cellular targets involved in the metabolism of physiological nucleosides and DNA synthesis. Unfortunately, various resistance mechanisms decrease the activity of these drugs, reducing their clinical efficacy. Here, we review different resistance mechanisms responsible for decreased in vitro and in vivo nucleoside analogue activity, and some of the strategies proposed to circumvent constitutive or acquired drug resistance.
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Antineoplásicos , Resistencia a Antineoplásicos , Nucleósidos , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Humanos , Proteínas de Transporte de Nucleósidos/metabolismo , Nucleósidos/química , Nucleósidos/metabolismo , Nucleósidos/farmacología , Células Tumorales CultivadasRESUMEN
In the present study, we compared the dynamics and composition of microtubules in cell lines derived from the human breast adenocarcinoma MCF-7 containing either the wild-type p53 (wt-p53; MN1) or a dominant-negative variant of p53 gene (mut-p53; MDD2). Mut-p53 cells were significantly resistant to the cytotoxicity of the microtubule-targeted drugs (vinca alkaloids and taxanes), as compared with wt-p53 cells. Studies by high-resolution time-lapse fluorescence microscopy in living cells indicated that the dynamics of microtubules of mut-p53 cells were altered in complex ways and were significantly increased as compared with microtubules in wt-p53 cells. The percentage of time microtubules spent in growing and shortening phases increased significantly, their catastrophe frequency increased, and their overall dynamicity increased by 33%. In contrast, their shortening rate and the mean length shortened decreased. Cells containing mut-p53 displayed increased polymerisation of tubulin, increased protein levels of the class IV beta-tubulin isotype, STOP and survivin, and reduced protein levels of class II beta-tubulin isotype, MAP4 and FHIT. We conclude that p53 protein may contribute to the regulation of microtubule composition and function, and that alterations in p53 function may generate complex microtubule-associated mechanisms of resistance to tubulin-binding agents.
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Ácido Anhídrido Hidrolasas , Adenocarcinoma/metabolismo , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos , Microtúbulos/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma/patología , Animales , Antígenos de Neoplasias/metabolismo , Western Blotting , Encéfalo/metabolismo , Neoplasias de la Mama/patología , Bovinos , Cartilla de ADN/química , Genes Supresores de Tumor , Humanos , Proteínas Inhibidoras de la Apoptosis , Luciferasas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación/genética , Proteínas de Neoplasias/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Regiones Promotoras Genéticas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Survivin , Transfección , Tubulina (Proteína)/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genéticaRESUMEN
This report analyzes clinical factors affecting outcome in 26 patients with inflammatory breast cancer. Peau d'orange was the most common clinical finding at diagnosis (65%). A palpable breast mass (PBM) was noted in 65% with axillary lymph node involvement in 81% of patients. Eighteen patients were staged as stage IIIB and eight as stage IV. Initial metastases included supraclavicular nodes (five of eight), bones (one of eight), skin (one of eight), and liver (one of eight). All patients were treated with neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil, 18 patients; other, 8 patients). Partial response was the best clinical response attained in 38% of patients. Only one patient was treated with total mastectomy after neoadjuvant chemotherapy, and 19 patients received radiotherapy followed (2 patients) or not (17 patients) by mastectomy. The progression rate in stage IIIB patients was 78%, with distant sites of progression in 93% of patients and only 7% with local progression. Mean time-to-progression was 13 months (Kaplan-Meier estimates of 45% and 11% at 24 and 48 months, respectively). The median overall survival (OS) value of the entire population was 13.2 months (Kaplan-Meier estimates at 24 and 48 months of 21% and 12.5%). By Kaplan-Meier method and log-rank test, a better OS was correlated with stage IIIB (p = 0.002), a PBM at diagnosis (p = 0.01), and a favorable response to initial chemotherapy (p = 0.03). Our results confirm the better clinical outcome of patients with stage IIIB and PBM at diagnosis. They also support the role for combined treatment as the best modality approach for this disease. However, overall prognosis remained poor, with recurrence and death resulting from the disease.
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Adenocarcinoma , Neoplasias de la Mama , Adenocarcinoma/diagnóstico , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Terapia Combinada , Femenino , Humanos , Mastectomía , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
In this study, we evaluated the safety and efficacy of a combination of oral ftorafur administered together with intramuscular thiotepa as adjuvant chemotherapy for "early" breast cancer patients. A total of 30 patients with operated breast cancer were treated with 500 mg/m2 oral ftorafur for 10 consecutive days plus 20 mg/m2 intramuscular (im) administered thiotepa on d 1 and 8 every 28 d adjuvant chemotherapy. Eleven patients were premenopausal and 19 were postmenopausal, with a median age of 53 yr. The total number of cycles delivered was 259 (median: 10 cycles per patient). Toxicity was low and usually consisted of leukopenia WHO grade I-II (14%) and neutropenia grade I-II (6%). Gastrointestinal toxicity was minimal. The 5-yr disease-free survival and overall survival were 55% and 84%, respectively. Relapse occurred as bone metastases (50%), local recurrence (25%), and liver (17%) and brain (8%) metastases. Our preliminary data showed that oral ftorafur and im thiotepa is a well-tolerated regimen and could be a useful alternative to the intravenous parenteral route as adjuvant treatment for early breast cancer. Randomized trials are needed to assess the possible advantage of this regimen over intravenous schedules.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Tegafur/administración & dosificación , Tiotepa/administración & dosificación , Administración Oral , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Inyecciones Intramusculares , Persona de Mediana Edad , Tegafur/efectos adversos , Tiotepa/efectos adversosRESUMEN
OBJECTIVES: To study the factors that determine malignant B cell growth in human immunodeficiency virus type 1 (HIV-1)-infected patients. STUDY DESIGN: B-cell lines (lymphocyte cell lines [LCL]) were developed after nonstimulated culture of peripheral blood mononuclear cells (PBMC) from HIV-1-positive (HIV-1(+)) patients. Human immunodeficiency virus type 1 replication in culture, Epstein-Barr virus (EBV) latent oncogene expression, and cell-to-cell interaction were studied after nonstimulated culture of HIV-1(+) PBMC, analyzing their contribution to LCL appearance. METHODS: Nonstimulated PBMC cultures of HIV-1(+) PBMC and controls (N-PBMC) were established. Lymphocyte cell lines were characterized. Epstein-Barr virus latent membrane protein 1 (LMP-1) and Epstein-Barr nuclear antigen 2 were detected by polymerase chain reaction (PCR). Clonality of LCL was determined by light chain restriction (flow cytometry) and immunoglobulin H chain rearrangement (semi-nested PCR). Peripheral blood mononuclear cell phenotypes were studied at different intervals of culture. RESULTS: Lymphocyte cell lines were obtained in 73% of HIV-1(+) PBMC cultures, compared with 6% in N-PBMC. All LCL were EBV-positive (EBV(+)). B-cell lineage was established, and up to 12 different B-cell clones were expanded from the same individual. Occurrence of LCL was more frequent in cultures with HIV-1 replication, high LMP-1 expression in viable B cells, and high CD4:CD8 ratio. Human immunodeficiency virus type 1 replication persisted in 53% of the LCL. CONCLUSIONS: In vitro HIV-1 replication and persistence of viable EBV(+) lymphoblasts favor spontaneous in vitro outgrowth of LCL in HIV-1(+) patients.
Asunto(s)
Linfocitos B/fisiología , Linfocitos B/virología , Línea Celular Transformada , Infecciones por VIH/virología , VIH-1/fisiología , Herpesvirus Humano 4/fisiología , Leucocitos Mononucleares/virología , Técnicas de Cultivo de Célula/métodos , Línea Celular , Células Cultivadas , Citometría de Flujo , Hemofilia A/complicaciones , Humanos , Leucocitos Mononucleares/fisiologíaRESUMEN
Cytarabine (ara-C) requires activation into its triphosphorylated form, ara-CTP, to exert cytotoxic activity. Cytoplasmic 5'-nucleotidase (5NT) dephosphorylates ara-CMP, a key intermediate, preventing accumulation of ara-CTP and may reduce cellular sensitivity to the cytotoxic activity of ara-C. To determine whether the level of expression of 5NT is correlated with clinical outcome in patients with acute myeloid leukemia (AML) treated with ara-C, this study analyzed the levels of messenger RNA expression of high Km 5NT by real-time polymerase chain reaction at diagnosis in blast cells of 108 patients with AML. High Km 5NT was expressed at diagnosis in the blast cells of 54% of patients. In univariate analysis, (1) patients whose blast cells contained high levels (values greater than the median value for total population) of high Km 5NT at diagnosis had significantly shorter disease-free survival (DFS) than patients with low levels of high Km 5NT (11 months versus 17.5 months, P =.02) and (2) high levels of high Km 5NT also predicted significantly shorter overall survival (15.7 months versus 39 months, P = .01) in young patients (< or = 57 years; median value for the entire population). In a multivariate analysis taking into account age, karyotype risk, and other factors found to have prognostic significance in univariate analysis, (1) high Km 5NT expression was an independent prognostic factor for DFS and (2) high levels of high Km 5NT also predicted significantly shorter overall survival in young patients. These results demonstrate that the expression of high levels of high Km 5NT in blast cells is correlated with outcome in patients with AML.
Asunto(s)
5'-Nucleotidasa/biosíntesis , Leucemia Mieloide/enzimología , Leucemia Mieloide/mortalidad , 5'-Nucleotidasa/genética , Enfermedad Aguda , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Estudios de Cohortes , Citarabina/administración & dosificación , Citarabina/uso terapéutico , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , ARN Neoplásico/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Transcripción Genética , Resultado del TratamientoRESUMEN
The present study was performed to gain insight into the role of p53 on the cytotoxicity of tubulin-binding agents (TBA) on cancer cells. Drug sensitivity, cell cycle distribution and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the MN-1 cell line containing wild-type p53 (wt-p53) and the MDD2 line, containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to the cytotoxic effects of vinblastine and paclitaxel than the MN1 cell line. MN1 cells, but not MDD2 cells, displayed wt-p53 protein accumulation as well as p21/WAF1 and cyclin G1 induction after exposure to TBA. Both cell lines arrested at G(2)/M after drug treatment. However exposure of MN1 cells to TBA resulted in a stronger variation in mitochondrial membrane potential, associated with cleavage of PARP, and more apoptosis, as measured by annexin V expression. After exposure to vinblastine, Raf 1 kinase activity was reduced in MDD2 cells but not in MN1 cells. Addition of flavopiridol to vinblastine- and paclitaxel-treated cells reversed the MDD2-resistant phenotype by inducing G(1)cell cycle arrest and inhibiting endoreduplication. We conclude that the p53 status of cancer cells influences their sensitivity to TBA cytotoxicity. This effect is likely to involve differences in the apoptotic cascade.
Asunto(s)
Antineoplásicos Fitogénicos/metabolismo , Tubulina (Proteína)/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Antineoplásicos Fitogénicos/toxicidad , Northern Blotting , Western Blotting , Caspasa 3 , Caspasa 9 , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclina G , Ciclina G1 , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/metabolismo , Resistencia a Antineoplásicos , Citometría de Flujo , Humanos , Paclitaxel/metabolismo , Paclitaxel/toxicidad , Proteínas Proto-Oncogénicas c-raf/metabolismo , Células Tumorales Cultivadas/metabolismo , Proteína p53 Supresora de Tumor/genética , Vinblastina/metabolismo , Vinblastina/toxicidadRESUMEN
Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disorders (fludarabine, cladribine) and are also used in the treatment of some solid tumors (gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring transport by specific membrane transporters, metabolism and interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data concerning mechanisms of action of and resistance to NA, with particular emphasis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to these compounds. We performed an extensive search of published in vitro and clinical data in which the levels of expression of nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented.