RESUMEN
The purpose of this chapter is to concentrate on what can be considered as definite milestones on the way from examples of inhibitors of farnesyl-protein transferase (FPTase) to candidate drugs actually being considered for or already being evaluated in clinical trials. Emphasis will be placed on results obtained using experimental tumour models in vivo, with a detailed discussion of these results and of the questions which remain to be studied or are still unanswered. The data discussed here are almost exclusively based on published reports, with only brief reference, in the chapter "use of the FPTase inhibitors in the clinic", to some of the newer compounds reported on during recent meetings, details of which have not yet appeared in the peer-reviewed literature. For those requiring a more extensive review of the catalogue of FPTase inhibitors now discovered, some excellent reviews have been committed to this purpose [1-3].
Asunto(s)
Antineoplásicos/farmacología , Prenilación de Proteína/efectos de los fármacos , Proteínas ras/metabolismo , Transferasas Alquil y Aril/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Neoplasias/tratamiento farmacológico , Transducción de SeñalRESUMEN
We describe the improvements created by successful implementation of a laboratory information system for a multi-institutional integrated delivery system, including an analysis of the financial results. Conditions at the outset of the project, methods of management and project design, selected aspects of services redesign and consolidation, integration of services among the sites and their effects on laboratory staff and productivity are illustrated. A method for and example of measuring the financial outcomes in the sense of quantifiable improvements in operating expenses and new revenue for a whole health system clinical laboratory computer system are discussed. In this health system, the measurable financial improvements facilitated by an information system were the ability to control operating expenses and to grow the hospital laboratory network through the development of an outreach program. With organizational commitment to process innovation and improvement, using team processes and customer-driven decision-making criteria, the financial performance of our consolidated laboratory network was enhanced substantially. A fully implemented laboratory information system is considered the major enabler of positive change when combined with a genuine commitment from all levels of staff and leadership. Over time, this system's financial return is several times that of the information system investment.
Asunto(s)
Sistemas de Información en Laboratorio Clínico/economía , Redes Comunitarias , Prestación Integrada de Atención de Salud , Análisis Costo-Beneficio , HumanosRESUMEN
PURPOSE: To identify and characterize the specificity and potency of topoisomerase II-interacting antitumour drugs in an in vivo model utilizing the yeast Saccharomyces cerevisiae. METHODS: Four yeast transformants were selected for the expression of either human or yeast DNA topoisomerase II at different, biologically relevant, levels under the tight control of promoters of various strengths. RESULTS: Analyses of 24 drugs permitted their classification into three distinct groups, depending on whether they induced topoisomerase II-related cytotoxicity (etoposide), showed nonspecific cytotoxicity (camptothecin), or exerted no cytotoxicity at all (vinorelbine). Within the first group different patterns of action were distinguishable: (1) classical topoisomerase II expression-dependent cytotoxicity for both species of enzyme (e.g. etoposide, amsacrine, doxorubicin, actinomycin D), although amsacrine and TOP 53 were more active, respectively, on human and yeast topoisomerase II; and (2) compounds that appeared to poison only one species of topoisomerase II with, for example, genistein and the bisdioxopiperazine ICRF-193 lethally targeting only the human type, and mitoxantrone only the yeast isozyme. Three of the 16 known topoisomerase II inhibitors tested were not correctly identified with this assay, possibly owing to restricted cell wall permeability or to the absence of correct processing pathways such as, for example, in the case of the prodrug etopophos. CONCLUSION: This methodology, in vivo in yeast, selected for a large range of potent topoisomerase II-targeting anticancer agents. Of particular interest in this yeast model, and in contrast to yeast topoisomerase II, human topoisomerase II was shown to confer dominant sensitivity in the presence of the series of bisdioxopiperazine derivatives tested. This assay therefore has the potential easily to identify and characterize the potency and specificity of synthesized anticancer drugs with modified original chemical structures or those present, for example, in natural plant extracts or marine organisms.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , ADN-Topoisomerasas de Tipo II/biosíntesis , Inhibidores Enzimáticos/farmacología , Saccharomyces cerevisiae/enzimología , Antineoplásicos Fitogénicos/análisis , Camptotecina/análisis , Camptotecina/farmacología , Permeabilidad de la Membrana Celular , Medios de Cultivo , Inhibidores Enzimáticos/análisis , Etopósido/análisis , Etopósido/farmacología , Humanos , Plásmidos , Saccharomyces cerevisiae/genética , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II , Vinblastina/análogos & derivados , Vinblastina/análisis , Vinblastina/farmacología , VinorelbinaRESUMEN
The transformation of the health-care industry holds great economic potential for laboratory diagnostic testing providers who understand the five market forces driving change and who are shaping their own roles in the emerging market. Because of these trends, provider-based laboratories (PBLs) are competing with independent laboratories (ILs) for the latter's traditional client base--outpatients and nonpatients. PBLs will continue to service acute care patients while becoming more IL-like in logistics, sales, customer service, and marketing. Forced to compete on price, ILs have engaged in mega-mergers and will try to break into acute care via joint ventures. The ILs will need to choose their markets carefully, solidly integrate with parent organizations, and find ways to be profit centers. Consumers' demands also are forcing change. Consumers want accurate, legible bills and simplified eligibility determination and registration. They want an emphasis on prevention and wellness, which means that diagnostic testing must address early identification and monitoring of high-risk groups. To realize cost-efficiencies under whole-life capitation, laboratory networks must be part of a completely integrated health-care system. The laboratory of the future will be multicentered, without walls, and with quick access to information through technology.
Asunto(s)
Sector de Atención de Salud/tendencias , Laboratorios de Hospital/economía , Capitación , Sistemas de Información en Laboratorio Clínico , Participación de la Comunidad , Análisis Costo-Beneficio , Competencia Económica/tendencias , Instituciones Asociadas de Salud/tendencias , Humanos , Laboratorios de Hospital/organización & administración , Laboratorios de Hospital/tendencias , Años de Vida Ajustados por Calidad de Vida , Gestión de la Calidad Total , Estados UnidosRESUMEN
A two-fold difference in sensitivity to cis-diamminedichloroplatinum(II) (cisplatin), as judged by colony forming assays, has been demonstrated in two human bladder carcinoma continuous cell lines. Approximately twice as many DNA-DNA interstrand cross-links (ISL) and a 2-fold greater inhibition of DNA synthesis occurred in the more sensitive T24 cell line than in the RT112 cell line after exposure to the same concentrations of cisplatin. Equitoxic concentrations of cisplatin resulted in similar extents of ISL and inhibition of DNA synthesis in both cell lines. Although drug uptake was identical, twice as much cisplatin was bound to the DNA of T24 cells than RT112 cells. However after equitoxic concentrations of cisplatin the DNA from both cell lines was platinated to a similar extent. In addition, levels of glutathione (GSH), glutathione reductase (GR) and total glutathione-S-transferases (GST) were higher in the less sensitive RT112 cell line.
Asunto(s)
Carcinoma de Células Transicionales/patología , Cisplatino/toxicidad , Replicación del ADN/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/patología , Transporte Biológico , Carcinoma de Células Transicionales/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cisplatino/metabolismo , ADN de Neoplasias/efectos de los fármacos , ADN de Neoplasias/metabolismo , Evaluación Preclínica de Medicamentos , Glutatión/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Humanos , Cinética , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
The potential value of continuous tumour cell lines for establishing in vitro patterns of cross-resistance and collateral sensitivity has been examined. Results are presented for a series of sublines of the murine L5178Y lymphoma in which resistance has been induced in vitro by repeated exposure to the following antitumour drugs: methotrexate, 5-fluorouracil, adriamycin, vincristine and vindesine. A comparison has also been made between data derived from a murine (L5178Y) and a human tumour (LoVo) cell line, derived from a colon carcinoma, in which 5-fluorouracil resistance has been induced. Preliminary results suggest that the human tumour model may be more relevant clinically. It has also been demonstrated that prior exposure to fractionated X-irradiation in vitro can result in the expression of resistance or collateral sensitivity, depending on the drug evaluated. Furthermore, the expression of cross-resistance to certain drugs appears to differ, depending on the method used to induce or select for resistance in vitro. If confirmed, these latter observations may have major clinical implications for the combined modality approach to cancer treatment.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos , Humanos , Leucemia L5178/tratamiento farmacológico , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias Experimentales/radioterapiaRESUMEN
Many chemotherapeutic drugs have been used to treat patients with advanced bladder cancer, but few of these have been evaluated adequately in phase II clinical trials. Continuous cell lines provide one means for comparing the in vitro cytotoxicities of anticancer agents. In this study, a continuous cell line derived from a transitional cell cancer of the human bladder, which still produces tumours histologically similar to the tumour of origin on xenotransplantation, was used to measure the in vitro cytotoxicities of twelve chemotherapeutic drugs by clonogenic assay. The most cytotoxic agents tested were methotrexate, mitoxantrone, adriamycin, mitomycin C and cisplatin. These in vitro findings are compatible with the activity of these drugs given systemically as single agents in phase II clinical trials in patients with advanced bladder cancer.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Transicionales/patología , Ensayo de Unidades Formadoras de Colonias , Ensayo de Tumor de Célula Madre , Neoplasias de la Vejiga Urinaria/patología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Desnudos , Trasplante de NeoplasiasRESUMEN
We have developed a rapid, specific, in vitro method for quantitatively assessing neurotoxicity of antitumour drugs and related compounds. Using cultures of foetal rat hypothalamic neurones and a staining procedure which specifically identifies neuronal cells, the neurotoxicity of 8 antitumour drugs has been evaluated. The order of neurotoxicity appears to correlate well with their known relative clinical toxicities. Neurotoxicity of the radiosensitizer misonidazole was also identified using this system. This method appears to provide a valuable preclinical screen for neurotoxicity which may be particularly useful in the development of new antitumour drug analogues and radiosensitizers.
Asunto(s)
Antineoplásicos/toxicidad , Neuronas/efectos de los fármacos , Animales , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Feto , Humanos , Hipotálamo , Misonidazol/toxicidad , Neuroblastoma , Neuronas/citología , RatasRESUMEN
Forty-three patients with metastatic breast cancer were treated with a total of 385 cycles of combination chemotherapy consisting of adriamycin, cyclophosphamide, 5-fluorouracil, methotrexate and vincristine sulphate given over 24 hr and followed by a leucovorin 'rescue'. Thirty patients (70%) responded with three complete remissions. Thirteen patients did not respond, including six in whom the progression of disease was apparently arrested. Duration of response ranged from 2 to 24 months. At 20 months, 10 of 30 responding patients were alive compared with 1 of 13 non-responders. Toxicity was minimal apart from nausea and vomiting. This study confirms previous reports that intensive chemotherapy can be given safely over 24 hr without loss of therapeutic effect. This regimen is now being tested as an adjuvant to mastectomy in node-positive operable breast surgery.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Quimioterapia Combinada , Estudios de Factibilidad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Metotrexato/administración & dosificación , Persona de Mediana Edad , Factores de Tiempo , Vincristina/administración & dosificaciónRESUMEN
Survival curves for several monolayer and suspension cultures following 24-hour exposures to various vincristine (VCR) or vindesine (VDS) concentration were all of the exponential-plateau type. Cytotoxicity increased with duration of exposure in hamster NIL8 cells and was comparable for both drugs. Murine L5178Y cells, although 200 times more sensitive than NIL8 cells, also showed similar sensitivities to VCR and VDS. Murine neuroblastoma cells proved approximately fivefold less sensitive to VDS than VCR, whereas qualitative and quantitative differences in the activity of these two drugs were noted in human neuroblastoma cells. The lethal effects of VCR and VDS were exerted solely on logarithmically growing NIL8 cells in the S-phase. Plateau-phase human neuroblastoma cells were also significantly less sensitive to both drugs than were logarithmically growing populations, were cell kill occurred during the S-phase. Complete mitotic arrest, induced by a 24-hour exposure to VCR or VDS, was only partially reversible, whereas rapid and complete reversibility occurred after only 5 hours of drug exposure.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Vinblastina/análogos & derivados , Vincristina/farmacología , Animales , Línea Celular , Ensayo de Unidades Formadoras de Colonias , Cricetinae , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Interfase , Ratones , Mitosis/efectos de los fármacos , Neuroblastoma/patología , Factores de Tiempo , Vinblastina/farmacología , VindesinaAsunto(s)
Antineoplásicos/administración & dosificación , Leucovorina/administración & dosificación , Neoplasias/tratamiento farmacológico , Pirimetamina/análogos & derivados , Antineoplásicos/efectos adversos , Enfermedades de la Médula Ósea/inducido químicamente , Esquema de Medicación , Quimioterapia Combinada , Humanos , Leucovorina/efectos adversos , Pirimetamina/administración & dosificación , Pirimetamina/efectos adversosRESUMEN
The application of some basic principles derived from studies of the cell cycle and proliferative kinetics of normal and malignant cells has provided a rational basis for designing cancer treatment protocols. Using this approach in advanced head and neck cancer it is possible (a) to increase the response rate, (b) to reduce toxicity and (c) to reduce in-patient hospital stay time. Seventy-one patients with advanced carcinoma of the head and neck were randomized for treatment between two combination schedules, one with and the other without adriamycin. Responses (more than 50% tumour regression) were 74% overall with 70% responding to the combination without adriamycin and 82% responding to the schedule containing it. The increase in response rate seen with adriamycin is not statistically significant. Prior radiotherapy significantly reduced the likelihood of response to chemotherapy. These results have major implications for adjuvant chemotherapy and suggest a possible way of increasing the survival time in this group of diseases.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Bleomicina/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Humanos , Leucovorina/uso terapéutico , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Células Neoplásicas Circulantes , Vincristina/uso terapéuticoRESUMEN
A multiple drug regimen was given to 36 patients with advanced carcinomas of the head and neck. In 19 of the 24 patients who were assessable the tumour regressed more than 50%; in one it regressed by 25%; and in four it did not respond at all. Multiple drug chemotherapy should be given much earlier in the course of these cancers, preferably as an adjuvant to surgery or radiotherapy.