RESUMEN
Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.
Asunto(s)
Antimaláricos/análisis , Antimaláricos/farmacología , Descubrimiento de Drogas , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Animales , Antimaláricos/aislamiento & purificación , Línea Celular , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos/efectos de los fármacos , Quimioterapia Combinada , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Ratones , Fenotipo , Filogenia , Plasmodium falciparum/metabolismo , Reproducibilidad de los Resultados , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
AIM OF THE STUDY: In two institutions, a retrospective analysis was performed on patients with histologically proven locally advanced pancreatic cancer without distant metastases. The aim of this analysis is to assess whether chemoradiotherapy provides survival benefit for patients with locally advanced pancreatic cancer. METHODS: Forty-five patients from the Erasmus Medical Centre (Erasmus MC), Rotterdam, received 5-fluorouracil (5-FU) and radiotherapy and, 38 patients from the Academic Medical Centre Amsterdam (AMC) were offered the best supportive care. Radiotherapy consisted of 50 Gy external upper abdomen radiation in two courses, concomitant with intravenous 5-FU 25 mg/kg/ 24 h continuously on the first 4 days of each treatment course. RESULTS: The treatment protocol was completed in 38 of 45 patients (84%) without complications. Radiological response was evaluated in 38 patients. Ten patients (26%) showed a partial response, stable disease was seen in 6 (16%) patients and progressive disease in 22 (58%) patients. A second-look operation was performed in 8 of 10 patients (72%) showing a radiological response, in 3 patients the tumour could be resected. Median overall survival time for the Erasmus MC group (n = 45) was 9.8 months compared to 7.6 months when the best supportive care was given (AMC group, p = 0.04). CONCLUSION: Although overall survival remains poor, treatment with 5-FU and radiotherapy might benefit some patients with locally advanced pancreatic cancer.