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Introducción. La valoración de la citotoxicidad in vitro de líneas celulares derivadas de tumores humanos se emplea como bioensayo preliminar para el tamizaje de productos de origen natural con potencial actividad anticancerígena. Objetivo. Fortalecer el modelo de valoración de citotoxicidad in vitro disponible en el laboratorio, ampliando el panel de líneas celulares y caracterizando su perfil de sensibilidad a los fármacos antineoplásicos. Materiales y métodos. Se adicionaron al panel las líneas celulares HeLa, MKN-45 y U-937, y se evaluó la sensibilidad de las siete líneas celulares (HEp-2, HT-29, MCF-7, SiHa, MKN-45, HeLa y U-937) a los fármacos antineoplásicos doxorrubicina HCl, taxol, cisplatino, ciclofosfamida y carmustina, usados en la terapia antineoplásica. Para la valoración de la citotoxicidad se empleó el método de reducción del metil-tiazol-tetrazolio. Resultados. Al comparar las concentraciones letales 50 (CL 50 ) calculadas, se evidenció una sensibilidad diferencial de las líneas celulares frente a doxorrubicina HCl, taxol y cisplatino, siendo HEp-2 la línea más sensible a todos los fármacos, en tanto que las HeLa y U-937 fueron las más resistentes. La respuesta de HEp-2 frente al taxol presentó un comportamiento bifásico, relacionado con su mecanismo de acción. Conclusión. En las condiciones empleadas no se observaron efectos frente a la ciclofosfamida y la carmustina.Palabras clave: ensayos de selección de medicamentos antitumorales, agentes antineoplásicos, línea celular. Sensitivity profile of a panel of cell lines designed for the evaluation of in vitro cytotoxicityIntroduction. Preliminary in vitro cytoxicity evaluations are determined in human tumor cell lines as a bioassay for the screening of potentially anticancer natural products. Objective. To strengthen the available in vitro cytotoxicity evaluation models, the panel of cell lines was expanded, and the sensitivity profile of each cell line was evaluated for its response to selected antineoplasic drugs. Materials and Methods. HeLa, MKN-45 and U-937 cell lines were added to the panel, and the sensitivity was determined for each of seven cell lines: HEp-2, HT-29, MCF-7, SiHa, MKN-45, HeLa and U-937.The effects of the antineoplasic drugs Doxorubicin HCl, Taxol, Cisplatin, Cyclophosphamide and Carmustin were examined, using the methyl thiazol tetrazolium (MTT) reduction assay. Results. A differential sensitivity to the drugs Doxorubicin HCl, Taxol and Cisplatin was established among the cell lines by comparing the lethal concentration 50 (LC50) values. HEp-2 was the most sensitive cell line, whereas HeLa and U-937 were the most resistant. HEp-2 exhibited a biphasic response to Taxol treatment; this was related to the reported mechanism of action of this compound. Conclusion. Cyclophosphamide and Carmustin did not show activity under test conditions.

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Somatic gain-of-function mutations in IDH1 have been identified in multiple tumor types including AML, glioma, cholangiocarcinoma and chondrosarcoma. The neo-enzymatic activity of mutant IDH1 results in accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), leading to a hyper-methylation phenotype, a block in cell differentiation, and tumor growth. Using a structure-based drug design approach, we have developed a highly potent covalent inhibitor of mutant IDH1. LY3410738 modifies a single cysteine (Cys269) in the allosteric binding pocket and rapidly inactivates the enzyme with a KI/Kinact = 84,257 M-1sec-1. The compound selectively inhibits the 2-HG in IDH1 mutant tumor cells without depleting the levels of a-ketoglutarate. Using patient-derived primary AML cells, we demonstrated that LY3410738 was more potent than AG120 in reversing the block in differentiation associated with IDH1 mutant activity. In vivo, LY3410738 displayed prolonged pharmacodynamic activity, depleting 2-HG levels in tumors at low circulating exposures and for an extended time after clearance of compound. Importantly, LY3410738 has the ability to cross the blood-brain barrier and can achieve concentrations in the brain that exceed those needed to engage the target. Consistent with this, LY3410738 effectively inhibits 2HG in orthotopic glioma models. Using patient-derived IDH1 mutant orthotopic AML models, we demonstrated that LY3410738 effectively inhibited 2-HG, induced differentiation, and cleared AML from mice. Collectively, LY3410738 represents the first covalent brain-penetrant mutant IDH1 inhibitor with potential for Best-in-Class activity. Citation Format: Nathan Brooks, Robin DeWalt, Serge Boulet, ZhaoHai Lu, Lisa Kays, Rachel cavitt, Sandra Gomez, John Strelow, Paul Milligan, Kenneth Roth, Renato Bauer, Stephen Antonysamy, Patric Hahn, Zoran Rankovic, Denis McCann, Gary Mo, Ramon Tiu, Timothy Burkholder, Sandaruwan Geeganage, Raymond Gilmour. Identification and characterization of LY3410738, a novel covalent inhibitor of cancer-associated mutant Isocitrate Dehydrogenase 1 (IDH1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-274.

The fragmentation of 12 full-scale one-row blasts has been measured by sieving a large portion of the muckpiles. The procedure followed, the difficulties encountered and the solutions adopted to construct the fragment size distribution curves are described in detail; 11 curves were finally constructed as production constraints prevented the required measurements on one of the blasts. The blasts covered a powder factor range between 0.42 and 0.88 kg/m3, and were initiated with two significantly different delays, 4 and 23 ms between holes, to assess the influence of both powder factor and delay on fragmentation. The size distributions are well represented by the Swebrec function, which strongly suggests that the dependence of fragmentation with the powder factor can be analyzed by the fragmentation-energy fan. The result is excellent, and the frag-energy fan model in its simplest form (a four-parameter function) is able to predict sizes between percentage passings 92 to 8% with a mean error of 14.4% and a determination coefficient R2 as high as 0.976. The powder factor above grade has been used, in its energy form obtained as the product of the mass powder factor by the explosive energy per unit mass. The incorporation of six more fragment size distributions, also obtained by sieving in a previous blasting project in the same rock mass, but with different layouts, explosives, delay and blast direction, only reduces R2 to 0.968 and increases the mean error to 15.3%. A strength dependence with the size of the blasted block (burden, bench height, etc.) has been tested for inclusion in the fan formulation, with minor improvement compared with the powder factor alone, as the variation in size of the blasts was very limited. Some size descriptors as in-situ block size and fracture intensity have also been tested, though variations were also limited as all blasts were carried out in the same quarry site, not improving the prediction errors when other blast dimensions (e.g., burden) are used. Incorporating the effect of delay in the fragmentation-energy fan model has been attempted with a cooperation function modifying the powder factor, increasing from instantaneous to an optimum delay value, then decreasing as the delay further increases. The effect of such a function is noticeable in terms of improved prediction; the data analyzed, however, do not allow for a definitive statement on an optimum delay value as calculations with different fan characteristics and data result in different optimum values. The effect of the delay on the fragment size varies with the percentile, from about 10–15% for the high percentiles to somewhat more than 30% for the lower percentiles.