Synthetic lethality: a framework for the development of wiser cancer therapeutics

The challenge in medical oncology has always been to identify compounds that will kill, or at least tame, cancer cells while leaving normal cells unscathed. Most chemotherapeutic agents in use today were selected primarily for their ability to kill rapidly dividing cancer cells grown in cell culture and in mice, with their selectivity determined empirically during subsequent animal and human testing. Unfortunately, most of the drugs developed in this way have relatively low therapeutic indices (low toxic dose relative to the therapeutic dose). Recent advances in genomics are leading to a more complete picture of the range of mutations, both driver and passenger, present in human cancers. Synthetic lethality provides a conceptual framework for using this information to arrive at drugs that will preferentially kill cancer cells relative to normal cells. It also provides a possible way to tackle 'undruggable' targets. Two genes are synthetically lethal if mutation of either gene alone is compatible with viability but simultaneous mutation of both genes leads to death. If one is a cancer-relevant gene, the task is to discover its synthetic lethal interactors, because targeting these would theoretically kill cancer cells mutant in the cancer-relevant gene while sparing cells with a normal copy of that gene. All cancer drugs in use today, including conventional cytotoxic agents and newer 'targeted' agents, target molecules that are present in both normal cells and cancer cells. Their therapeutic indices almost certainly relate to synthetic lethal interactions, even if those interactions are often poorly understood. Recent technical advances enable unbiased screens for synthetic lethal interactors to be undertaken in human cancer cells. These approaches will hopefully facilitate the discovery of safer, more efficacious anticancer drugs that exploit vulnerabilities that are unique to cancer cells by virtue of the mutations they have accrued during tumor progression

Mucin impedes cytotoxic effect of 5-FU against growth of human pancreatic cancer cells: overcoming cellular barriers for therapeutic gain

Mucins are high molecular weight glycoproteins expressed on the apical surface of normal epithelial cells. In cancer disease mucins are overexpressed on the entire cellular surface. Overexpression of MUC1 mucin in pancreatic tumours has been correlated with poor patient survival. Current chemotherapeutic approaches such as 5-fluorouracil (5-FU) has produced limited clinical success. In this study we investigated the role of mucin in cytotoxic drug treatment to determine whether the extracellular domain of mucin impedes cytotoxic drug action of 5-FU. Human pancreatic cancer cells revealed high and relatively moderate MUC1 levels for Capan-1 and HPAF-II, respectively, compared to MUC1 negative control (U-87 MG glioblastoma) that showed relatively non-specific anti-MUC1 uptake. Benzyl-α-GalNAc (O-glycosylation inhibitor) was used to reduce mucin on cell surfaces, and neuraminidase was used to hydrolyse sialic acid at the distal end of carbohydrate chains. Benzyl-α-GalNAc had no effect on cell morphology or proliferation at the concentrations employed. The inhibition of O-glycosylation resulted in significant 5-FU antiproliferative activity against Capan-1 and HPAF-II, but not against U-87 MG. However, the exposure of cells to neuraminidase failed to improve the cytotoxic action of 5-FU. Our experimental findings suggest that the overexpression of mucin produced by human pancreatic tumours might limit the effectiveness of chemotherapy

On a biophysical and mathematical model of pgp-mediated multidrug resistance: understanding the “space–time” dimension of MDR

Multidrug resistance (MDR) is explained by drug transporters with a drug-handling activity. Despite much work, MDR remains multifaceted, and several conditions are required to generate drug resistance. The drug pumping was conceptually described using a kinetic, i.e., temporal, approach. The re-emergence of physical biology has allowed us to take into account new parameters focusing on the notion of space. This, in turn, has given us important clues regarding the process whereby drug and transporter interact. We will demonstrate that the likelihood of drug-transporter meeting (i.e., the affinity) and thus interaction are also driven by the mechanical interaction between drug molecular weight (MW) and the membrane mechanical properties. This should allow us to mechanically control drug delivery

Short-term lethality and sediment avoidance assays with endrin-contaminated sediment and two oligochaetes from Lake Michigan

Mean 96-hr LC 50 values and standard deviations for the oligochaetes S. heringianus and L. hoffmeisteri exposed to endrin-contaminated sediment were 2,588±1,974 μg/g dry weight sediment for 4 assays and 2,725±955 μg/g for 2 assays, respectively. Mixed species testing data suggested that the toxicity to L. hoffmeisteri was reduced in the presence of S. heringianus , yet further testing is required. Ninety-six hour EC 50 burrowing avoidance values for both species (19 and 15.3 μg/g for S. heringianus and 59 μg/g for L. hoffmeisteri ) were approximately 46 and 150 times lower than their respective mean 96-hr LC 50 values. Both S. heringianus and L. hoffmeisteri initially burrowed in contaminated sediment and then returned to the surface in numbers somewhat proportional to the sediment concentration and the length of exposure. Future use of oligochaete behavioral responses to subiethal sediment contamination for pollutant impact on benthic communities is promising.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48067/1/244_2005_Article_BF01055159.pd

Efecto de la combinación fungicida protectante y variedad sobre el tizón tardío [Phythopthora Infestas (Montagne) De Bary] en el cultivo de papa (Solanum tuberosum L.) en época de primera localidad La Tejera, San Nicolás, Estelí, 2008

El objetivo principal de este estudio fue el de evaluar el efecto de tres intervalos de aplicación del fungicida clorotalonil y tres variedades de papa con diferentes niveles de resistencia sobre la epidemiología y manejo del tizón tardío [Phytophthora infestans (Montagne) De Bary] en el cultivo de papa (Solanum tuberosum L.) El trabajo experimental se realizó de Julio a Octubre 2008, en la localidad “La Tejera”, municipio de San Nicolás, departamento de Estelí, localizado en las coordenadas geográficas 12º58'23” latitud norte y 86º24'21” longitud oeste, a una altura de 1,328 metros sobre el nivel del mar. Se evaluaron doce epidemias de tizón tardío que resultaron de la combinación de tres variedades de papa (Cal White, Granola y Jacqueline Lee) y cuatro tratamientos (tres intervalos de aplicación del fungicida clorotalonil y un testigo en el cual no se aplicó fungicida). Los tratamientos fueron distribuidos en bloques completos al azar. El manejo experimental fue el mismo que realiza el productor convencionalmente. Las variables epidemiológicas evaluadas fueron: severidad, área bajo la curva de progreso de la enfermedad (ABCPE) y la tasa de infección aparente (r). Además, se midieron variables climáticas como temperatura, humedad relativa y precipitaciones y se determinó el rendimiento de las variedades incluidas en el estudio. Las doce epidemias analizadas en este estudio iniciaron con varios días de diferencia, en dependencia del nivel de resistencia de la variedad y del intervalo de aplicación del fungicida protectante clorotalonil. La severidad de la enfermedad alcanzó casi el 100% en las variedades susceptibles (Cal White y Granola) en las parcelas donde no se aplicó el fungicida clorotalonil, pero el porcentaje de severidad en las parcelas tratadas disminuyó conforme el intervalo de aplicación se fue acortando. En la variedad Jacqueline Lee los porcentajes de severidad fueron bajos, incluso en las parcelas que no fueron tratadas con el fungicida clorotalonil, lo cual demuestra que esta variedad es resistente a P. infestans. Ninguno de los intervalos de aplicación (cada 4, 7 y 14 días) del fungicida clorotalonil detuvo el avance de las epidemias de tizón tardío una vez que éstas iniciaron, principalmente, en las parcelas con variedades susceptibles. El rendimiento obtenido en cada una de las variedades evaluadas fue menor al compararlo con otro estudio de validación llevado a cabo en 2007 en tres localidades de Matagalpa y Jinotega. Los resultados de este estudio const ituyen una contribución muy importante para el desarrollo de futuras estrategias encaminadas, no a la erradicación total del tizón tardío de los campos de papa y/o tomate de Nicaragua, pero si para lograr mitigar su efecto devastador sobre tan importantes cultivos tanto desde el punto de vista nutritivo como económico