Ku-0063794 treatment. These data were consistent with a `synthetic lethal’ model that explained why synergy only occurred in cells with mutant PIK3CA, increased glycolysis and low extracellular glucose but not in cells with only some of these features. Another study employing pancreatic cancer cell lines and culturing them in LG and hypoxia demonstrated emergence of resistance to gemcitabine, which was partially sensitized by L Y294002 and UCN-01 . The mechanism of resistance was attributed to a reduction in the proliferation rate of the cells in LG and hypoxic conditions. However, sorafenib cytotoxicity was significantly increased in rat liver stem cells upon glucose withdrawal and inhibition of glycolysis by 2-deoxyglucose. This result suggests 
that a reduction of glucose in the culture medium does not necessarily have to be associated with drug resistance. It may also lead to an enhancement of drug activity particularly if the cells or tumour are dependent on glycolysis and mitochondrial damage. Conclusion and perspectives Attrition rates for anticancer drugs are high compared with other therapeutic areas. While the introduction of UNC0642 site high-throughput technologies has enhanced the understanding of cancer biology, it has not been very successful in improving the dismal success rates in transitioning anticancer agents from the laboratory to the clinic. This is in part due to the multifaceted nature of the disease itself, with factors that include genetic and clonal heterogeneity and the complexity of the tumour environment. The fact that the effectiveness of drugs is tested in models that poorly simulate the tumour microenvironment should be considered as it is also likely to have a role in the attrition. It can be presumed that Warburg’s observations of the high glucose requirement of cells had a role in the practice of supplementing cells with extremely high glucose concentration. However, we and others have now begun to demonstrate that cancer cells can be cultured in normoglycaemic and hypoglycaemic conditions, and a different drug response can be expected. In addition, the blood versus The concept of `Native Culture’ System. British Journal of Pharmacology 173 970979 975 BJP B Bhattacharya et al. glucose concentration of the mice used for in vivo testing also simulates an extreme diabetic state. In addition to better efficacy prediction, the testing of anticancer agents on cancer cells in models closer to their `native’ microenvironment may also help to define a new range of active compounds. The `native’ culture conditions should utilize physiological or hypoglycaemic levels of glucose in the culture medium along with the creation of a lactic acidosis like condition and incubating cancer cells in hypoxic conditions. The combination of these three very important factors can therefore simulate the aspects of tumour microenvironment in an artificial model system. Understandably, many validation steps, for example, optimization of cell proliferation and other phenotypic characterization, need to be performed concurrently with standard culture conditions. However, once characterized, cells cultured in `native’ conditions retain the potential to be very informative in early-phase or even late-phase drug screens. Inclusion of other microenvironment components such as PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19822652 immune cells and fibroblasts can also be incorporated to study the immune response and therapeutic index of investigational agents. Furthermore, a drug repurposing screen can a