Since CYP1A1 inducibility strongly correlates with CYP1A1 gene polymorphism fairly we also tested Inhibitors,Modulators,Libraries the genotypic asset of our cell lines regarding the two main polymorphic forms of CYP1A1. All the tested cell lines carried a wild type homozygous genotype for both the polymorphisms and so we can exclude that different genotypes are involved in the different capability of metabolizing gefitinib. The role of CYP1A1 polymorphism as a predictor of clinical outcome to EGFR TKIs in patients with advanced lung cancer has very recently been reported. The authors note that CYP1A1 2A polymorphism correlates with the response to EGFR TKIs of NSCLC, wild type T/T patients having an improved response of inhibitors versus T/C and C/C alleles.

Studies have shown that the hepatic metabolism of gefitinib is primarily catalyzed via CYP3A4, conse quently the effects of known inducers and inhibitors of CYP3A4 activity have been investigated. Our results indicate that, in NSCLC cells metabolizing gefitinib, CYP1A1 inhibition could lead to increased local exposure to the active drug. In fact, inhibition Inhibitors,Modulators,Libraries by a naphthoflavone was associated with lower gefitinib metabolism and consequently with a prolonged expo sure to locally active drug. This leads to enhanced inhi bition of EGFR, MAPK and AKT phosphorylation and cell proliferation, with the result of reduced IC50 for gefitinib in proliferation assays of EGFR wild Inhibitors,Modulators,Libraries type NSCLC cell lines. From a medicinal chemistry perspective, these results stress the importance of considering drug pharmacoki netics at the intratumoral cellular level, focusing on the roles of transport and metabolism in the target cells.

While the structure of gefitinib makes it a substrate of transporters, thus enhancing its activity toward Inhibitors,Modulators,Libraries intra cellular targets, it also harbors metabolic liabilities in tumor cells. From this point of view, its interaction with CYP3A4 seems mainly related to total body exposure gefi tinib, while CYP1A1 is mainly responsible of its metabo lism in tumor cells. A program Inhibitors,Modulators,Libraries of structural optimization should thus consider the effects of structure modulation on all these processes in combination. In addition, a strategy of increasing gefitinib activity by using specific CYP inhibitors, could be pursued in the context of optimizing the use of gefitinib for the treatment of EGFR wild type gefitinib sensitive tumors.

Interstitial lung disease has been reported as a serious adverse effect of gefitinib treatment. The incidence of acute ILD during gefitinib treatment varies between different DAPT secretase CAS ethnic groups occurring more fre quently in Japanese patients than in Caucasian. Although the precise mechanism of ILD induced by gefitinib remains unknown, it has been pro posed that bioactivation of gefitinib by CYP1A1 in the lung may be related to the risk of developing ILD mainly in smokers.