Determination of drug interactions occurring with the metabolic pathways of irinotecan, Drug Metab. Dispos

, and involves cytochrome P450 (3A4 isoform); the second one leads to SN-38 glucuronide (SN-38G) and involves UDP-glucuronosyltransferase (UGT). Using human hepatic microsomes, we studied the interactions of 15 drugs of common use in colorectal cancer patients on these metabolic pathways. Only nifedipine had a significant effect on SN-38 formation, decreasing carboxylesterase activity by 50% at 100 M and 35% at 10 M. Three drugs had a significant effect on SN-38G formation: clonazepam increased UGT activity by 50% at 100 M and 30% at 10 M, and nifedipine and vinorelbine inhibited the activity by 65 and 55% at 100 M, respectively, with no effect at 10 M. Five drugs exerted a significant inhibition on SN-38 formation at 100 M: clonazepam (70%), methylprednisolone (50%), nifedipine (80%), omeprazole (85%), and vinorelbine (100%). Only omeprazole and vinorelbine still exerted a significant inhibition at 10 M (30 and 90%, respectively), whereas only vinorelbine had a significant effect at 2 and 0.5 M (70 and 40%, respectively). In conclusion, potential clinical interactions with the metabolism of irinotecan are likely to be important for vinorelbine, which strongly inhibits irinotecan catabolism by CYP3A4 at clinically relevant concentrations, but not for the other drugs, which exert an effect at concentrations not achievable in patients. Irinotecan [CPT-11 1 ; 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecine] is a water-soluble derivative of camptothecine The availability of SN-38 to its targets is, therefore, determined by a variety of enzyme activities, both for its formation and its detoxification. Since these enzymes are subjected to a wide individual variability, due to both genetic and environmental factors, there should be a similar variability in SN-38 availability, which could explain in turn at least part of the variability in response to irinotecan (about 20% responders in untreated as well as in 5-fluorouracilpretreated patients as stated by Materials and Methods Chemicals and Reagents. Pure irinotecan, SN-38, and NPC were supplied by Aventis (Vitry-sur-Seine, France). 20(S)-Camptothecine was obtained from Sigma-Aldrich Chimie (Saint-Quentin-Fallavier, France). The drugs used for interaction studies were obtained from various sources: carbamazepine, clonazepam, dexamethasone, ftorafur, methylprednisolone, nifedipine, omeprazole, phenobarbital, phenytoine, ranitidine, valproic acid, and warfarin were obtained as pure chemicals from Sigma-Aldrich Chimie, as was bilirubin; capecitabine, gemcitabine, and vinorelbine were obtained as clinical formula

Studying Chemosensory Perception and Its Hedonic Component in an Anthropological Context: From Genetics to Psychophysical Measures

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Studying Chemosensory Perception and Its Hedonic Component in an Anthropological Context: From Genetics to Psychophysical Measures

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KDM5A and KDM5B histone-demethylases contribute to HU-induced replication stress response and tolerance

International audienceABSTRACT KDM5A and KDM5B histone-demethylases are overexpressed in many cancers and have been involved in drug tolerance. Here, we describe that KDM5A, together with KDM5B, contribute to replication stress (RS) response and tolerance. First, they positively regulate RRM2, the regulatory subunit of ribonucleotide reductase. Second, they are required for optimal levels of activated Chk1, a major player of the intra-S phase checkpoint that protects cells from RS. We also found that KDM5A is enriched at ongoing replication forks and associates with both PCNA and Chk1. Because RRM2 is a major determinant of replication stress tolerance, we developed cells resistant to HU, and show that KDM5A/B proteins are required for both RRM2 overexpression and tolerance to HU. Altogether, our results indicate that KDM5A/B are major players of RS management. They also show that drugs targeting the enzymatic activity of KDM5 proteins may not affect all cancer-related consequences of KDM5A/B overexpression

Cancer Therapy Improvement with Mesoporous Silica Nanoparticles Combining Targeting, Drug Delivery and PDT

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