Ancer therapies to overcome MDR. Molecular pathways-targets for MDR attenuation or even reversal by redox-active substances will be described in detail.regulations are similar to those characteristic for acquired/ chemotherapy-induced MDR. In this line, the development of intrinsic MDR correlates with increased risk of carcinogenesis, and the process is under network-like redox control (for comprehensive review, see [1]). It appears that the classical paradigm of cancer chemoprevention with redoxactive nontoxic substances could be interpreted in terms of intrinsic MDR prevention. Furthermore, intrinsic MDR is a hallmark of stem cells, both normal and tumour, because high resistance to any toxin would guarantee survival and maintenance of stem cell populations. 2.2. Gene Polymorphisms Influencing Drug Metabolising Enzymes May Result in Ultrafast Drug Elimination or Extremely Slow Formation of Cytotoxic Redox By-Products. The cytochrome P450 (CYP) system is a superfamily of isozymes, get VP 63843 located in the smooth endoplasmic reticulum, mainly in the liver, but also in extrahepatic tissues (e.g., intestinal mucosa, lung, kidney, brain, lymphocytes, placenta, and skin), involved in the biotransformation of numerous lipophilic xenobiotics into more hydrophilic, less toxic, and more easily excreted metabolites [11, 24, 25]. The major CYP enzymes involved in human drug metabolism belong to families 1, 2, and 3, the specific drug metabolising isoforms being Cyp1A2, Cyp2C9, Cyp2C19, Cyp2D6, and Quinagolide (hydrochloride)MedChemExpress Quinagolide (hydrochloride) Cyp3A4/3A5. Each CYP isoform is a product of specific gene. For some isoforms, the existence of genetic polymorphisms has been demonstrated. The allelic variants may be due to the deletion2. Intrinsic Multidrug Resistance (MDR): Is It Possible to Overcome It by Redox Modulation?2.1. Inherited Overexpression of Drug Transporters Accelerates Drug Efflux from Target Cells. Some individuals possess the so-called intrinsic MDR having never been exposed to chemotherapy. Genetical predisposition to resist xenobiotic stress could, in principle, be explained in terms of single nucleotide polymorphisms (SNPs) of complex MDR system components, starting from drug transporters, censoring receptors, and xenobiotic/drug metabolising enzymes (see several examples below). On the other hand, a leading hypothesis indicates intrinsic MDR as a result of chronic (“silent”) exposure to low-level xenobiotic stressors or endogenous disturbances of lipid, glucose, and/or hormone metabolism. Therefore, the molecular pathways of itsOxidative Medicine and Cellular Longevity of the entire gene, SNPs, deletion or insertion of fragments of DNA within the gene, or multiplication of gene copies, leading to absent, deficient, or enhanced enzyme activity. Thus, the population can be classified into Extensive Metabolisers (EM, individuals with normal capacity), Poor Metabolisers (PM, individuals with reduced/null metabolic activity), and Ultrarapid Metabolisers (UM, individuals with a higherthan-normal metabolic activity). It seems that opposite populations of PM and UM could be at risk of constitutive MDR, because UM would rapidly metabolise/excrete parent molecules of anticancer drugs, while PM would not produce ROS as by-products of anticancer drug metabolism. These by-products possess strong cytotoxicity against cancer cells. Hence, the routine clinical diagnostics based on determination of CYP SNPs produce a reliable prediction of individual chemosensitivity/chemoresistance/MDR to anticancer th.Ancer therapies to overcome MDR. Molecular pathways-targets for MDR attenuation or even reversal by redox-active substances will be described in detail.regulations are similar to those characteristic for acquired/ chemotherapy-induced MDR. In this line, the development of intrinsic MDR correlates with increased risk of carcinogenesis, and the process is under network-like redox control (for comprehensive review, see [1]). It appears that the classical paradigm of cancer chemoprevention with redoxactive nontoxic substances could be interpreted in terms of intrinsic MDR prevention. Furthermore, intrinsic MDR is a hallmark of stem cells, both normal and tumour, because high resistance to any toxin would guarantee survival and maintenance of stem cell populations. 2.2. Gene Polymorphisms Influencing Drug Metabolising Enzymes May Result in Ultrafast Drug Elimination or Extremely Slow Formation of Cytotoxic Redox By-Products. The cytochrome P450 (CYP) system is a superfamily of isozymes, located in the smooth endoplasmic reticulum, mainly in the liver, but also in extrahepatic tissues (e.g., intestinal mucosa, lung, kidney, brain, lymphocytes, placenta, and skin), involved in the biotransformation of numerous lipophilic xenobiotics into more hydrophilic, less toxic, and more easily excreted metabolites [11, 24, 25]. The major CYP enzymes involved in human drug metabolism belong to families 1, 2, and 3, the specific drug metabolising isoforms being Cyp1A2, Cyp2C9, Cyp2C19, Cyp2D6, and Cyp3A4/3A5. Each CYP isoform is a product of specific gene. For some isoforms, the existence of genetic polymorphisms has been demonstrated. The allelic variants may be due to the deletion2. Intrinsic Multidrug Resistance (MDR): Is It Possible to Overcome It by Redox Modulation?2.1. Inherited Overexpression of Drug Transporters Accelerates Drug Efflux from Target Cells. Some individuals possess the so-called intrinsic MDR having never been exposed to chemotherapy. Genetical predisposition to resist xenobiotic stress could, in principle, be explained in terms of single nucleotide polymorphisms (SNPs) of complex MDR system components, starting from drug transporters, censoring receptors, and xenobiotic/drug metabolising enzymes (see several examples below). On the other hand, a leading hypothesis indicates intrinsic MDR as a result of chronic (“silent”) exposure to low-level xenobiotic stressors or endogenous disturbances of lipid, glucose, and/or hormone metabolism. Therefore, the molecular pathways of itsOxidative Medicine and Cellular Longevity of the entire gene, SNPs, deletion or insertion of fragments of DNA within the gene, or multiplication of gene copies, leading to absent, deficient, or enhanced enzyme activity. Thus, the population can be classified into Extensive Metabolisers (EM, individuals with normal capacity), Poor Metabolisers (PM, individuals with reduced/null metabolic activity), and Ultrarapid Metabolisers (UM, individuals with a higherthan-normal metabolic activity). It seems that opposite populations of PM and UM could be at risk of constitutive MDR, because UM would rapidly metabolise/excrete parent molecules of anticancer drugs, while PM would not produce ROS as by-products of anticancer drug metabolism. These by-products possess strong cytotoxicity against cancer cells. Hence, the routine clinical diagnostics based on determination of CYP SNPs produce a reliable prediction of individual chemosensitivity/chemoresistance/MDR to anticancer th.