Numerous cell lines derived from human tumors are not HeLa contaminants. Of 192 lines established in this or other laboratories, 169 lines were found to be G6PD type B. Twenty-three lines were type A as HeLa; three of these were of Negroid origin. There is reasonable doubt that the remaining 20 lines will all be shown to be confounded with HeLa.

Oral CP-122,721 200 mg decreased emetic episodes compared with ondansetron (4 mg intravenously) during the first 24 h after gynecologic surgery; however, there was no difference in patient satisfaction.

Pregnane X receptor (PXR) is a ligand-activated nuclear receptor (NR) that was originally identified as a master regulator of xenobiotic detoxification. It regulates the expression of drug-metabolizing enzymes and transporters to control the degradation and excretion of endobiotics and xenobiotics, including therapeutic agents. The metabolism and disposition of drugs might compromise their efficacy and possibly cause drug toxicity and/or drug resistance. Because many drugs can promiscuously bind and activate PXR, PXR antagonists might have therapeutic value in preventing and overcoming drug-induced PXR-mediated drug toxicity and drug resistance. Furthermore, PXR is now known to have broader cellular functions, including the regulation of cell proliferation, and glucose and lipid metabolism. Thus, PXR might be involved in human diseases such as cancer and metabolic diseases. The importance of PXR antagonists is discussed in the context of the role of PXR in xenobiotic sensing and other disease-related pathways. This review focuses on the development of PXRantagonists, which has been hampered by the promiscuity of PXR ligand binding. However, substantial progress has been made in recent years, suggesting that it is feasible to develop selective PXR antagonists. We discuss the current status, challenges, and strategies in developing selective PXR antagonists. The strategies are based on the molecular mechanisms of antagonism in related NRs that can be applied to the design of PXR antagonists, primarily driven by structural information.The nuclear receptor (NR) pregnane X receptor (PXR, NR1I2) plays a prominent role in the detoxification system that humans and other organisms utilize to eliminate endobiotics such as steroid hormones, bile acids, and glucose and xenobiotics such as therapeutic agents. Upon the binding of a ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and transporters, leading to the metabolism and, ultimately, clearance of endobiotics and xenobiotics. These chemicals undergo biotransformation and disposition through a series of processes comprising oxidation and conjugation reactions (involving cytochrome P450 enzymes [CYPs], such as CYP3A4, UDP-glucuronosyltransferases, and glutathione-S-transferases, sulfotransferases) and active efflux (involving the transporter proteins multidrug resistance proteins and multidrug resistance-associated proteins). [1][2][3][4] PXR and the detoxification system represent a double-edged sword: Although detoxification serves as a beneficial protection mechanism against toxic compounds, it also compromises therapeutic outcomes by decreasing drug efficacy and possibly inducing drug toxicity and resistance. Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug-induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as wel...

Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body’s natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes. Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR) and the cytochrome P450 (CYP) 3A4 and 3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands. Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them.