China 
Africa 
Explore chapters and articles related to this topic
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Due to inactivation of the active metabolite SN-38 by the enzyme UGT1A1 through glucuronidation, there are pharmacogenomic issues relating to the use of irinotecan. Some patients (~10% of Caucasians) with variants of the UGT1A1 enzyme known as “TA7” or “*28 variant” express lower levels of UGT1A1 enzymes in their liver and often suffer from Gilbert’s syndrome. During chemotherapy they effectively receive a larger dose of irinotecan than anticipated as they are unable to clear irinotecan as rapidly as other patients, and this can give rise to higher incidences of severe neutropenia and diarrhea. In 2004 a clinical study validated the ability of genetic testing for the “*28 variant” to predict severe toxicity prior to starting chemotherapy. As a result, in 2005 the FDA made changes to the labeling of irinotecan to add pharmacogenomics recommendations that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in the UGT1A1 gene (i.e., the “*28 variant”) should be considered for reduced drug doses, although a pharmacogenomic recommendation of this type has not yet been made in the UK. Thus, irinotecan was one of the first widely used chemotherapy agents to be dosed according to the recipient’s genotype.
UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Tristan M. Sissung, Roberto Barbier, Lisa M. Cordes, William D. Figg
Data published on UGT1A1 present a complex picture of genetic and environmental effects on anticancer therapy. An extremely wide variety of therapeutics interact in some way with UGT1A1 (Table 12.1), and numerous endogenous molecules and food constituents also interact with the enzyme (Tables 12.2 and 12.3). Several other factors also affect UGT1A1 activity: race, bilirubin serum concentration, variants in other genes that metabolize or transport UGT1A1 substrates. Therefore, a wide amount of inter- and intra-individual variability in UGT1A1 enzyme function is attributable to polypharmacy and environmental effects that are very difficult to quantify.
The rise of genomics and personalized medicine
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
Impairment of this enzyme system leads to the accumulation of metabolite that should be eliminated. There are 117 members in this family, but the most clinically important one is UGT1. UGT1A1 is the hepatic isoform and the most studied one for genetic variations. An important substrate for UGT1A1 is bilirubin, and loss of UGT1A1 activity causes hyperbilirubinemia. More than 30 inactivating SNPs have been identified.
Effects of common genetic variants of human uridine diphosphate glucuronosyltransferase subfamilies on irinotecan glucuronidation
Published in Toxicology Mechanisms and Methods, 2023
Kouji Tagawa, Yoshihiro Maruo, Yu Mimura, Shinichi Ikushiro
The limitations of our study are as follows. First, we only compared the glucuronidation activity between each UGT1A and UGT1A variant toward SN-38, and did not consider the UGT1A isoform distribution in the human body. If UGT1A10 is expressed more than UGT1A7, the variants of UGT1A10 may be increasingly associated with irinotecan toxicity. Moreover, gastrointestinal toxicity due to SN-38 is caused not only by insufficient SN-38, but also by deconjugation via bacteria (Takasuna et al. 1998). Therefore, we should also consider this bacterial effect. Second, we only examined the relationship between UGT1As and their variants and SN-38 glucuronidation, and we did not consider the relationship between UGT2As and glucuronidation activity toward SN-38. Third, we did not examine the effect of multiple variants of UGT1As. Teng et al. (2007) reported that patients with two variants (UGT1A1*6 and UGT1A7*3) were seen in 30% of Gilbert syndrome and 7% of the control cohort. Patients with these variants may have more severe irinotecan toxicity than patients with either variant. To overcome these limitations, further analysis of patients who show severe adverse effects should be performed.
The relationship between UGT1A1 gene & various diseases and prevention strategies
Published in Drug Metabolism Reviews, 2022
Dan Liu, Qi Yu, Qing Ning, Zhongqiu Liu, Jie Song
UGT1A1 metabolism and detoxification of bilirubin is an important physiological process in the body. The above has given a detailed overview of many related diseases caused by bilirubin metabolism disorders. Therefore, the biomolecular mechanism of the interaction between bilirubin and UGT1A1 is essential for in-depth knowledge of disease occurrence and prevention and treatment of diseases. However, the eutectic structure of UGT1A1 and bilirubin has not been resolved. In our previous studies, we construct the interaction relationship between UGT1A1 and bilirubin through molecular docking (Figure 4) (Liu et al. 2021). The 65S, 67Y, 69R, and 119D residues of UGT1A1 are responsible for the recognition of bilirubin; 38S, 39H, 221 F, 374 G, 394 F, and 396 D are responsible for the recognition of UDPGA. Among them, the 65S, 67Y, and 69 R residues are located near 71 G. A short-chain glycine (71 G) becomes the long-chain arginine, the side chain increases the steric hindrance of bilirubin toward UDPGA, which restricts the role of amino acids in the recognition pocket, leading to decline in activity.
A review of FDA-approved acute myeloid leukemia therapies beyond ‘7 + 3’
Published in Expert Review of Hematology, 2021
Alexandre Bazinet, Sarit Assouline
Enasidenib is a small molecule inhibitor of IDH2 that is active against the IDH2 R140 and IDH2 R172 variants [68]. In a phase I/II trial in relapsed/refractory IDH2-mutated AML, enasidenib (100 mg orally once daily) produced a 40.3% ORR (including 19.3% CR) [79]. A median OS of 9.3 months compared favorably to standard therapies in this difficult-to-treat population. Enasidenib was well tolerated. As with IDH1 inhibitors, this treatment can induce an IDH differentiation syndrome. In addition, elevations of unconjugated bilirubin (without transaminitis) are common and likely related to off-target inhibition of UGT1A1, mimicking Gilbert syndrome [79]. QT prolongation is not seen with enasidenib [80]. FDA approval for enasidenib was granted in 2017 for relapsed/refractory IDH2-mutated AML [81]. Unfortunately, the phase III trial (IDHENTIFY) comparing enasidenib to CCRs in relapsed/refractory IDH2-mutated AML in older patients did not meet its OS primary endpoint [82]. As with ivosidenib, enasidenib combined with ICT and AZA backbones in the first-line setting is safe and has shown promising response rates [75,76]. It is also being combined with ICT in the phase III HOVON150AML trial (NCT03839771).