Explore chapters and articles related to this topic
Bioenergetics
Published in Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan, Strength and Conditioning in Sports, 2023
Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan
Regulation of the Krebs cycle is partially controlled by the need for energy (ATP) and therefore by reactions producing NADH2+ or FADH2+ and the ratio of oxidized to reduced coenzymes (O:Rc). The O:Rc is controlled by ADP and Pi availability for oxidative phosphorylation in the ETS. The rate at which the Krebs cycle proceeds becomes limited if the coenzymes FAD+ and NAD+ are not available to accept electrons (along with H+ in biological systems). Additionally, accumulation of guanine triphosphate (GTP) can result in an increase in succinyl-CoA which inhibits the initial Krebs cycle reaction: oxaloacetate + acetyl-CoA → citrate + CoA. Isocitrate → α-ketoglutarate is the rate-limiting step for the Krebs cycle, which is catalyzed by isocitrate dehydrogenase. Isocitrate dehydrogenase is generally inhibited by ATP and strongly allosterically stimulated by the accumulation of ADP. Secondarily, the Krebs cycle is controlled by α-ketoglutarate dehydrogenase which catalyzes the conversion of α-ketoglutarate to succinyl-CoA and produces NADH, thus, providing electrons for the ETS. α-ketoglutarate dehydrogenase is inhibited by increased concentrations of succinyl-CoA and NADH, which are produced by the reaction that it catalyzes. α-ketoglutarate dehydrogenase and the Krebs cycle rate are inhibited by a high energy charge (high concentration of ATP). General control of the ETS is relatively simple: stimulated by ADP and inhibited by ATP (35, 171, 283).
Tumor Markers
Published in Paloma Tejero, Hernán Pinto, Aesthetic Treatments for the Oncology Patient, 2020
Finally, for central nervous system tumors, several biomarkers have been identified and included in daily clinical practice. The determination of isocitrate dehydrogenase (IDH1/2) gene mutations has a clear diagnostic value and is associated with a favorable prognosis. The analysis of 1p/19q codeletion is also very helpful for diagnosis, since it is often found in oligodendroglial tumors, enabling a differential diagnosis with other neoplasias. Furthermore, it may serve as a response-predictive marker because the presence of codeletion is associated with more favorable responses after first-line chemotherapy and radiotherapy treatments. The determination of enzyme O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter methylation constitutes another new biomarker characteristic of this type of tumor; hypermethylation of said gene has a favorable prognostic value and is predictive of response to alkylating agents (temozolomide) [23].
D-2-hydroxyglutaric (DL-2-hydroxyglutaric) aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The key to the molecular defect in type 2 patients came from observations in cancer cells in which D-2-hydroxyglutarate accumulated in glioblastoma cells with superactivity of isocitrate dehydrogenase. Two genes IDH1 and IDH2 code for isocitrate dehydrogenase (see Figure 11.2). Fifteen patients were found to have gain of function mutations in IDH2 [11]. It is recommended in the workup of patients in whom 2-hydroxyglutarate is found on organic acid analysis that the optical rotation D or L be determined first; in those with the D form, mutational analysis is carried out on D-2-HGH and IDH2.
Biological therapy in elderly patients with acute myeloid leukemia
Published in Expert Opinion on Biological Therapy, 2023
Giulia Ciotti, Giovanni Marconi, Alessandra Sperotto, Maria B Giannini, Michele Gottardi, Giovanni Martinelli
Isocitrate dehydrogenase (IDH) mutations can be detected in almost 20% of AML cases [143]. Given their role in leukemogenesis, several small inhibitors have reached clinical investigation. IDH2-inhibitor enasidenib [144] and IDH1-inhibitor ivosidenib showed the most solid data and are both currently investigated in association with VEN, with or without AZA [145]. Based on phase 3 AGILE trial the IVO plus AZA combination was recently approved by Food and Drug Administration (FDA) in elderly or unfit newly diagnosed IDH1R132-mutated AML (ndAML) patients [146]. The preliminary results on IVO plus VEN showed a pretty impressive composite CR rate of 87% with 63% of patients achieving MRD negativity by multiparametric flow cytometry (MFC). Median OS was 42 months and 4/30 patients experienced differentiation syndrome; toxicity was overall expected and almost all grade ≥3 events were reversible [147]. Despite solid data, enasidenib and ivosidenib have not yet received approval from European Medicines Agency (EMA), limiting their use outside the clinical trial in Europe.
Ivosidenib: an investigational drug for the treatment of biliary tract cancers
Published in Expert Opinion on Investigational Drugs, 2021
Angelos Angelakas, Angela Lamarca, Richard a Hubner, Mairéad G McNamara, Juan W. Valle
Isocitrate dehydrogenase-1 plays a significant role in the cytoplasmic Krebs cycle, by converting isocitrate to α-ketoglutarate (α-KG). Mutations in IDH1 occur in approximately 13% of iCCAs [18], leading to elevated D-2-hydroxyglutarate (2-HG) which, in turn, affects liver progenitor cell proliferation and differentiation that is crucial in cholangiocarcinoma pathogenesis [19]. Ivosidenib (AG-120) inhibits the mutated IDH1 and is administered orally daily. It has been approved by the FDA for treatment of acute myeloid leukemia (AML) with an IDH1 mutation in treatment-naïve adults with newly diagnosed disease, aged 75 years or older (or who have health problems that prevent the use of certain chemotherapy treatments), as well as for adults with AML following disease relapse or progression on previous therapy [20,21]. This review will discuss the mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of ivosidenib in patients with advanced iCCA.
Pharmacotherapeutic options for biliary tract cancer: current standard of care and new perspectives
Published in Expert Opinion on Pharmacotherapy, 2019
Roberto Filippi, Pasquale Lombardi, Virginia Quarà, Elisabetta Fenocchio, Giacomo Aimar, Michela Milanesio, Francesco Leone, Massimo Aglietta
Isocitrate dehydrogenase (IDH, isoforms 1 and 2) is physiologically involved in cell metabolism. Genomic point mutations at hotspot codons 132 and 172 are gain-of-function: mutated IDH1/2 aberrantly synthesizes 2-hydroxyglutarate (2-HG), an oncometabolite that promotes epigenetic changes [113]. Disrupting this mechanism via targeted IDH1 inhibition (Ivosidenib) decreases 2-HG blood levels and produces morphological and molecular changes in CC tissue, increasing expression of liver-related genes [114]. In a phase-I trial with 73 patients with advanced, IDH1-mutant CC, Ivosidenib proved safe, as only 5% of patients experienced treatment-related G3-4 toxicity; 6% of patients experienced a PR and 56% achieved SD [115]. In May 2019 a press release announced that the phase-III ClarIDHy trial (NCT02989857) investigating the role of Ivosidenib as second- or third-line treatment had reached the primary endpoint, becoming the first positive randomized trial with a TT in aBTC. Other inhibitors, selective for IDH1 (IDH305), IDH2 (Enasidenib) or both isoforms (AG-881), are under study.