Cancer is the abnormal growth of cells in the body whereby the cells fail to respond to body control mechanisms such as programmed cell death. Cancer can affect any body part, and the symptoms include a change in bowel movement, unexplained weight loss, abnormal bleeding, lump and a prolonged cough. Cancer is named according to the part of the body affected, and the causative factors are many although, some predisposing factors such as tobacco, obesity, excessive alcohol intake, sedentary lifestyle and exposure to ionizing radiation among other factors increase cancer chances. Treatment of cancer can be through radiology and chemotherapy. Radiology uses radiations to destroy cancer cells while chemotherapy has to do with the use of drugs to kill cancer cells. Most of the drugs used in treating cancer promote the death of cancer cells, however, other drugs such as AGI-5198 that promote cell differentiation are used when treating brain cancer. This study seeks to provide information on why such drugs are used.
Most human cancers including acute myeloid leukemia, sarcoma and glioma and are associated with somatic mutations that happen in the enzyme called Isocitrate Dehydrogenase. Catalytic pockets of IDH2 and IDH1 in Arginine residues provide maps for the mutations, and these catalytic pockets confer on the enzymes a different catalytic activity. Mechanism of the pathogenesis of human glioma by mutant IDH1 remains not well understood. These mutations are present in a range of 50 to 80 percent of human glioma with low-grade. (Wang, Hansen, Yang & Murray, 2015) This disease then advances to lethal WHO grade three and WHO grade four. These tumors develop in a period ranging from three to fifteen years. IDH1 mutations precede an occurrence of other mutations, and these mutations are associated with certain clinicopathological features, island methylator phenotype, and DNA hypermethylation. AGI-5198 is an IDH1-R132H mutant homodimer inhibitor compound. This compound when added to TS603 glioma cells, it impairs colony formation by 40 to 60 % but does not interfere with colony formation of glioma lines derived from a patient, and this proves that AGI-5198 is selective (Li, Paz, Wilky, Johnson, Galoian & Rosenberg, 2015). When orally administered, AGI-5198 shows a reduction of antibody staining against the Ki-67 protein. This is a marker applied to quantify proliferation of tumor cell in brain tumors. The growth inhibitory effects caused by AGI-5198 results from impaired tumor cell proliferation and not through the induction of programmed cell death. When IDHI-mutant xenografts derived from glioma are subjected to AGI-5198 treatment, there is the promotion of a gene expression program that is analogous to gliogenic differentiation. When developing the CNS, differentiation of glioma is controlled via histone methylation and DNA changes. Mutant IDH1 has an effect to both the epigenetic processes via the mediated suppression of jumonji-C domain histone demethylases and ten-eleven translocation methylcytosine hydroxylases.
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Rohle, Yang, and Kunii (2014) validated the association between tumorigenesis and these mutations. They established the D-2HG biomarker that was to be used in the cancer activity for the IDH-mutant. Through the use of AGI-5198, Rohle et al. (2014) validated that mutant IDH1 inhibition blocked the D-2HG production. AGI-5198 causes reduced levels of D-2HG in the cells in a manner that is dose-dependent. AGI-5198 decreases D-2HG levels in a dose-dependent manner in R132C and R132G mutations in IDH1. AD-2HG stereoisomer (L-2HG) is not easily detectable, and this suggests that L-2HG I not likely to contribute to tumorigenesis and hence to support the hypothesis that D-2HG can be used as a biomarker for the IDH-mutant enzyme activity in cancer. To emphasize on this further, there is a reduction of D-2HG levels in post-resection urine and blood samples of IDH2 R172S. It is interesting to learn that the level does not decrease to undetectable form in patients with IDH-mutant leukemia. To rule out whether this resulted from clearance from the patient investigations are necessary. An answer to this may be provided by clinical trials that have been on rising regarding mutant IDH2 inhibitor present in solid tumors, and this may comprise measuring D-2HG levels. There is no short-term inhibition of programmed cell death or cell viability with AGI-5198 treatment in cancer cells. Wang et al. (2015) demonstrated that IDH1 mutant in leukemia cells reversed genomic DNA methylation state and the DNA and induced cellular differentiation. According to Rohle et al. (2014), under near- complete D-2HG inhibition conditions, the mutant inhibitor-induced expression of gliogenic differentiation-associated genes and histone H3K9me 3 demethylation. From these findings, we can conclude that AGI-5198 preferentially affects migration because of the induction of epigenetic changes causing differentiation of the cell. This study had the purpose of investigating the in vitro traits of IDH-mutated cancer cells as well as demonstrating mutant IDH1 inhibitor AGI-5198 anti-tumor activity. As earlier stated, mutant IDH enzymes cannot convert isocitrate into –KG. The antitumorigenic activity of AGI-5198 is present in high drug concentration and this case, the 2HG production is nearly blocked. According to the study, D-2HG is likely to act as a mutant IDH activity biomarker in cancer. (Rohle et al., 2014).
References
Li, L., Paz, A., Wilky, B., Johnson, B., Galoian, K., & Rosenberg, A. (2015). Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells. PLOS ONE, 10(9), e0133813. doi: 10.1371/journal.pone.0133813
Rohle, D., Yang, H., & Kunii, K. (2014). An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells. NIH Public Access, 626-630. doi: 10.1126/science.1236062.
Wang, F., Hansen, E., Yang, H., & Murray, S (2015). Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation.
