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Cytotoxic Phenanthridone Alkaloid Constituents of the Amaryllidaceae
Published in Spyridon E. Kintzios, Maria G. Barberaki, Evangelia A. Flampouri, Plants That Fight Cancer, 2019
Jerald J. Nair, Johannes van Staden
General and specific terms: AIF, apoptosis inducing factor; AKT, protein kinase B; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; Bax, Bcl-2 associated X-protein; Bcl-2, B-cell lymphoma 2; Bid, BH3-interacting domain death agonist; c-Abl, Abelson murine leukemia viral oncogene homolog 1; DNA-PK, DNA-dependent protein kinase; DR, death receptor; EC, endothelial cell; eEF1A, eukaryotic translation elongation factor 1 alpha; HUVEC, human umbilical vein endothelial cell; JNK, c-Jung N-terminal kinase; LPS, lipopolysaccharide; Mcl-1, induced myeloid leukemia cell differentiation protein; MMP, mitochondrial membrane permeabilization; MND, motor neuron disease; NF-κB, nuclear factor κB; NHF, normal human fibroblast; NO, nitric oxide; NOAEL, no adverse effect level; p53, tumor suppressor protein; PARP, poly(ADP-ribose) polymerase; PBMC, peripheral blood mononuclear cell; PCD, programmed cell death; PI(3)kinase, phosphoinositide 3 kinase; ROS, reactive oxygen species; SAPK, stress-activated protein kinase; TAM, Tamoxifen; T/C, treatment to control index; TNF, tumor necrosis factor; TM, traditional medicine; VEGF, vascular endothelial growth factor.
Biologically Targeted Agents in Head and Neck Cancers
Published in John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford, Head & Neck Surgery Plastic Surgery, 2018
Kevin J. Harrington, Magnus T. Dillon
Different types of radiation-induced DNA damage are sensed by mechanisms that activate specific DDR kinases: ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), which phosphorylate the checkpoint kinases, Chk1 and Chk2. In turn, these proteins transfer the signal to different effector molecules. The specific pathways involved are illustrated in Figure 30.3.
Tumor Biology
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Apoptosis can be initiated either through a “cell extrinsic pathway” or through a “cell intrinsic pathway.” The cell extrinsic pathway involves the death receptors in the cell membrane. Fas receptor when bound to Fas ligand, or TNFa receptor when bound to its TNFα ligand, can initiate the cell extrinsic pathway of apoptosis. Whole hosts of integrin receptors present at the basal surface of epithelial cells are attached to the basement membrane underneath and can induce apoptosis when they are not bound to their ligand. These phenomena in epithelial cells are called “anoikis”—detachment-induced cell death. The cell intrinsic pathway involves the mitochondrial apoptotic pathway initiated by a DNA damage signal from the nucleus. Exposure to chemical genotoxins or radiation results in the blockage of DNA replication, which leads to collapse of replication forks and DNA double strand breaks (DSB) formation. These DSBs are thought to be crucial downstream apoptosis–triggering lesions. DSBs are detected by ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) proteins, which signal downstream to CHK1, CHK2 (checkpoint kinases), and p53. p53 induces transcriptional activation of proapoptotic factors such as FAS, p53 upregulated modulator of apoptosis (PUMA), and BCL-2 associated X protein (BAX). Many tumors harbor mutations in p53. There are p53 backup systems that involve CHK1- and/or CHK2-driven E2F1 activation and p73 upregulation, which in turn transcribes BAX, PUMA, and NOXA. The end point of the mitochondrial pathway of apoptosis is release of cytochrome C.
Emerging cell cycle inhibitors for treating metastatic castration-resistant prostate cancer
Published in Expert Opinion on Emerging Drugs, 2018
The ATR (ataxia-telangiectasia and Rad3 related protein) inhibitor M-6620 (previously VX-970) developed by Vertex Pharmaceuticals, is being investigated for the treatment of patients with advanced solid tumors including prostate cancer. Currently, a phase II trial sponsored by the National Cancer Institute will be recruiting patients to evaluate the efficacy of M-6620 and carboplatin with or without docetaxel in treating patients with mCRPC. The primary objective of this study is to assess the difference in response rate by either PSA reduction >50% or radiographic response by RECIST 1.1 for the combination of M-6620 and carboplatin versus combination docetaxel and carboplatin. Secondary objectives will assess the difference in time to PSA progression by PCWG2, describe (rPFS) and (PFS), assess the relationship with homologous recombination deficiency (HRD) detected from baseline tumor biopsy with response and describe the safety profile of each combination (NCT03517969).
Emerging precision therapies for gastric cancer
Published in Expert Review of Precision Medicine and Drug Development, 2020
Elizabeth Cartwright, Avani Athauda, Ian Chau
Defective DNA damage repair (DDR) is an emerging target for treatment across multiple solid tumor types. Molecular features of advanced GC suggest assessment of DDR is warranted. Subgroups of patients appear to have defined defects in components of DDR, such as ATM defects, ARID1A defects, and mutational scars indicative of homologous recombination (HR), which confer sensitivity to therapeutic targeting by Ataxia telangiectasia and Rad3-related protein (ATR) or poly ADP ribose polymerase (PARP) inhibition [68,69].
Ras-Mediated Activation of NF-κB and DNA Damage Response in Carcinogenesis
Published in Cancer Investigation, 2020
Ataxia telangiectasia and Rad3-related protein (ATR) is another enzyme that is encoded by ATR gene belonging to the phosphatidylinositol 3-kinase-related kinase family of proteins and gets activated in response to DNA single stand breaks. The DNA damage response kinase ATR and its effector kinases are needed for cancer cell survival in oncogene-induced replication stress because oncogene activation frequently starts an AR-dependent replication stress response. The ATR targeting molecules and drugs exhibit their therapeutic usefulness in oncology clinical stages (207,208). Another example is DNA repair and recombination protein RAD51 and RAD54 genes that encode RAD51 and RAD54 proteins respectively. RAD54 belongs to the DEAD-like helicase superfamily and RAD51 family members are homologous to the bacterial RecA, Archaeal RadA, and yeast Rad51 that are highly conserved in almost all eukaryotes from yeast to humans. These are known to get somatically altered in a number of cancers and deficiency of these leads to the chromosomal instability in mammalian cells. The tumor cells which are lacking in these are reported to be sensitive to some of the chemotherapeutic drugs through synthetic lethal interactions (209–211). DNA excision repair cross-complementing (ERCC) is a set of proteins which are needed in DNA repair and are encoded by ERCC genes. ERCC lacking cells show enhanced levels of DNA damage and exhibit increased predisposition to the ATR pathway-targeted chemotherapeutic agents. ERCC performs the repair of bulky DNA adducts, DNA double strand break repair, separates the sister chromatids, and also repairs the interstrand crosslinks. In that way, ERCC has been explored as a significant biomarker in triple negative breast cancer, lung cancer and other types of cancers. A number of Phase II clinical trials are currently in progress which determines ERCC protein levels to assess which category of chemotherapeutics should be administered to which ERCC deficiency (212–214).