Current Drug Targets

Francis J. Castellino
Kleiderer-Pezold Professor of Biochemistry
Director, W.M. Keck Center for Transgene Research
Dean Emeritus, College of Science
230 Raclin-Carmichael Hall, University of Notre Dame
Notre Dame, IN 46556
USA

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Hematological Targets of Radiation Damage

Author(s): Shilpa Kulkarni, Sanchita P. Ghosh, Martin Hauer-Jensen and K. Sree Kumar

Affiliation: Armed Forces Radiobiology Research Institute, Scientific Research Department, 8901 Wisconsin Ave., Bethesda, MD 20889, USA.

Keywords: Radiation countermeasures, gamma tocotrienol, pancytopenia, hematopoietic stem cells, countermeasures, tocotrienol, hematopoietic, radiotherapy, chemotherap, progenitor cells, (BM), (ROS), (RNS), (MODS), (GI), (TBI), AML, leukemogenesis, (HSCs), cytokines, DNA, protein, (SCF), (G-CSF), (GM-CSF), (LIF), (FLT3), IL-6, (IL-11), (EPO), (N1ICD), Wnt, (Dvl), (MMPs), mobilization, chemokines, (NER), Chk1, Chk2, (TLRs), CFUS, GT3

Abstract:

Radiation-induced myelosuppression remains a rate-limiting factor of radiotherapy and chemotherapy. Therefore, hematological targets of radiation damage are of great significance for radiation oncology and normal tissue injury and protection. Protection of hematopoietic stem and progenitor cells is pivotal. In order to develop therapeutic targets, it is necessary to understand the mechanisms of stem cell renewal and differentiation. Recent advances in the molecular pathology of hematopoietic stem cells indicate a fine balance between various extrinsic and intrinsic signaling pathways in preserving the self-renewal and proliferative capacity of stem cells. Extrinsic signaling involves microenvironment niche factors such as neighboring stromal cells, osteoblasts, and adipocytes secreting cytokines, chemokines, and metalloproteinases; intrinsic regulation involves Wnt/hedgehog/Notch signaling, DNA damage-induced epigenetic alterations, telomere shortening, and early senescence. Various drugs including synthetic cytokine mimetics, cytokine stimulators, and DNA repair modulators are being tested as radioprotectants. Colony-stimulating factors are routinely used in clinics to treat neutropenia induced by chemotherapy and radiotherapy as well as to mobilize and expand progenitors used in autologous transplantation. However, toxicity has limited their use. The vitamin E isoform gamma tocotrienol, a potent free radical scavenger that has displayed promising anticarcinogenic properties, was recently shown to protect bone marrow (BM) from radiation injury and to stimulate hematopoiesis in a murine model. This chapter focuses on the potential targets of radiation damage in BM and speculates on the mechanisms of protection by γ- tocotrienol and how these mechanisms can contribute to radioprotection in general and to protection of BM during chemotherapy and radiotherapy in particular.

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Article Details

VOLUME: 11
ISSUE: 11
Page: [1375 - 1385]
Pages: 11
DOI: 10.2174/1389450111009011375