Nucleoside Radiosensitizers

Shewach, Donna S.; Lawrence, Theodore S.

doi:10.1007/978-1-59745-148-2_13

Cited by 9 publications

(8 citation statements)

References 154 publications

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“…The majority of these studies have focused on the relationship between radiosensitization and cell cycle specific effects, production of DNA double-strand breaks and inhibition of their repair [reviewed in (34)]. Although the ability to radiosensitize CHO cells with antimetabolites has generally corresponded to an ability to radiosensitize human tumor cells, specific differences between CHO and human tumor cells have been noted with respect to mechanism (35).…”

Section: Discussionmentioning

confidence: 99%

Drug Metabolism and Homologous Recombination Repair in Radiosensitization with Gemcitabine

Flanagan

Ackroyd

et al. 2015

Radiation Research

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Gemcitabine (difluorodeoxycytidine; dFdCyd) is a potent radiosensitizer, noted for its ability to enhance cytotoxicity with radiation at noncytotoxic concentrations in vitro and subchemotherapeutic doses in patients. Radiosensitization in human tumor cells requires dFdCyd-mediated accumulation of cells in S phase with inhibition of ribonucleotide reductase, resulting in ≥80% deoxyadenosine triphosphate (dATP) depletion and errors of replication in DNA. Less is known of the role of specific DNA replication and repair pathways in the radiosensitization mechanism. Here the role of homologous recombination (HR) in relationship to the metabolic and cell cycle effects of dFdCyd was investigated using a matched pair of CHO cell lines that are either proficient (AA8 cells) or deficient (irs1SF cells) in HR based on expression of the HR protein XRCC3. The results demonstrated that the characteristics of radiosensitization in the rodent AA8 cells differed significantly from those in human tumor cells. In the AA8 cells, radiosensitization was achieved only under short (≤4 h) cytotoxic incubations, and S-phase accumulation did not appear to be required for radiosensitization. In contrast, human tumor cell lines were radiosensitized using noncytotoxic concentrations of dFdCyd and required early S-phase accumulation. Studies of the metabolic effects of dFdCyd demonstrated low dFdCyd concentrations did not deplete dATP by ≥80% in AA8 and irs1SF cells. However, at higher concentrations of dFdCyd, failure to radiosensitize the HR-deficient irs1SF cells could not be explained by a lack of dATP depletion or lack of S-phase accumulation. Thus, these parameters did not correspond to dFdCyd radiosensitization in the CHO cells. To evaluate directly the role of HR in radiosensitization, XRCC3 expression was suppressed in the AA8 cells with a lentiviral-delivered shRNA. Partial XRCC3 suppression significantly decreased radiosensitization [radiation enhancement ratio (RER) = 1.6 ± 0.15], compared to nontransduced (RER = 2.7 ± 0.27; P = 0.012), and a substantial decrease compared to nonspecific shRNA-transduced (RER =2.5 ± 0.42; P =0.056) AA8 cells. Although the results support a role for HR in radiosensitization with dFdCyd in CHO cells, the differences in the underlying metabolic and cell cycle characteristics suggest that dFdCyd radiosensitization in the nontumor-derived CHO cells is mechanistically distinct from that in human tumor cells.

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Section: Discussionmentioning

confidence: 99%

Drug Metabolism and Homologous Recombination Repair in Radiosensitization with Gemcitabine

Flanagan

Ackroyd

et al. 2015

Radiation Research

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“…1,2 All of the antimetabolite radiosensitizers target DNA replication; however, there may be distinct differences between their actions that lead to cytotoxicity versus radiosensitization. Since then, several other antimetabolites have been shown to have radiosensitizing properties in vitro, which have been translated to clinical success for drugs such as fluorouracil (FU), 5-fluoro-2Ј-deoxyuridine (FdUrd) and hydroxyurea (HU).…”

Section: Introductionmentioning

confidence: 99%

Antimetabolite Radiosensitizers

Shewach

Lawrence

2007

JCO

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101

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Radiosensitization with antimetabolites has improved clinical outcome for patients with solid malignancies, especially cancers of the GI tract, cervix, and head and neck. Fluorouracil (FU) and hydroxyurea have been widely used clinically during the last four decades, and promising results have been observed more recently with gemcitabine. Although the antimetabolites all target DNA replication, they differ with respect to the mechanisms by which they produce radiosensitization. The antimetabolite radiosensitizers may inhibit thymidylate synthase (TS) or ribonucleotide reductase, and the nucleoside/nucleobase analogs can be incorporated into DNA. Radiosensitization can result from chemotherapy-induced increase in DNA double-strand breaks or inhibition of their repair. Studies of repair pathways involved in radiosensitization with antimetabolites implicate base excision repair with the TS inhibitors, homologous recombination with gemcitabine, and mismatch repair with FU and gemcitabine. Gemcitabine can also stimulate epidermal growth factor receptor (EGFR) phosphorylation; inhibiting this effect with EGFR inhibitors can potentiate cytotoxicity and radiosensitization. Additional work is necessary to determine more precisely the processes by which antimetabolites act as radiation sensitizers and to define the optimal sequencing of these agents with EGFR inhibitors to provide better guidance for clinical protocols combining these drugs with radiotherapy.

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“…AraG is selectively cytotoxic towards T-lymphoblasts compared to B-lymphoblasts whereas araC exhibits equal toxicity towards T-and B-cells [2^4]. The molecular basis of the di¡erent pharmacological pro¢les of araC and araG is not elucidated, but several studies show that T-cells accumulate higher levels of araG-TP than B-cells, whereas araC-TP levels are similar in cells of both B-and T-cell lineages [3,4]. These ¢ndings suggest that the metabolism of araG is di¡erent between T-and B-cells, and that this di¡erence constitutes a possible explanation for the selective cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Differential incorporation of 1‐β‐D‐arabinofuranosylcytosine and 9‐β‐D‐arabinofuranosylguanine into nuclear and mitochondrial DNA

2000

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The anti-leukemic nucleoside analogs 1-L L-D-arabinofuranosylcytosine (araC) and 9-L L-D-arabinofuranosylguanine (araG) are dependent on intracellular phosphorylation for pharmacological activity. AraC is efficiently phosphorylated by deoxycytidine kinase (dCK). Although araG is phosphorylated by dCK in vitro, it is a preferred substrate of mitochondrial deoxyguanosine kinase. We have used autoradiography to show that araC was incorporated into nuclear DNA in Molt-4 and CEM T-lymphoblastoid cells as well as in Chinese hamster ovary cells. In contrast, araG was predominantly incorporated into mitochondrial DNA in the investigated cell lines, without detectable incorporation into nuclear DNA. These data suggest that the molecular targets of araG and araC may differ.z 2000 Federation of European Biochemical Societies.

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Nucleoside Radiosensitizers

Cited by 9 publications

References 154 publications

Drug Metabolism and Homologous Recombination Repair in Radiosensitization with Gemcitabine

Drug Metabolism and Homologous Recombination Repair in Radiosensitization with Gemcitabine

Antimetabolite Radiosensitizers

Differential incorporation of 1‐β‐D‐arabinofuranosylcytosine and 9‐β‐D‐arabinofuranosylguanine into nuclear and mitochondrial DNA

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