The Role of Bcl-X<sub>S</sub>in Radiation Sensitivity

Morgan, Meredith A.; Poynter, Jenny N.; Maybaum, Jonathan; Lawrence, Theodore S.

doi:10.1667/rr3169

Cited by 3 publications

(3 citation statements)

References 22 publications

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“…these results were corroborated by previous findings (Chen et al, 2000;Morgan et al, 2004;Ostruszka and Shewach, 2000;Shewach and Lawrence, 2007). MDA-MB-231 cells showed increased radioresistant to dFdCyd at equimolar concentration and at IC 50 concentration (and more sensitive to radiation only).…”

Section: Discussionsupporting

confidence: 89%

Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines

Salem

Abou-Tarboush

Saeed

et al. 2012

Gene

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Section: Discussionsupporting

confidence: 89%

Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines

Salem

Abou-Tarboush

Saeed

et al. 2012

Gene

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“…oxygen-dependent radiosensitivity of HeLa cells under our conditions is independent of both Bcl-2 and Bax, consistent with other reports that Bcl-2 proteins [28,29,36,37] and apoptosis [38][39][40] are not important determinants of radiosensitivity.…”

Section: Discussionsupporting

confidence: 93%

Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines

Anoopkumar‐Dukie

Conere²,

Sisk³

et al. 2009

BJR

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ABSTRACT. Oxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 mM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 mM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 mM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK ATP ) channels or mitochondrial Ca 2+ uptake. In conclusion, calcineurinindependent protection by cyclosporin A suggests that MPT but not mitoK ATP or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.

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“…We found that caspase-9 dominant negative overexpression blocks apoptosis and inhibits gemcitabine-mediated radiosensitization (Figure 2). (However, overexpression of the pro-apoptotic protein bcl-x S in fibroblasts, did not affect gemcitabine radiosensitization (29)). P53 does not seem to have a direct effect on gemcitabine-radiosensitization (30-32).…”

Section: Cellular Effects Of Radiation and Gemcitabinementioning

confidence: 99%

Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review

Morgan

Parsels

Maybaum

et al. 2008

Clinical Cancer Research

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In the last three decades, gemcitabine has progressed from the status of a laboratory cytotoxic drug to a standard clinical chemotherapeutic agent and a potent radiation sensitizer. In an effort to improve the efficacy of gemcitabine, additional chemotherapeutic agents have been combined with gemcitabine (both with and without radiation) but with toxicity proving to be a major limitation. Therefore, the integration of molecularly targeted agents, which potentially produce less toxicity than standard chemotherapy, with gemcitabine radiation is a promising strategy for improving chemoradiation. Two of the most promising targets, described in this review, for improving the efficacy of gemcitabine radiation are epidermal growth factor receptor and checkpoint kinase 1.Gemcitabine was first introduced into the clinic as a chemotherapeutic agent nearly 3 decades ago. Since then, both laboratory and clinical investigations have shown gemcitabine to be a potent radiation sensitizer. In this review, we will begin with a discussion of gemcitabine biochemistry and its mechanisms of interaction with radiation, highlighting observations that may lead to improving the design of clinical trials combining gemcitabine with radiation. Previous attempts to improve the efficacy of gemcitabine radiotherapy have included the addition of other chemotherapeutic agents (1 -3) such as cisplatin (4) and oxaliplatin (5). More recent studies have focused on the addition of molecularly targeted therapies, to gemcitabine, and radiation (6, 7). In this review, we will present our rationale for integrating checkpoint kinase 1 (Chk1)-and epidermal growth factor (EGFR) molecularly targeted agents with gemcitabine radiation therapy. Gemcitabine Biochemistry and RadiosensitizationThe antitumor activity of gemcitabine depends on a series of sequential phosphorylations. In the first rate-limiting step, deoxycytidine kinase converts gemcitabine to the monophosphorylated metabolite, dFdCMP [this has motivated the study of fixed-dose-rate infusion (10 mg/m 2 /min), which increases intracellular metabolites compared with bolus treatment (8, 9), but in the majority of trials, does not significantly improve survival (10)]. Subsequent phosphorylations lead to the accumulation of gemcitabine diphosphate and triphosphate (dFdCDP and dFdCTP) that are both active metabolites (Fig. 1). Whereas dFdCTP can interfere with DNA synthesis by competing with endogenous dCTP for misincorporation into replicating DNA, dFdCDP is a potent inhibitor of ribonucleotide reductase, reducing the synthesis of deoxynucleoside triphosphates, primarily dATP (in solid tumor cells).

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The Role of Bcl-X_Sin Radiation Sensitivity

Cited by 3 publications

References 22 publications

Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines

Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines

Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines

Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review

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The Role of Bcl-XSin Radiation Sensitivity

Cited by 3 publications

References 22 publications

Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines

Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines

Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines

Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review

Contact Info

Product

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The Role of Bcl-X_Sin Radiation Sensitivity