General aspects of the cellular response to low- and high-LET radiation

Pouget, Jean‐Pierre; Mather, Stephen J.

doi:10.1007/s002590100484

Cited by 138 publications

(90 citation statements)

References 119 publications

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“…However, apoptosis was not the only mode of cell death observed, consistent with the suggestion that the cell death in single CaP cells and spheroids exposed to aimmunoconjugates can occur via different pathways (9,41). Many genes and interdependent pathways are involved in the cellular response to ionizing radiation (42). The simultaneous activation of several genes and different pathways can lead to cell death and/or cell proliferation.…”

Section: Discussionsupporting

confidence: 58%

Inhibition of Micrometastatic Prostate Cancer Cell Spread in Animal Models By 213Bilabeled Multiple Targeted α Radioimmunoconjugates

Song

Rizvi

et al. 2009

Clinical Cancer Research

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Purpose: To investigate the therapeutic potential of 213 Bilabeled multiple targeted a-radioimmunoconjugates for treating prostate cancer (CaP) micrometastases in mouse models. Experimental Design: PC-3 CaP cells were implanted s.c., in the prostate, and intratibially in NODSCID mice. The expression of multiple tumor^associated antigens on tumor xenografts and micrometastases was detected by immunohistochemistry.Targeting vectors were two monoclonal antibodies, and a plasminogen activator inhibitor type 2 that binds to cell surface urokinase plasminogen activator, labeled with 213 Bi using standard methodology. In vivo efficacy of multiple a conjugates (MTAT) at different activities was evaluated in these mouse models. Tumor growth was monitored during observations and local regional lymph node metastases were assessed at the end of experiments. Results: The take rate of PC-3 cells was 100% for each route of injection. The tumor-associated antigens (MUC1, urokinase plasminogen activator, and BLCA-38) were heterogeneously expressed on primary tumors and metastatic cancer clusters at transit. A single i.p. injection of MTAT (test) at high and low doses caused regression of the growth of primary tumors and prevented local lymph node metastases in a concentration-dependent fashion; it also caused cancer cells to undergo necrosis and apoptosis. Conclusions: Our results suggest that MTATcan impede primary PC-3 CaP growth at three different sites in vivo through induction of apoptosis, and can prevent the spread of cancer cells and target lymph node micrometastases in a concentration-dependent manner. MTAT, by targeting multiple antigens, can overcome heterogeneous antigen expression to kill small CaP cell clusters, thus providing a potent therapy for micrometastases.The incidence of prostate cancer (CaP) is increasing; the high mortality rate is associated with widespread metastatic disease. Despite surgery and radiation therapy that can treat localized disease and the possibility of early diagnosis through testing for serum prostate-specific antigen, up to 30% of treated CaP patients suffer relapse. Most of these show an initial response to androgen-ablation therapy because early CaP growth is androgen dependent but eventually progress to hormone refractory CaP; this no longer responds to androgen ablation.At that stage, there is no curative therapy for metastatic CaP and median survival is f1 year. Nonhormonal agents have been evaluated for patients with hormone refractory CaP but have had limited antitumor activity, an objective response rate of <20% and did not show survival benefit (1). Combined radiation therapy and chemotherapy (2) or radiation and bisphosphonates (3) have shown only limited success in controlling CaP progression. Furthermore, although recent phase II studies with docetaxel (taxotere) display important single agent (4) or combination activity (5) in patients with hormone refractory CaP, the increase in survival is only a median of f2 months in f40% of patients. As such, metastatic horm...

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Section: Discussionsupporting

confidence: 58%

Inhibition of Micrometastatic Prostate Cancer Cell Spread in Animal Models By 213Bilabeled Multiple Targeted α Radioimmunoconjugates

Song

Rizvi

et al. 2009

Clinical Cancer Research

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“…38 DNA DSBs in HepG2 cells exposed to X-rays in the presence of TPZs-AuNPs and PEG-AuNPs were then investigated to clarify whether the increased cell lethality was derived from nucleus or cytoplasm damages.…”

Section: Resultsmentioning

confidence: 99%

The synergistic radiosensitizing effect of tirapazamine-conjugated gold nanoparticles on human hepatoma HepG2 cells under X-ray irradiation

Liu

Zhang

et al. 2016

IJN

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Reductive drug-functionalized gold nanoparticles (AuNPs) have been proposed to enhance the damage of X-rays to cells through improving hydroxyl radical production by secondary electrons. In this work, polyethylene glycol-capped AuNPs were conjugated with tirapazamine (TPZ) moiety, and then thioctyl TPZ (TPZs)-modified AuNPs (TPZs-AuNPs) were synthesized. The TPZs-AuNPs were characterized by transmission electron microscopy, ultraviolet-visible spectra, dynamic light scattering, and inductively coupled plasma mass spectrometry to have a size of 16.6±2.1 nm in diameter and a TPZs/AuNPs ratio of ~700:1. In contrast with PEGylated AuNPs, the as-synthesized TPZs-AuNPs exhibited 20% increment in hydroxyl radical production in water at 2.0 Gy, and 19% increase in sensitizer enhancement ratio at 10% survival fraction for human hepatoma HepG2 cells under X-ray irradiation. The production of reactive oxygen species in HepG2 cells exposed to X-rays in vitro demonstrated a synergistic radiosensitizing effect of AuNPs and TPZ moiety. Thus, the reductive drug-conjugated TPZs-AuNPs as a kind of AuNP radiosensitizer with low gold loading provide a new strategy for enhancing the efficacy of radiation therapy.

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“…Because the lifetime of these radicals is very short, only those proteins that are located within several nanometers of the DNA at the time of irradiation can become cross-linked. Alternatively, radiation exposure can potentially produce cross-links on a delayed time scale as a result of the generation of reactive aldehydes or possibly other longer lived species (47,48).…”

Section: Discussionmentioning

confidence: 99%

Identification of Mammalian Proteins Cross-linked to DNA by Ionizing Radiation

Barker¹,

Weinfeld²,

Zheng

et al. 2005

Journal of Biological Chemistry

109

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Ionizing radiation (IR) is an important environmental risk factor for various cancers and also a major therapeutic agent for cancer treatment. Exposure of mammalian cells to IR induces several types of damage to DNA, including double-and single-strand breaks, base and sugar damage, as well as DNA-DNA and DNA-protein crosslinks (DPCs). Little is known regarding the biological consequences of DPCs. Identifying the proteins that become cross-linked to DNA by IR would be an important first step in this regard. We have therefore undertaken a proteomics study to isolate and identify proteins involved in IR-induced DPCs. DPCs were induced in AA8 Chinese hamster ovary or GM00637 human fibroblast cells using 0 -4 gray of ␥-rays under either aerated or hypoxic conditions. DPCs were isolated using a recently developed method, and proteins were identified by mass spectrometry. We identified 29 proteins as being cross-linked to DNA by IR under aerated and/or hypoxic conditions. The identified proteins include structural proteins, actin-associated proteins, transcription regulators, RNA-splicing components, stress-response proteins, cell cycle regulatory proteins, and GDP/GTP-binding proteins. The involvement of several proteins (actin, histone H2B, and others) in DPCs was confirmed by using Western blot analysis. The dose responsiveness of DPC induction was examined by staining one-dimensional SDS-polyacrylamide gels with SYPRO Tangerine followed by analysis using fluorescence imaging. Quantitation of the fluorescence signal indicated no significant difference in total yields of IR-induced DPCs generated under aerated or hypoxic conditions, although differences were observed for several individual protein bands.

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General aspects of the cellular response to low- and high-LET radiation

Cited by 138 publications

References 119 publications

Inhibition of Micrometastatic Prostate Cancer Cell Spread in Animal Models By 213Bilabeled Multiple Targeted α Radioimmunoconjugates

Inhibition of Micrometastatic Prostate Cancer Cell Spread in Animal Models By 213Bilabeled Multiple Targeted α Radioimmunoconjugates

The synergistic radiosensitizing effect of tirapazamine-conjugated gold nanoparticles on human hepatoma HepG2 cells under X-ray irradiation

Identification of Mammalian Proteins Cross-linked to DNA by Ionizing Radiation

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