Anticancer Radiation Research Articles

High-Throughput Screening Identifies Two Classes of Antibiotics as Radioprotectors: Tetracyclines and Fluoroquinolones

Discovery of agents that protect or mitigate normal tissue from radiation injury during radiotherapy, accidents, or terrorist attacks is of importance. Specifically, bone marrow insufficiency, with possible infection due to immunosuppression, can occur after total body irradiation (TBI) or regional irradiation and is a major component of the acute radiation syndrome. The purpose of this study was to identify novel radioprotectors and mitigators of the hematopoietic system. High-throughput screening of small-molecule libraries was done using viability of a murine lymphocyte line as a readout with further validation in human lymphoblastoid cells. The selected compounds were then tested for their ability to counter TBI lethality in mice. All of two major classes of antibiotics, tetracyclines and fluoroquinolones, which share a common planar ring moiety, were radioprotective. Furthermore, tetracycline protected murine hematopoietic stem/progenitor cell populations from radiation damage and allowed 87.5% of mice to survive when given before and 35% when given 24 h after lethal TBI. Interestingly, tetracycline did not alter the radiosensitivity of Lewis lung cancer cells. Tetracycline and ciprofloxacine also protected human lymphoblastoid cells, reducing radiation-induced DNA double-strand breaks by 33% and 21%, respectively. The effects of these agents on radiation lethality are not due to the classic mechanism of free radical scavenging but potentially through activation of the Tip60 histone acetyltransferase and altered chromatin structure. Tetracyclines and fluoroquinolones can be robust radioprotectors and mitigators of the hematopoietic system with potential utility in anticancer radiotherapy and radiation emergencies.

Molecular mechanism of HSP70 involved in carcinogenesis and tumor resistance

Heat shock protein 70 ( HSP70) is overexpressed in a wide range of human tumor cells. It is closely associated with tumor malignant degree,therapy and prognosis. As a molecular chaperone,HSP70 partici-pates in cell cycle,differentiation and apoptosis,and it may lead to disorder of cell cycle and abnormality of cell differentiation. HSP70 could inhibit the apoptosis mediated by anticancer drugs, radiotherapy and other fac-tors. HSP70 not only is involved in tumor development and progression,also plays an important role in tumor re-sistance. Key words: Heat-shock proteins 70; Neoplastic processes; Drug resistance,neoplasm

Radiosensitization of Human Vascular Endothelial Cells Through Hsp90 Inhibition With 17- N-Allilamino-17-Demethoxygeldanamycin

In addition to invasive tumor cells, endothelial cells (ECs) of the tumor vasculature are an important target for anticancer radiotherapy. The purpose of the present work is to investigate how 17-N-allilamino-17-demethoxygeldanamycin (17AAG), known as an anticancer drug inhibiting heat shock protein 90 (Hsp90), modifies radiation responses of human vascular ECs. The ECs cultured from human umbilical veins were exposed to gamma-irradiation, whereas some EC samples were pretreated with growth factors and/or 17AAG. Postirradiation cell death/survival and morphogenesis were assessed by means of terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick end labeling or annexin V staining and clonogenic and tube-formation assays. The 17AAG-affected expression and phosphorylation of radioresistance-related proteins were probed by means of immunoblotting. Dominant negative or constitutively activated Akt was transiently expressed in ECs to manipulate Akt activity. It was found that nanomolar concentrations of 17AAG sensitize ECs to relatively low doses (2-6 Gy) of gamma-irradiation and abolish the radioprotective effects of vascular endothelial growth factor and basic fibroblast growth factor. The drug-induced radiosensitization of ECs seems to be caused by prevention of Hsp90-dependent phosphorylation (activation) of Akt that results in blocking the radioprotective phosphatidylinositol 3-kinase/Akt pathway. Clinically achievable concentrations of 17AAG can decrease the radioresistance intrinsic to vascular ECs and minimize the radioprotection conferred upon them by tumor-derived growth factors. These findings characterize 17AAG as a promising radiosensitizer for the tumor vasculature.

Adjuvant role for cell death during chemo- and radiotherapy of cancer?

Evaluation of: Apetoh L, Ghiringhelli F, Tesniere A et al. Toll-like receptor 4-dependent contribution of the immune system to anti-cancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).Chemotherapy and radiotherapy are supposed to mediate their anticancer activity via the direct elimination of tumor cells. Dying cells, however, also release molecules that promote the activation and the functional maturation of the most potent antigen-presenting cells, the dendritic cells. Mature dendritic cells are endowed with the ability to cross-prime T cells against the antigens contained in the dead cells. This paper evaluates the results from a recent article in which the success of some protocols for anticancer therapy depends, besides their direct cytotoxic effect, on the induction of a specific immune response: the effect is mediated both in mice and humans through the release by dying tumor cells of the nuclear protein high-mobility group 1 protein and by its interaction with Toll-like receptor 4. Larger studies on various therapeutic regimens are needed to evaluate the general relevance of this observation.

Radiobiological features of the anti-cancer strategies involving synchrotron X-rays

Synchrotrons are opening new paths in innovative anti-cancer radiotherapy strategies. Indeed, the fluence of X-rays induced by synchrotrons is so high (10(6) times higher than standard medical irradiators) that it enables the production of X-ray beams tunable in energy (monochromatic beams) and in size (micrometric beams). Monochromatic synchrotron X-ray beams theoretically permit photoactivate high-Z elements to be introduced in or close to tumours in order to increase the yield of damage by enhanced energy photoabsorption. This is notably the case of attempts with iodinated contrast agents used in tumour imaging (the computed tomography therapy approach) and with platinated agents used in chemotherapy (the PAT-Plat approach). Micrometric synchrotron X-ray beams theoretically permit very high radiation doses to accumulate in tumours by using arrays of parallel microplanar beams that spare the surrounding tissues (the microbeam radiation therapy approach). These anti-cancer applications of synchrotron radiation have been developed at the European Synchrotron Radiation Facility to be applied to glioma, one of the tumour tissues most refractory to standard treatments. In the present paper the molecular and cellular mechanisms involved in these three approaches are reviewed, in the context of recent advances in radiobiology. Furthermore, by considering the unavoidable biases, an attempt to propose a comparison of the different results obtained in preclinical trials dealing with rats bearing tumours is given.

ATM-NF-κB Connection as a Target for Tumor Radiosensitization

Ionizing radiation (IR) plays a key role in both areas of carcinogenesis and anticancer radiotherapy. The ATM (ataxia-telangiectasia mutated) protein, a sensor to IR and other DNA-damaging agents, activates a wide variety of effectors involved in multiple signaling pathways, cell cycle checkpoints, DNA repair and apoptosis. Accumulated evidence also indicates that the transcription factor NF-kappaB (nuclear factor-kappaB) plays a critical role in cellular protection against a variety of genotoxic agents including IR, and inhibition of NF-kappaB leads to radiosensitization in radioresistant cancer cells. NF-kappaB was found to be defective in cells from patients with A-T (ataxia-telangiectasia) who are highly sensitive to DNA damage induced by IR and UV lights. Cells derived from A-T individuals are hypersensitive to killing by IR. Both ATM and NF-kappaB deficiencies result in increased sensitivity to DNA double strand breaks. Therefore, identification of the molecular linkage between the kinase ATM and NF-kappaB signaling in tumor response to therapeutic IR will lead to a better understanding of cellular response to IR, and will promise novel molecular targets for therapy-associated tumor resistance. This review article focuses on recent findings related to the relationship between ATM and NF-kappaB in response to IR. Also, the association of ATM with the NF-kappaB subunit p65 in adaptive radiation response, recently observed in our lab, is also discussed.

SiRNA-mediated MDM2 inhibition sensitizes human lung cancer A549 cells to radiation

MDM2 (murine double minute 2) is well-documented to play a key role in radiation response and tumor radiosensitivity, thus offering an attractive clinic drug target to enhance tumor sensitivity to anti-cancer radiotherapy. In this study, we designed and tested two siRNA fragments against human MDM2 in non-small cell human lung cancer A549 cells. Transfection of mammalian expression vector pUR/U6 containing either MDM2 siRNA1 or siRNA2 fragment was shown to reduce MDM2 mRNA levels by 72% and 31%, respectively. Western blotting detected a similar inhibition of MDM2 protein levels in cells transfected with MDM2 siRNA1. A549 cells transfected with the expression vector for siRNA1 significantly decreased cell proliferation and rendered cells more sensitive to radiation. The basal apoptotic and necrotic cells, 1% and 2%, respectively, detected among A549 cells were increased to 2.6% and 14.4% after gamma-irradiation with 5 Gy. Transfection of MDM2 siRNA1 induced 30.1% apoptosis and 12.7% necrosis while combined treatment of siRNA1 and 5-Gy radiation increased apoptosis and necrosis to 45.9% and 15.2%, respectively. These data provide the first evidence that specific siRNA fragment (MDM2 siRNA1) targeting human MDM2 mRNA is able to enhance lung cancer radiosensitivity.

Interferon regulatory factor-5-regulated pathways as a target for colorectal cancer therapeutics

Colorectal cancer is the second most common cause of cancer-related death. A significant obstacle to successful management of patients with colorectal cancer is intrinsic drug resistance or, in patients who initially responded to chemotherapy, acquired drug resistance. Failure in normal apoptotic pathways often contributes to resistance to anticancer drugs or radiotherapy. As a result, the identification of genes that control cell death and apoptosis has come to the forefront of cancer research, leading to new targets and novel therapeutic strategies in the treatment of colorectal cancer. To this effect, the authors have recently identified a new apoptotic signaling pathway that occurs through the transcription factor interferon regulatory factor-5. Here, the different strategies for targeting the interferon regulatory factor-5 signaling pathway in colorectal cancer are discussed. These strategies can be applied to a new generation of cytotoxic agents, as well as to novel biological compounds that are directed at inducing and/or activating interferon regulatory factor-5 or key components of this pathway.

Chronic Myeloid Leukemia as a Secondary Neoplasm After Anti-cancer Radiotherapy: a Report of Three Cases and a Brief Review of the Literature

Chemotherapy-related acute leukemias or myelodysplasias are well-recognized entities. On the other hand, little is known about the possible occurrence of secondary chronic myeloid leukemia (CML) after radiotherapy, albeit accidental irradiation represents a classical predisposing factor for this disease. We report here three cases of Philadelphia-positive CML appearing one to 25 years after breast or uterine cervix cancer radiotherapy. One patient had also received chemotherapy. Clinical and biological characteristics of these cases did not significantly differ from those of de novo CMLs. A brief review of the literature is made about this possible peculiar entity. Large registries appear warranted to assess the real risk of developing CML after anti-cancer radiotherapy.

High dose pamidronate

Eighty-six patients with heavily pretreated progressive bone metastases (52 with breast carcinoma, 17 with prostate carcinoma, and 17 others) were included in 2 studies designed to assess the clinical and biochemical effects of a single 120 mg, 2-hour infusion of pamidronate. No other systemic anticancer treatment or radiotherapy were administered. Pamidronate had a significant beneficial effect, with a reduction in a symptom score measuring pain, World Health Organization performance status, and analgesic consumption and improvement in quality of life when compared with a placebo infusion. Symptomatic improvement corresponded with changes in the rate of bone resorption as indicated by the concentrations of pyridinoline crosslinks in the urine. In patients with the highest rates of bone resorption (N-terminal peptide-bound portion of the collagen crosslink or crosslaps excretion ≥ twice that of normal) clinical response or normalization of the rate of bone resorption were rarely observed, with all clinical responses occuring in those patients with bone resorption rates of 10%) fall in tumor marker levels, suggesting a possible effect of bisphosphonates on tumor activity. Cancer 1997; 80:1686-90. © 1997 American Cancer Society.

Long-term survival with carcinoma arising from a congenital choledochal cyst

We report a case of 11-year survival with carcinoma arising from a congenital choledochal cyst. A 34-year-old Japanese woman was admitted due to epigastric discomfort. Ultrasonography revealed a choledochal cyst involving a polypoid tumor. Endoscopic retrograde cholangiopancreatography revealed pancreaticobiliary maljunction in which the main pancreatic duct joined the dilated common bile duct 2 cm above the papilla of Vater. A choledochal cyst containing a polypoid tumor was resected with the regional lymph nodes. Grossly, a 2×2-cm papillary tumor was noted in the posterior wall of the choledochal cyst. Microscopically, the tumor was well-differentiated tubular adenocarcinoma invading the mucosa and fibromuscular layer. Neither anticancer chemotherapy nor radiotherapy was performed. The patient recovered uneventfully after the operation and has been well for 11 years without evidence of recurrent cancer. The good results in this patient may have been due to the early stage of the cancer.