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Volume 48, Issue 5
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Regular Papers
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AJ COLQUHOUN, LA MCHUGH, E. TULCHINSKY, M. KRIAJEVSKA, JK MELLON2007 Volume 48 Issue 5 Pages 351-360
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: July 03, 2007JOURNAL FREE ACCESSPurpose: External beam radiotherapy (EBRT) is the principal bladder-preserving monotherapy for muscle-invasive bladder cancer. Seventy percent of muscle-invasive bladder cancers express epidermal growth factor receptor (EGFR), which is associated with poor prognosis. Ionising radiation (IR) stimulates EGFR causing activation of cytoprotective signalling cascades and thus may be an underlying cause of radioresistance in bladder tumours.
Materials and methods: We assessed the ability of IR to activate EGFR in bladder cancer cells and the effect of the anti-EGFR therapy, gefitinib on potential radiation-induced activation. Subsequently we assessed the effect of IR on signalling pathways downstream of EGFR. Finally we assessed the activity of gefitinib as a monotherapy, and in combination with IR, using clonogenic assay in vitro, and a murine model in vivo.
Results: IR activated EGFR and gefitinib partially inhibited this activation. Radiation-induced activation of EGFR activated the MAPK and Akt pathways. Gefitinib partially inhibited activation of the MAPK pathway but not the Akt pathway. Treatment with combined gefitinib and IR significantly inhibited bladder cancer cell colony formation more than treatment with gefitinib alone (p = 0.001-0.03). J82 xenograft tumours treated with combined gefitinib and IR showed significantly greater growth inhibition than tumours treated with IR alone (p = 0.04).
Conclusions: Combining gefitinib and IR results in significantly greater inhibition of invasive bladder cancer cell colony formation in vitro and significantly greater tumour growth inhibition in vivo. Given the high frequency of EGFR expression by bladder tumours and the low toxicity of gefitinib there is justification to translate this work into a clinical trial.
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Niranjan ACHARYA, Nagla Fathi ABU-NASR, Genta KAWAGUCHI, Masaru IMAI, ...2007 Volume 48 Issue 5 Pages 361-368
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: July 05, 2007JOURNAL FREE ACCESSThe endogenous tonB gene of Escherichia coli was used as a target for 9-aminoacridine-induced mutations that were identified in recA- and uvrA- cells. The cytotoxicity of 9-aminoacridine was enhanced in the uvrA and recA strains compared to the wild-type strain, and the mutagenicity of 9-aminoacridine in the uvrA and recA strains was similar to that in the wild type. For all three strains, the most common mutations were minus frameshifts in repetitive G:C base-pairs followed by minus frameshfits in nonrepetitive G:C base-pairs. 9-aminoacridine-induced minus frameshifts in the wild-type strain were distributed with several hot and warm spots. These sites were also hot and warm spots for minus frameshifts in the recA and uvrA stains. Furthermore, they were hot and warm sites in a 9-aminoacridine-treated strain carrying the target tonB gene oriented in the opposite direction. 9-Aminoacridine is known to interact with DNA to form intercalations which are involved in minus frameshift mutagenesis. In this study, we therefore argue that 1) 9-aminoacridine can induce bulky DNA lesions which are excised by nucleotide excision repair and not involved in mutagenesis, 2) the presence or absence of a recA-dependent repair pathway does not influence the mutagenic effect of 9-aminoacridine, and 3) both leading strand and lagging strand replication equally produce minus frameshifts, therefore gene orientation is not an important determinant of the formation of hot and warm spots by 9-aminoacridine.
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Dani MATHEW, Cherupally Krishnan K. NAIR, Jasmin A. JACOB, Nandita BIS ...2007 Volume 48 Issue 5 Pages 369-376
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: August 28, 2007JOURNAL FREE ACCESSAscorbic acid monoglucoside (AsAG), a glucoside derivative of ascorbic acid, has been examined for its antioxidant and radioprotective abilities. AsAG neutralized 1, 1 diphenyl -2-picryl-hydrazyl (DPPH), a stable free radical in a concentration dependent manner thus indicating its antioxidant ability. AsAG protected mice liver tissues in vitro from peroxidative damage in lipids (measured as TBARS) resulting from 25Gy γ irradiation. It also protected plasmid pBR322 DNA from gamma-radiation induced strand breaks as evidenced from studies on agarose gel electrophoresis of the plasmid DNA after radiation exposure. Oral administration of AsAG to mice prior to whole body gamma radiation exposure (4Gy) resulted in a reduction of radiation induced lipid peroxides in the liver tissue indicating in vivo radiation protection of membranes. Pulse radiolysis studies indicated that AsAG offered radioprotection by scavenging free radicals. The rate constants for the reactions OH and N3 radicals with AsAG were determined to be 6.4 × 109 dm 3 mol-1 s-1 and 2.3 × 109 dm3 mol-1 s -1, respectively at pH 7. It was observed that AsAG radicals undergo conjugation as the pH of the solution is raised to 11 in the case of a one-electron oxidation reaction. As the OH· radical adds to the ring, the conjugation effect starts appearing at pH 10.
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Tomoyasu YASHIRO, Kumiko KOYAMA-SAEGUSA, Takashi IMAI, Takehiko FUJISA ...2007 Volume 48 Issue 5 Pages 377-383
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: August 08, 2007JOURNAL FREE ACCESSUsing cultured and nude mouse tumor cells (IA) derived from a human lung cancer, we previously demonstrated their radiosensitivity by focusing attention on the dynamics of tumor clonogens and the early and rapid survival recovery (potential lethal damage repair: PLD repair) occurring after X-ray irradiation. To the authors' knowledge, this is the first study demonstrating gene expression in association with PLD repair after carbon-ion beam or X-ray irradiation to cancer cells. In this study we tried to detect the mechanism of DNA damage and repair of the clonogens after X-ray or carbon-ion beam irradiation. At first, colony assay method was performed after irradiation of 12 Gy of X-ray or 5 Gy of carbon-ion beam to compare the time dependent cell survival of the IA cells after each irradiation pass. Second, to search the genes causing PLD repair after irradiation of X-ray or carbon-ion beam, we evaluated gene expressions by using semi-quantitative RT-PCR with the selected 34 genes reportedly related to DNA repair. The intervals from the irradiation were 0, 6, 12 and 24 hr for colony assay method, and 0, 3, 18 hr for RT-PCR method. From the result of survival assays, significant PLD repair was not observed in carbon-ion beam as compared to X-ray irradiation. The results of RT-PCR were as follows. The gene showing significantly higher expressions after X-ray irradiation than after carbon-ion beam irradiation was PCNA. The genes showing significantly lower expressions after X-ray irradiation rather than after carbon-ion beam irradiation were RAD50, BRCA1, MRE11A, XRCC3, CHEK1, MLH1, CCNB1, CCNB2 and LIG4. We conclude that PCNA could be a likely candidate gene for PLD repair.
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Kook Jin CHUN, Gwang Ho YOO2007 Volume 48 Issue 5 Pages 385-395
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: August 03, 2007JOURNAL FREE ACCESSData required for the determination of the absolute air kerma rate for 60Co and 137Cs gamma-rays using spherical cavity chambers were calculated using the EGS4 Monte Carlo system. Mass energy-absorption coefficient ratio and the stopping power ratio were calculated for a 10 cm3 primary standard graphite-walled ionization chamber from the unfolded energy pulse height distributions of 60Co and 137Cs sources. Wall correction factors and non-uniformity correction factors for two graphite and one air equivalent plastic walled ionization chambers were also calculated with EGS4 code. The wall correction factors were compared with those determined by an experimental extrapolation method.
To check the accuracy of the calculations the results were compared with those obtained from other primary standard laboratories such as NIST and NRCC. For a 10 cm3 graphite ionization chamber, the mass energy-absorption coefficient ratios were 0.99917 for 60Co and 1.0004 for 137Cs. The values differed by 0.02~0.05 % for 60Co and 0.11 % for 137Cs from those of two laboratories. The stopping power ratios were 0.99984 for 60Co and 1.0087 for 137Cs. Comparison with NIST values showed differences of 0.06 % for 60Co and 0.04 % for 137Cs.
The wall correction factors were obtained and they were different by 0.6~1.1 % for 60Co and 137Cs compared to the experimental linear extrapolation method. These values were compared with Monte Carlo derived values from other laboratories.
The non-uniformity correction factors were also calculated and they differed from unity, the traditional value used in most standard national metrology laboratories.
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Satoru ENDO, Masashi TAKADA, Yoshihiko ONIZUKA, Kenichi TANAKA, Naoko ...2007 Volume 48 Issue 5 Pages 397-406
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: August 09, 2007JOURNAL FREE ACCESSMicrodosimetric single event spectra as a function of depth in a phantom for the 290 MeV/nucleon therapeutic carbon beam at HIMAC were measured by using a tissue equivalent proportional counter (TEPC). Two types of geometries were used: one is a fragment particle identification measurement (PID-mode) with time of flight (TOF) method without a backward phantom, and the other is an in-phantom measurement (IPM-mode) with a backward phantom.
On the PID-mode geometry, fragments produced by carbon beam in a phantom are identified by the ΔE-TOF distribution between two scintillation counters positioned up- and down-stream relative to the tissue equivalent proportional counter (TEPC). Lineal energy distributions for carbon and five ion fragments (proton, helium, lithium, beryllium and boron) were obtained in the lineal-energy range of 0.1-1000 keV/μm at eight depths (7.9-147.9 mm) in an acrylic phantom. In the IPM-mode geometry, the total lineal energy distributions measured at eight depths (61.9-322.9 mm) were compared with the distributions in the PID-mode. Both spectra are consistent with each other. This shows that the PID-mode measurement can be discussed as the equivalent of the phantom measurement. The dose distribution of the carbon beam and fragments were obtained separately. In the depth dose curve, the Bragg peak was observed.
Relative biological effectiveness (RBE) for the carbon beam in the acrylic phantom was obtained based on a biological response function as a lineal-energy. The RBE of carbon beam had a maximum of 4.5 at the Bragg peak. Downstream of the Bragg peak, the RBE rapidly decreases. The RBE of fragments is dominated by Boron particles around the Bragg peak region.
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Cha Soon KIM, Jin-Mo KIM, Seon Young NAM, Kwang Hee YANG, Meeseon JEON ...2007 Volume 48 Issue 5 Pages 407-415
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: July 27, 2007JOURNAL FREE ACCESSThis study shows the human cellular responses and the mechanism of low-dose ionizing radiation in CCD 18 Lu cells, which are derived from normal human lung fibroblasts. Cell proliferation and viability assay were measured for the cells following γ-irradiation using trypan blue, BrdU incorporation, and Wst-1 assay. We also examined genotoxicity using a micronuclei formation assay. The activation of the MAPKs pathway was determined by Western blot analysis, and the siRNA system was used to inhibit the expression of ERK1/2 and p38. We found that 0.05 Gy of ionizing radiation stimulated cell proliferation and did not change Micronuclei frequencies. In addition, 0.05 Gy of ionizing radiation activated ERK1/2 and p38, but did not activate JNK1/2 in cells. A specific ERK1/2 inhibitor, U0126, decreased the phosphorylation of ERK1/2 proteins induced by 0.05 Gy of ionizing radiation, and a similar suppressive effect was observed with a p38 inhibitor, PD169316. Suppression of ERK1/2 and p38 phosphorylation with these inhibitors decreased cell proliferation, which was stimulated by 0.05 Gy of ionizing radiation. Furthermore, downregulation of ERK1/2 and p38 expression using siRNA blocked the cell proliferation that had been increased by 0.05 Gy of ionizing radiation. These results suggest that 0.05 Gy of ionizing radiation enhances cell proliferation through the activation of ERK1/2 and p38 in normal human lung fibroblasts.
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Shin-Ichiro YONEKURA, Nobuya NAKAMURA, Takashi DOI, Hiroshi SUGIYAMA, ...2007 Volume 48 Issue 5 Pages 417-424
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: July 18, 2007JOURNAL FREE ACCESSBacteria and eukaryotes possess redundant enzymes that recognize and remove oxidatively damaged bases from DNA through base excision repair. DNA glycosylases remove damaged bases to initiate the base excision repair. The exocyclic methyl group of thymine does not escape oxidative damage to produce 5-formyluracil (5-foU) and 5-hydroxymethyluracil (5-hmU). 5-foU is a potentially mutagenic lesion. A homolog of E. coli endonuclease III (SpNth1) had been identified and characterized in Shizosaccharomyces pombe. In this study, we found that SpNth1 recognizes and removes 5-foU and 5-hmU from DNA with similar efficiency. The specific activities for the removal of 5-foU and 5-hmU were comparable with that for thymine glycol. The expression of SpNth1 reduced the hydrogen peroxide toxicity and the frequency of spontaneous mutations in E. coli nth nei mutant. It was also revealed that SpNth1 had DNA glycosylase activity for removing 8-oxo-7,8-dihydroguanine (8-oxoG) from 8-oxoG/G and 8-oxoG/A mispairs. These results indicated that SpNth1 has a broad substrate specificity and is involved in the base excision repair of 8-oxoG and thymine residues oxidized in the methyl group in S. pombe.
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F. POUZOULET, S. ROCH-LEFÈVRE, AL. GIRAUDET, A. VAURIJOUX, Pa. ...2007 Volume 48 Issue 5 Pages 425-434
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: August 31, 2007JOURNAL FREE ACCESSPurpose: To compare translocation rate using either M-FISH or FISH-3 in two patients treated for head and neck cancer, with a view to retrospective dosimetry.
Materials and methods: Translocation analysis was performed on peripheral blood lymphocyte cultures from blood samples taken at different times during the radiotherapy (0 Gy, 12 Gy and 50 Gy) and a few months after the end of the treatment (follow-up).
Results: Estimated translocation yield varied according to the FISH technique used. At 50 Gy and follow-up points, the translocation yields were higher with FISH-3 than with M-FISH. This difference can be attributed to three events. First, an increase in complex aberrations was observed for 50 Gy and follow-up points compared with 0 Gy and 12 Gy points. Second, at the end of treatment for patient A, involvement of chromosomes 2, 4, 12 in translocations was less than expected according to the Lucas formula. Third, a clone bearing a translocation involving a FISH-3 painted chromosome was detected.
Conclusions: More translocations were detected with M-FISH than with FISH-3, and so M-FISH is expected to improve the accuracy of chromosome aberration analyses in some situations.
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Jinsil SEONG, Hae Jin OH, Jiyoung KIM, Jeung Hee AN, Wonwoo KIM2007 Volume 48 Issue 5 Pages 435-441
Published: 2007
Released on J-STAGE: September 20, 2007
Advance online publication: August 23, 2007JOURNAL FREE ACCESSIn this study, we investigated the molecular factors determining the induction of apoptosis by radiation. Two murine tumors syngeneic to C3H/HeJ mice were used: an ovarian carcinoma OCa-I, and a hepatocarcinoma HCa-I. Both have wild type p53, but display distinctly different radiosensitivity in terms of specific growth delay (12.7 d in OCa-I and 0.3 d in HCa-I) and tumor cure dose 50% (52.6 Gy in OCa-I and > 80 Gy in HCa-I). Eight-mm tumors on the thighs of mice were irradiated with 25 Gy and tumor samples were collected at regular time intervals after irradiation. The peak levels of apoptosis were 16.1 ± 0.6% in OCa-I and 0.2 ± 0.0% in HCa-I at 4 h after radiation, and this time point was used for subsequent proteomics analysis. Protein spots were identified by peptide mass fingerprinting with a focus on those related to apoptosis. In OCa-I tumors, radiation increased the expression of cytochrome c oxidase and Bcl2/adenovirus E1B-interacting 2 (Nip 2) protein higher than 3-fold. However in HCa-I, these two proteins showed no significant change.
The results suggest that radiosensitivity in tumors with wild type p53 is regulated by a complex mechanism. Furthermore, these proteins could be molecular targets for a novel therapeutic strategy involving the regulation of radiosensitivity.
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