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Conclusions: It is likely that the in vitro and in vivo repopulation seen in our experiment was associated with repressed expression of CDK inhibitors p16 and p57 and low levels p53 transactivation activity. Furthermore, our data suggest the modification of p53-dependent transcriptional machinery as a possible mechanism of repopulation. Author Disclosure: T. Nishioka, None; M. Yasuda, None; H. Shirato, None. 2679 The Effect of NQO1 Polymorphisms on Prognosis of Non-Small Cell Lung Cancer After Postoperative Radiation Therapy S. Y. Song 1 , H. J. Park 2 , J. E. Lee 3 , S. S. Shin 1 , S. Lee 1 , S. D. Ahn 1 , J. H. Kim 1 , J. S. Lee 4 , C. I. Park 5 , E. K. Choi 1 1 Dept. of Radiation Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea, 2 Dept. of Microbiology, College of Medicine, Inha University, Incheon, Republic of Korea, 3 DNA Link Inc., Seoul, Republic of Korea, 4 Dept. of Medical Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea, 5 Dept. of Radiation Oncology, College of Medicine, Seoul National University, Seoul, Republic of Korea Purpose/Objective(s): NQO1 is an enzyme that catalyzes the two-electron reduction of the more toxic quinone to less toxic hydroquinone. It is known that NQO1 may decrease the risk of cancer development in normal human tissue, and NQO1 polymorphism affect on the treatment outcome after chemotherapy in lung cancer. We investigated the effect of NQO1 polymorphism on radiation therapy on non-small cell lung cancer (NSCLC) patients treated with surgery followed by postoperative radiation therapy. Materials/Methods: One hundred and fifty-two patients who were histologically proven NSCLC treated with surgery and postoperative radiation therapy from January 2000 to August 2005 at Asan Medical Center were analyzed. We determined NQO1 genotypes from peripheral blood of patients. NQO1 genotypes were classified as three groups, and each genotype had different enzymatic activities; C/C is wild type with normal activity, C/T is heterozygous mutated with decreased activity, and T/T is homozygous mutated with no enzymatic activity. Thereafter, we analyzed the correlation between NQO1 genotypes and the survival outcome after postoperative radiation therapy. For the authenticity of genotype from peripheral blood, genotypic analysis directly from tumor tissue was performed. Results: Numbers of patients in each NQO1 genotype were 41 patients for C/C, 83 patients for C/T, and 28 patients for T/T genotype. Patients characteristics including combined chemotherapy were not different between groups. Median follow-up period was 19.7 months. NQO1 genotype had an effect on loco-regional control and survival. Patients expressing C/C and C/T genotype who had NQO1 enzymatic activity had significant longer loco-regional progression free survival (89.2% vs. 68.3% at 2yr, p0.034) and overall survival (90.2% vs. 70.6% at 2yr, p0.020) than patients expressing T/T genotype who had no enzymatic activity. Conclusions: NQO1 polymorphisms had an effect on survival outcome in NSCLC patients treated with surgery and postoperative radiation therapy. NQO1 could be a useful prognostic factor for NSCCL after radiation therapy, although further study with more patients and long-term follow-up should be needed. Author Disclosure: S.Y. Song, None; H.J. Park, None; J.E. Lee, None; S.S. Shin, None; S. Lee, None; S.D. Ahn, None; J.H. Kim, None; J.S. Lee, None; C.I. Park, None; E.K. Choi, None. 2680 Microarray Analysis of the Transcriptional Response To Carbon Ion Irradiation in Murine Tumors K. Nojiri, K. Imadome, M. Sakai, M. Goto, Y. Matumoto, A. Ishikawa, M. Iwakawa National Institute of Radiological Sciences, Chiba, Japan Purpose/Objective(s): The purpose of this study was to identify molecular mechanism induced by carbon ion radiotherapy in order to provide information on potential targets for prediction of its effectiveness. Materials/Methods: Murine squamous cell carcinomas, NR-S1 (resistant to gamma-irradiation), and SCCVII (sensitive), were transplanted in hind legs of C3H/He male mice and established solid tumors (7.5– 8.5 mm in diameter) were locally irradiated with carbon ion beam at 30Gy. Carbon-12 ions were accelerated by the Heavy Ion Medical Accelerator in Chiba or HIMAC synchrotron up to 290 MeV/u with a dose rate of approximately 3 Gy /min. Tumor growth delay (TGD) time, reduction rate of tumor, and recurrence rate of tumor were investigated as parameters of radiosensitivity of tumors. The mice were sacrificed and immediately dissected before irradiation and after different time points, such as 6,12,18h, 1, 3, 5, 7, 10, 15, 20 days after irradiation or recurrence for transcriptome assays and pathological investigation. Expression analyses were performed using single-color analysis microarrays consisting of 55k genes. Principal Compornent Analysis (PCA) was used to investigate similarity of comprehensive overview of the changes in gene expression between expression profiles of two tumors. Analysis of variance (ANOVA) was applied to the intensity of each tumor at different time point to evaluate significant differences. Results: TGD time of NR-S1 and SCCVII was 30 days and 56 days, reduction rate of NR-S1 and SCCVII was 40% and 100%, and recurrence rate of NR-S1 and SCCVII was 75% and 50%, respectively.PCA showed that all expression profiles of NR-S1 were identified as a group, while those of SCCVII were identified as another group. Recurred tumors showed different profiles from non-irradiation control tumors. We detected genes, whose expressions were significantly up-regulated or down regulated at each time point after carbon-irradiation (p value 0.0001). At 6 hours after irradiation, fourteen genes, which were related with cell cycle regulation, were differentially expressed in both tumors. Eleven genes, which were related with inflammation or extracellular matrix, were up-regulated at 6 hours in both tumors, however, their expression changes on time-course were different. Pathological specimen showed duplet cells in both tumors 1 day after irradiation and continuous infiltration of inflammatory cells in SCCVII. Conclusions: Tumor growth assays revealed that two murine tumors, which have different radiosensitivity to gamma irradiation, kept their intrinsic radiosensitivity to carbon-ion irradiation. Transcriptional profiling of two tumors identified a number of carbon-ion irradiation response genes in murine tumors. We have also identified genes as being candidates for predictive markers of radiosensitivity to carbon-ion therapy. S587 Proceedings of the 48th Annual ASTRO Meeting
Transcript of 2679
Conclusions: It is likely that the in vitro and in vivo repopulation seen in our experiment was associated with repressedexpression of CDK inhibitors p16 and p57 and low levels p53 transactivation activity. Furthermore, our data suggest themodification of p53-dependent transcriptional machinery as a possible mechanism of repopulation.
Author Disclosure: T. Nishioka, None; M. Yasuda, None; H. Shirato, None.
2679 The Effect of NQO1 Polymorphisms on Prognosis of Non-Small Cell Lung Cancer After PostoperativeRadiation Therapy
S. Y. Song1, H. J. Park2, J. E. Lee3, S. S. Shin1, S. Lee1, S. D. Ahn1, J. H. Kim1, J. S. Lee4, C. I. Park5, E. K. Choi1
1Dept. of Radiation Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea,2Dept. of Microbiology, College of Medicine, Inha University, Incheon, Republic of Korea, 3DNA Link Inc., Seoul, Republicof Korea, 4Dept. of Medical Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic ofKorea, 5Dept. of Radiation Oncology, College of Medicine, Seoul National University, Seoul, Republic of Korea
Purpose/Objective(s): NQO1 is an enzyme that catalyzes the two-electron reduction of the more toxic quinone to less toxichydroquinone. It is known that NQO1 may decrease the risk of cancer development in normal human tissue, and NQO1polymorphism affect on the treatment outcome after chemotherapy in lung cancer. We investigated the effect of NQO1polymorphism on radiation therapy on non-small cell lung cancer (NSCLC) patients treated with surgery followed bypostoperative radiation therapy.
Materials/Methods: One hundred and fifty-two patients who were histologically proven NSCLC treated with surgery andpostoperative radiation therapy from January 2000 to August 2005 at Asan Medical Center were analyzed. We determinedNQO1 genotypes from peripheral blood of patients. NQO1 genotypes were classified as three groups, and each genotype haddifferent enzymatic activities; C/C is wild type with normal activity, C/T is heterozygous mutated with decreased activity, andT/T is homozygous mutated with no enzymatic activity. Thereafter, we analyzed the correlation between NQO1 genotypes andthe survival outcome after postoperative radiation therapy. For the authenticity of genotype from peripheral blood, genotypicanalysis directly from tumor tissue was performed.
Results: Numbers of patients in each NQO1 genotype were 41 patients for C/C, 83 patients for C/T, and 28 patients for T/Tgenotype. Patients characteristics including combined chemotherapy were not different between groups. Median follow-upperiod was 19.7 months. NQO1 genotype had an effect on loco-regional control and survival. Patients expressing C/C and C/Tgenotype who had NQO1 enzymatic activity had significant longer loco-regional progression free survival (89.2% vs. 68.3%at 2yr, p�0.034) and overall survival (90.2% vs. 70.6% at 2yr, p�0.020) than patients expressing T/T genotype who had noenzymatic activity.
Conclusions: NQO1 polymorphisms had an effect on survival outcome in NSCLC patients treated with surgery andpostoperative radiation therapy. NQO1 could be a useful prognostic factor for NSCCL after radiation therapy, although furtherstudy with more patients and long-term follow-up should be needed.
Author Disclosure: S.Y. Song, None; H.J. Park, None; J.E. Lee, None; S.S. Shin, None; S. Lee, None; S.D. Ahn, None; J.H.Kim, None; J.S. Lee, None; C.I. Park, None; E.K. Choi, None.
2680 Microarray Analysis of the Transcriptional Response To Carbon Ion Irradiation in Murine Tumors
K. Nojiri, K. Imadome, M. Sakai, M. Goto, Y. Matumoto, A. Ishikawa, M. Iwakawa
National Institute of Radiological Sciences, Chiba, Japan
Purpose/Objective(s): The purpose of this study was to identify molecular mechanism induced by carbon ion radiotherapy inorder to provide information on potential targets for prediction of its effectiveness.
Materials/Methods: Murine squamous cell carcinomas, NR-S1 (resistant to gamma-irradiation), and SCCVII (sensitive), weretransplanted in hind legs of C3H/He male mice and established solid tumors (7.5–8.5 mm in diameter) were locally irradiatedwith carbon ion beam at 30Gy. Carbon-12 ions were accelerated by the Heavy Ion Medical Accelerator in Chiba or HIMACsynchrotron up to 290 MeV/u with a dose rate of approximately 3 Gy /min. Tumor growth delay (TGD) time, reduction rateof tumor, and recurrence rate of tumor were investigated as parameters of radiosensitivity of tumors. The mice were sacrificedand immediately dissected before irradiation and after different time points, such as 6,12,18h, 1, 3, 5, 7, 10, 15, 20 days afterirradiation or recurrence for transcriptome assays and pathological investigation. Expression analyses were performed usingsingle-color analysis microarrays consisting of 55k genes. Principal Compornent Analysis (PCA) was used to investigatesimilarity of comprehensive overview of the changes in gene expression between expression profiles of two tumors. Analysisof variance (ANOVA) was applied to the intensity of each tumor at different time point to evaluate significant differences.
Results: TGD time of NR-S1 and SCCVII was 30 days and 56 days, reduction rate of NR-S1 and SCCVII was 40% and 100%,and recurrence rate of NR-S1 and SCCVII was 75% and 50%, respectively.PCA showed that all expression profiles of NR-S1were identified as a group, while those of SCCVII were identified as another group. Recurred tumors showed different profilesfrom non-irradiation control tumors. We detected genes, whose expressions were significantly up-regulated or down regulatedat each time point after carbon-irradiation (p value� 0.0001). At 6 hours after irradiation, fourteen genes, which were relatedwith cell cycle regulation, were differentially expressed in both tumors. Eleven genes, which were related with inflammationor extracellular matrix, were up-regulated at 6 hours in both tumors, however, their expression changes on time-course weredifferent. Pathological specimen showed duplet cells in both tumors 1 day after irradiation and continuous infiltration ofinflammatory cells in SCCVII.
Conclusions: Tumor growth assays revealed that two murine tumors, which have different radiosensitivity to gammairradiation, kept their intrinsic radiosensitivity to carbon-ion irradiation. Transcriptional profiling of two tumors identified anumber of carbon-ion irradiation response genes in murine tumors. We have also identified genes as being candidates forpredictive markers of radiosensitivity to carbon-ion therapy.
S587Proceedings of the 48th Annual ASTRO Meeting
