The p53 gene has a significant role in controlling genomic stability of cancer. The purpose of this study was to evaluate the tumor response of allograft colorectal tumor treated with Ad5CMV-p53 in a syngeneic rat model. Two weeks after the inoculation of WB-2054-M5 tumor cells in the flank of rats, rats were randomly assigned by tumor size to one of three groups (n=18 in each): phosphate buffered saline (PBS), Ad5CMV, and Ad5CMV-p53. Recombinant adenovirus or PBS was administered through intratumoral injection at three divided doses every other day for 4 weeks. Apoptosis of the tumors was evaluated using TUNEL assay. After 2 and 4 weeks of treatment, the volume (cm3) of tumors in PBS, Ad5CMV, and Ad5CMV-p53 was as follows: 2 week: 1.66 +/-0.43, 1.40 +/-0.47, 0.75 +/-0.26 (p<0.001), 4 week: 4.41 +/-0.88, 3.93 +/-1.86, 2.33 +/-0.51 (p<0.001). Tumor growth showed no statistically significant difference between the PBS and Ad5CMV groups (6-week vol. p=0.32). The TUNEL assay results revealed more apparent apoptotic cells in Ad5CMV-p53-treated tumors than in other groups. Growth of allograft colorectal cancer in the syngeneic rat model was significantly suppressed by intratumoral Ad5CMV-p53 gene therapy. These results demonstrate that gene replacement therapy with p53 may provide a novel modality of treatment in conjunction with other present treatments for metastatic colorectal cancer.
Adenocarcinoma/genetics/pathology/therapy ; Adenoviridae/*genetics ; Animals ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival/genetics ; Colorectal Neoplasms/*genetics/pathology/*therapy ; Disease Models, Animal ; Female ; Gene Therapy/*methods ; Gene Transfer Techniques ; Men ; Protein p53/*genetics/*therapeutic use ; Rats ; Rats, Inbred WF ; Recombinant Proteins/therapeutic use ; Research Support, Non-U.S. Gov't ; Transplantation, Isogeneic ; Treatment Outcome

PURPOSE: It was studied that the relationship between radiation dose, dose rate and the frequency of chromosomal aberrations in peripheral lymphocytes. METHODS AND MATERIALS: Peripheral lymphocytes were irradiated in vitro with 6 MeV X-ray at dose ranges from 50 cGy to 800 cGy. The variations of the frequency of chromosomal aberrations were observed according to different radiation dose rate from 20 cGy/min to 400 cGy/min at constant total dose of 400 cGy which it was considered as factor to correct biological radiation dose measurement. RESULTS: The yields of lymphocytes with chromosomal aberrations (dicentric chromosome, ring chromosome, acentric fragment pairs) are 0% at 50 cGy, 9% at 100 cGy, 20% at 200 cGy, 27% at 300 cGy, 55% at 400 cGy, 88% at 600 cGy, and 100% at 800 cGy. The value of Ydr is 0.000 at 50 cGy, 0.093 at 100 cGy, 0.200 at 200 cGy, 0.364 at 300 cGy, 0.612 at 400 cGy, 2.040 at 600 cGy, and 2.846 at 800 cGy. The relationship between radiation (D) and the frequency of dicentric chromosomes and ring chromosomes (Ydr) can be expressed as Ydr=0.188x10-2/GyxD+0.422x10-4/Gy2xD2. The value of Qdr is 0.000 at 50 cGy, 1.000 at 100 cGy, 1.000 at 200 cGy, 1.333 at 300 cGy, 1.118 at 400 cGy, 2.318 at 600 cGy, and 2.846 at 800 cGy. When 400 cGy is irradiated with different dose rate each of 20, 40, 60, 80, 100, 160, 240, 320, and 400 cGy/min, Ydr is each of 0.982, 0.837, 0.860, 0.732, 0.763, 0.966, 0.909, 1.006, and 0.806, and Qdr is each of 1.839, 1.565, 1.654, 1.333, 1.381, 1.750, 1.6000, 1.710, and 1.318. CONCLUSION: There are not the significant variations of Ydr and Qdr values according to different dose rate. And so radiation damage is influenced by total exposed radiation doses and is influenced least of all by different dose rate when it is acute single exposure.
Chromosome Aberrations* ; Lymphocytes* ; Ring Chromosomes