PURPOSE: Histone deacetylase inhibitors (HDIs) are emerging as potentially useful components of anticancer therapy and their radiosensitizing effects have become evident. Specific HDIs are now available that preferentially inhibit specific HDAC classes; TSA inhibits Class I and II HDACs, and SK7041 inhibits Class I HDACs. MATERIALS AND METHODS: We tested the differential radiosensitization induced by two different classes of HDIs in HeLa cells. We next tested the hypothesis that p53 expression in cancer cells may influence the susceptibility to HDIs by using pharmacologic modification of the p53 status under an isogenic background. RESULTS: It is interesting that p53 expression in the HeLa cells clearly increased the degree of radiosensitization by TSA compared to that of the class I specific inhibitor SK7041. This suggests that p53 may, in part, be responsible for the mechanistic role for the greater radiosensitization induced by Class I & II inhibitors compared to that of the class I specific inhibitors. Thus, these studies are useful in distinguishing between events mediated solely by the Class I HDACs versus those events involving the other classes of HDACs as well. CONCLUSION: The anticancer efficacy of targeting Class I and II HDACs, in conjunction with radiation therapy, may be further enhanced by the restoration of p53 expression.
HeLa Cells* ; Histone Deacetylase Inhibitors ; Humans ; Radiation-Sensitizing Agents

PURPOSE: To evaluate the effect of all-trans-retinoic acid on radiosensitivity and radiation-induced apoptosis in NHOK, HEp-2 and FaDu cell lines. Material and Methods : We measured the changes in survival fraction at 2 Gy (SF2), alpha and beta after treatment of retinoic acid (1 microM) prior to irradiation with doses of 2, 4, 6 and 10 Gy and correlated the radiosensitizing effect of retinoic acid with them. Also, apoptosis induction was assayed with the flow cytometry on days 1, 2, 3, 4 and 5 after irradiation (2, 10 and 20 Gy) combined with retinoic acid. Results and CONCLUSION: SF2 values for NHOK, HEp-2 and FaDu cell lines were 0.54, 0.64 and 0.41, respectively and the cell line of FaDu was the most radiosensitive. For cell lines of NHOK and HEp-2, pretreatment of cells with retinoic acid resulted in a significant decrease of the SF2 values. The alpha/betaratios of x-ray survival curve were 8.714 (NHOK), 4.098 (HEp-2) and 11.79 (FaDu). The alpha/beta ratio for NHOK decreased on pretreatment with retinoic acid, whereas those for HEp-2 and FaDu increased. Radiation induced apoptosis in all cell lines but, retinoic acid did not affect the apoptosis.
Apoptosis* ; Carcinoma, Squamous Cell* ; Cell Line* ; Flow Cytometry ; Head* ; Neck* ; Radiation Tolerance* ; Radiation-Sensitizing Agents ; Tretinoin*

To evaluate the influence of tourniquet ischemia and hyperthermia on the radiation effect of skin, theexperimental study was undertaken using a total of 344 mice. A single dose of irradiation from 2000 rads to 8000rads was delivered on skin of mouse tail after hyperthermia of 40degrees(C) to 42degrees(C) with or withouttourniquet application in various subgroups. The resuls are summarized as follows; 1. Tourniquet ischemia duringirradiation caused radioprotective effect. 2. Hyperthermia before irradiation induced radiosensitizing effect,which was increased with temperature elevation of hyperthermia. 3. In combination of tourniquet ischemia andhyperthermia, evident radiosensitizing effect waas noticed. This enhancing effect on irradiation was greater thanthe effect i hyperthermia only. It could be suggested that the combination of tourniquet application andhyperthermia might be intorduced in clinical radiotherapy after trail of clinical experiments on applicable typeand sutiable location of tumors.
Animals ; Fever ; Ischemia ; Mice ; Radiation Effects ; Radiation-Sensitizing Agents ; Radiotherapy ; Skin ; Tail ; Tourniquets

The author evaluated the effects of taxol, a microtubular inhibitor, as a possible radiation sensitizer and the production of prostaglandins on three human cancer cell lines(KB, RPMI-2650 and SW-13) and one murine cell line(L929). Each cell line was divided into four groups(control, taxol only, radiation only and combination of taxol and radiation). The treatment consisted of a single irradiation of 10 Gy and graded doses(5, 50, 100, 200, 300, 500 nM) of taxol for a 24-h period. The cytotoxicity of taxol alone was measured at 1 day after(1-day group) and 4 days after(4-day group) the treatment. The survival ratio of cell was analyzed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-dimethyl tetrazolium bromide) test. Prostaglandins(PGE2 and PGI2) were measured in the culture medium by a radioimmunoassay. The results obtained were as follows ; 1. There was a significantly in creased cytotoxicity of KB cells in 4-day group than those in 1-day group. Therr was a high correlation between doses of taxol and cell viability in both groups(1-day group R=0.82741, 4-day group R=0.84655). 2. There was a significantly increased cytotoxicity of RPMI-2650 cells treated with high concentration of taxol in 4-day group than those in 1-day group. Also there was a high correlation between doses of taxol and cell viability in 4-day group(R=0.93917). 3. There was a significantly increased cytotoxicity of SW-13 cell treated with high concentration of taxol in 4-day group than those in 1-day group. However no high correlation was observed between doses of taxol and cell viability in both groups(1-day group R=0.46362, 4-day group R=0.65425). 4. There was a significantly increased cytotoxicity of L929 cells treated with low concentration of taxol in 4-day group than those in 1-day group. At the same time, there was a low correlation between doses of taxol and cell viability in both groups(1-day group R=0.34237, 4-day group R=0.23381). 5. In 1-day group of L929 cells, higher cytotoxicities were observed in the groups treated with 500 nM taxil than given 10 Gy radiation alone showed a radiosensitizing effect by taxol. 6. In addition to L929 cells, all cancer cells treated with a commbinationof taxol and radiation in 4-day group appeared ti have some fragmented nuclei and to float on the medium. In addition, L929 cells appeared to be more confluent. 7. The level of PGE2 production was the highest in the contol KB cells. This appeared to increase in every experimental group of all three cancer except L929 cells. There was a significantly increased production of PGE2 in SW-13 cells treated with a combination taxol and radiation compared to the other experimental groups. 8. The level of PGI2 production in the contol group RPMI-2650 cells was the highest. This appeared to increase in every experimental group of all cells except in SW-13 cells. This also increased signigicantly in RPMI-2650 cells treated with a cimbination of taxol and radiation compared to the other experimental groups.
Cell Line ; Cell Survival ; Dinoprostone ; Epoprostenol ; Humans ; KB Cells ; Paclitaxel* ; Prostaglandins ; Radiation Dosage ; Radiation, Ionizing* ; Radiation-Sensitizing Agents ; Radioimmunoassay

PURPOSE: Flavopiridol enhanced radiation-induced apoptosis of cancer cells in our previous in vitro study. The purpose of this study was to assess if flavopiridol could enhance the radioresponse of mouse mammary tumors in vivo. MATERIALS AND METHODS: Balb/c mice bearing EMT-6 murine mammary carcinoma were treated with flavopiridol only, radiation only, or both for 7 days. Flavopiridol was administered 2.5 mg/kg twice a day intraperitoneally (IP). Radiation was delivered at a 4 Gy/fraction at 24-h intervals for a total dose of 28 Gy. Tumor volume was measured and compared among the different treatment groups to evaluate the in vivo radiosensitizing effect of flavopiridol. Tumors were removed from the mice 20 days after treatment, and TUNEL and Immunohistochemical stainings were performed. RESULTS: Significant tumor growth delay was observed in the radiation only and combined treatment groups, when compared with the control group. However, there was no significant difference between the tumor growth curves of the control and flavopiridol only group or between the radiation only and combination treatment group. Apoptotic cells of different treatment groups were detected by terminal deoxynucleotidyl transferase-medicated nick end labeling (TUNEL) staining. The expressions of Ku70 in tumor tissues from the different groups were analyzed by immunohistochemistry. Similarly, no significant difference was found between the apoptotic rate or Ku70 expression among the different treatment groups. CONCLUSION: Flavopiridol did not show evidence of enhancing the radioresponse of mouse mammary tumors in this study.
Animals ; Apoptosis ; Flavonoids ; Immunohistochemistry ; In Situ Nick-End Labeling ; Mice ; Piperidines ; Radiation-Sensitizing Agents ; Tumor Burden ; Ursidae

PURPOSE: Capecitabine is an attractive oral chemotherapeutic agent that has a radiosensitizing effect and tumor-selectivity. This study was performed to evaluate the efficacy and toxicity of preoperative chemoradiation therapy, when used with oral capecitabine, for locally advanced rectal cancer. MATERIALS AND METHODS: A prospective phase II trial of preoperative chemoradiation for locally advanced adenocarcinomas of the lower two-thirds of the rectum was conducted. A radiation dose of 50 Gy over five weeks and a daily dose of 1650 mg/m2 capecitabine in two potions was administered during the entire course of radiation therapy. Surgery was performed with standardized total mesorectal excision four to six weeks after completion of the chemoradiation. RESULTS: Between January 2002 and September 2003, 61 patients were enrolled onto this prospective phase II trial. The pretreatment clinical stages were T3 in 64% (n=39), T4 in 36% (n=22) and N1-2 in 82% (n=50) of these patients. Fifty-six (92%) patients completed the chemoradiation as initially planned and a complete resection performed in 58 (95%). Down-staging was observed in 45 patients (74%) and a pathologic complete response in 6 (10%). Among the 37 patients with tumors located within 5 cm from the anal verge on colonoscopy, 27 (73%) underwent a sphincter-preserving procedure. No grade 3 and 4 proctitis or hematological toxicities were observed. CONCLUSION: Preoperative chemoradiation therapy with capecitabine achieved encouraging rates of tumor down-staging and sphincter preservation, with a low toxicity profile. This combined modality can be regarded as a safe and effective treatment for locally advanced rectal cancer.
Adenocarcinoma ; Chemoradiotherapy ; Colonoscopy ; Humans ; Proctitis ; Prospective Studies* ; Radiation-Sensitizing Agents ; Rectal Neoplasms* ; Rectum ; Capecitabine

Esophageal cancer is still a virulent disease that leads to death. Surgery has been regarded as the treatment of choice in patients suffering this type of cancer and recent improvements in surgical techniques and perioperative management have significantly increased the resection rate and reduced the operative mortality. Nevertheless, long-term survival rates remain poor. The poor prognosis reflects the fact that the disease is usually advanced at the time of diagnosis. Therefore, a combination of chemotherapy and radiotherapy has recently been developed as a treatment for advanced esophageal cancer patients. Chemoradiation therapy is based on the concept of the biochemical modulation effects and radiosensitizing effects of the chemotherapeutic agents. How ever, the optimal choice of chemotherapeutic agents and their doses, as well as the chemotherapy and radiotherapy regimens have not been precisely established. We report a case of concurrent chemoradiation protocol by which a complete response was achieved. 5-FU (1,800 mg/body/day) was continuously infused over 24 hours and cisplatin (45 mg/ body/day) was administered 1 hour before radiotherapy for 3 days. This chemotherapy course was repeated once more after 4 weeks. The radiotherapy (180 cGy/day) was scheduled for 5 consecutive days, followed by a 2-day withdrawal, and a total dose of 5,940 cGy within 7 weeks. Our concurrent chemoradiation therapy is deemed rational, effective and safe because an endoscopically and pathologically complete response was achieved 1 year after chemoradiation therapy without any severe side effects. Therefore, we believe that our concurrent chemoradiation therapy can be recommended as a treatment for advanced esophageal cancer patients.
Cisplatin ; Diagnosis ; Drug Therapy ; Esophageal Neoplasms* ; Fluorouracil ; Humans ; Mortality ; Prognosis ; Radiation-Sensitizing Agents ; Radiotherapy ; Survival Rate

OBJECTIVE: This study was performed to evaluate the radiosensitizing effect of combined administration of 13-cis-retinoic acid (cRA) and interferon-alpha-2a (INF) in normal cervical keratinocyte and cervical cancer cell lines. METHODS: cRA, INF and radiotherapy was applied to cervical cancer cell lines (HT-3 and HeLa cells) to obtain optimum dose 20% cytotoxicity in MTT assay from each treatment. The dose was determined as 1.8 Gy for radiation, 10uM for cRA, and 1,000 U/ml for INF. Primary cultured cervical keratinocyte (PCCK), HT-3 and HeLa cells were treated with cRA and INF alone or in combination and compared with untreated control cells. Finally, radiotherapy was added to the cRA and INF treatment. RESULTS: The treatment of cRA and INF-alpha reduced significantly the mean number of colony of HT-3 cells from 250 (SD, 19) to 143 (SD, 32). In contrast, PCCK and HeLa cells exhibited less than 15% reduction of colony formation with the treatment of cRA and INF-alpha. Irradiation of HT-3 cells reduced the colony formation significantly (from 63.6% to 18.4%, p=0.002) after treatment of cRA and INF-alpha. However, PCCK and HeLa cells showed 13.2% (from 70.0 to 56.8%, p=0.807) and 8.4% (from 60.8% to 52.4%, p=0.816) reduction of their colonies respectively. CONCLUSION: These results suggested that the treatment of cRA and INF-alpha showed significant radiosensitizing effect in HPV-negative HT-3 cells but not in the normal cervical cells or HPV-positive HeLa cervical cancer cells.
Cell Line* ; HeLa Cells ; Humans ; Isotretinoin* ; Keratinocytes* ; Radiation-Sensitizing Agents* ; Radiotherapy ; Uterine Cervical Neoplasms*

We have developed an HPLC method for the determination of tirapazaming (3-Amino-1,2,4-Benzotriazine -1,4-dioxide, TPZ) in rabbits and have studied the related pharmacokinetics in rabbits. After protein was precipitated, TPZ in plasma was determinated on HPLC with UV detection at 266 nm, and the mobile phase consisted of methyl alcohol and phosphoric buffer (10: 90, adjusted to pH6.5 +/- 0.1 with NaOH). TPZ and endogenous substances could be separated. Its calibration curve was linear (r=0.9995) within the range of 0.150-59. 98 mg/L, the detection limits was 0.5 ng (S/N>3), the recovery was more than 95% (n=3), the intra-day and inter-day precision was less than 6.0% (n = 5). The concentration-time curve of TPZ in rabbit plasma could be fitted to two-compartment model. These data indicate the method is sensitive, simple and reliabe. It is suitable for the pharmacokinetic study of TPZ in rabbits.
Animals ; Chromatography, High Pressure Liquid ; Rabbits ; Radiation-Sensitizing Agents ; pharmacokinetics ; Sensitivity and Specificity ; Triazines ; blood ; pharmacokinetics

PURPOSE: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Paclitaxel is an active agent against NSCLC and it has a radiosensitizing effect. We investigated the efficacy and toxicity of weekly paclitaxel administration along with concurrent radiotherapy for treating locally advanced and locally recurrent NSCLC. MATERIALS AND METHODS: Twenty-five previously untreated stage III or locally recurrent NSCLC patients received weekly paclitaxel (60 mg/m2) and concurrent radiotherapy. Chemotherapy was given on days 1, 8, 15 and 22. Concurrent radiotherapy at 1.5 Gy was given twice a day to a total dose of 54 Gy in 3.5 weeks. After the completion of CCRT, consolidation chemotherapy was delivered if possible. RESULTS: The overall response rate was 72% with one complete response and 17 partial responses. The median overall survival was 16 months with a 2 year survival rate and a 5 year survival rate of 38% and 24%, respectively. The rate of grade > 3 radiation pneumonitis was 16% (4 patients) and 2 patients were died from the pneumonitis. The rate of grade 3 radiation esophagitis was 12% (3 patients) and the hematologic toxicities were not significant. CONCLUSION: Weekly paclitaxel with concurrent radiotherapy is effective for treating locally advanced and locally recurrent NSCLC, but radiation pneumonitis is the major toxicity and this is potentially fatal.
Carcinoma, Non-Small-Cell Lung ; Chemoradiotherapy ; Consolidation Chemotherapy ; Esophagitis ; Humans ; Paclitaxel ; Pneumonia ; Radiation Pneumonitis ; Radiation-Sensitizing Agents ; Survival Rate