A comparison of outcomes between concurrent chemoradiotherapy and radiotherapy alone in cancer of the uterine cervix: a single institutional experience.

PURPOSE: To compare failure patterns and evaluate prognostic factors related to survival rates after concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone in cervical cancer. MATERIALS AND METHODS: From January 1996 to December 2006, 218 patients with cervical cancer (FIGO Stage IB2 - III) treated with CCRT or RT alone as primary treatments were included, retrospectively. One-hundred eight patients were treated with CCRT and 110 with RT alone. RESULTS: There was no significant difference in failure patterns between the treatment groups, but distant metastasis was the predominant pattern in both groups. The frequent metastatic sites were supraclavicular lymph node, lung, and brain. Treatment group, diabetes, and FIGO Stage were found to be significant for overall survival (OS) and disease-free survival (DFS), and initial hemoglobin level for DFS. CONCLUSION: Distant metastasis is the predominant failure pattern and diabetes is one of the independent prognostic factors to survival rates in this study.

DctA- and Dcu-independent transport of succinate in Escherichia coli: contribution of diffusion and of alternative carriers.

Quintuple mutants of Escherichia coli deficient in the C(4)-dicarboxylate carriers of aerobic and anaerobic metabolism (DctA, DcuA, DcuB, DcuC, and the DcuC homolog DcuD, or the citrate/succinate antiporter CitT) showed only poor growth on succinate (or other C(4)-dicarboxylates) under oxic conditions. At acidic pH (pH 6) the mutants regained aerobic growth on succinate, but not on fumarate. Succinate uptake by the mutants could not be saturated at physiological succinate concentrations (< or =5 mM), in contrast to the wild-type, which had a K(m) for succinate of 50 microM and a V(max) of 35 U/g dry weight at pH 6. At high substrate concentrations, the mutants showed transport activities (32 U/g dry weight) comparable to that of the wild-type. In the wild-type using DctA as the carrier, succinate uptake had a pH optimum of 6, whereas succinate uptake in the mutants was maximal at pH 5. In the mutants succinate uptake was inhibited competitively by monocarboxylic acids. Diffusion of succinate or fumarate across phospholipid membranes (liposomes) was orders of magnitude slower than the transport in the wild-type or the mutants. The data suggest that mutants deficient in DctA, DcuA, DcuB, DcuC, DcuD (or CitT) contain a carrier, possibly a monocarboxylate carrier, which is able to transport succinate, but not fumarate, at acidic pH, when succinate is present as a monoanion. Succinate uptake by this carrier was inhibited by addition of an uncoupler. Growth by fumarate respiration (requiring fumarate/succinate antiport) was also lost in the quintuple mutants, and growth was not restored at pH 6. In contrast, the efflux of succinate produced during glucose fermentation was not affected in the mutants, demonstrating that, for succinate efflux, a carrier different from, or in addition to, the known Dcu and CitT carriers is used.

In vitro radiosensitization of human cervical carcinoma cells by combined use of 13-cis-retinoic acid and interferon-alpha2a.

BACKGROUND: Significant antitumor activity has been reported with the combined use of 13-cis-retinoic acid (cRA) and interferon-alpha2a (IFN-alpha) in the treatment of advanced-stage cervical cancers and skin cancers. Since IFN-alpha has been shown to be a modest radiation enhancer for selected malignant tumor cells and the cytotoxic activity is more enhanced by combining cRA and IFN-alpha, we hypothesized that the exposure of selected human carcinoma cells to combined cRA and IFN-alpha would render the cells highly radiosensitive. METHODS AND MATERIALS: Two human cervical carcinoma cell lines, ME-180 and HeLa-S3, were chosen for the present study because of the different characteristics of the retinoic acid receptor status of the cell lines. To demonstrate the effects of combined cRA and IFN-alpha treatment on radiation response, we exposed the cells to cRA, IFN-alpha, or a combination of the drugs for 72 h before radiation. Experiments were carried out at minimally cytotoxic concentrations of the drug for radiation studies. End points of the study were cell growth inhibition and clonogenic ability of the single-plated cells. Effects of cRA and IFN-alpha on radiation response were quantitatively analyzed by constructing the radiation cell survival curves of ME-180 and HeLa cells. RESULTS: ME-180 cells exhibited varying degrees of cytotoxicity with cRA and IFN-alpha, while HeLa cells showed no toxic effects with the same treatment. Combined treatment of cRA and IFN-alpha produced an additive cytotoxic effect in ME-180 cells. Radiosensitization was minimal when ME-180 cells were treated with either cRA or IFN-alpha before radiation. When ME-180 cells were exposed to 10 microM cRA for 48 h and 1000 U/ml IFN-alpha for 24 h prior to radiation, there was a significant enhancement in radiation-induced cell killing; the dose modification factor was 2.1 +/- 0.9 at the 1% cell-survival level. On the other hand, HeLa-S3 cells exhibited no increased cytotoxicity or radiation enhancement under the same experimental conditions. CONCLUSION: The present data provide a radiobiological basis for using cRA and IFN-alpha as a combination radiosensitizer in selected human carcinoma cells.

Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents.

PURPOSE: To demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents. METHODS AND MATERIALS: Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses of irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation. RESULTS: The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 micrograms/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 +/- 0.1 and 1.3 +/- 0.1, respectively. Exposure of cells to 10 micrograms/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 +/- 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone. CONCLUSION: An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors.

Effects of x-irradiation on survival and extracellular matrix gene expression of cultured keloid fibroblasts.

Survival and extracellular matrix gene expression were studied by viable cell count assay and Northern transfer analysis to compare the sensitivity of normal skin and keloid fibroblasts towards x-irradiation. As the dosage of radiation increased, the numbers of viable cells in irradiated groups were remarkably decreased exponentially, with no significant difference between normal and keloid cell lines. By Northern blot analysis, there was no change in size of the mRNAs for pro alpha 1(I) collagen, fibronectin and beta-actin. By slot-blot hybridization, pro alpha 1(I) collagen mRNA levels in x-irradiated fibroblasts were markedly decreased compared with non-irradiated controls. The amounts of fibronectin and beta-actin mRNAs were also decreased. This study suggests that both normal skin and keloid fibroblasts are sensitive to x-irradiation, and that extracellular matrix gene expression is also affected by such exposure.