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Results for “Radiosensitivity”

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PubMed1989

Auger electron contribution to bromodeoxyuridine cellular radiosensitization.

Halogenated thymidine analogs become incorporated into the DNA of proliferating cells during S-phase and may be used clinically to radiosensitize tumors that are otherwise poorly responsive to radiation. Although radiosensitization has been studied for years, mechanisms of radiosensitization are poorly understood. One possible mechanism involves the release of short range, high-LET, Auger electrons following photoelectric absorption of an X ray by the K-shell of the incorporated halogen. Such absorption occurs only with X ray energies slightly greater than the K-shell binding energy. We report the results of an experiment designed to measure this effect, in which cultured monolayers of Chinese hamster V79 cells, with 32% replacement of thymidine by bromodeoxyuridine (BUdR), were exposed to monoenergetic X rays just below (13.450 KeV) or above (13.490 KeV) the K-edge (13.475 KeV) of bromine. Enhancement ratios calculated in five different ways were slightly increased (3-12%) above the K-edge compared to below. However, only a calculation using a linear-quadratic fit to the data and a surviving fraction of 0.01 demonstrated a statistically significant increased enhancement ratio (12%) above the K-edge. We conclude that Auger electrons produced following photoelectric absorption of X rays by the K-shell of bromine contribute minimally to observed BUdR cellular radiosensitization.

Animals↗

PubMed1989

Selective radiosensitization and cytotoxicity of human melanoma cells using halogenated deoxycytidines and tetrahydrouridine.

The halogenated pyrimidines 5-chloro-2'-deoxycytidine (CldCyd) and 5-bromo-2'-deoxycytidine (BrdCyd) can act as radiosensitizers and cytotoxic agents. It was hypothesized that tumor cells and normal cells might use different metabolic pathways to incorporate these halogenated deoxycytidines into DNA. This difference could potentially be exploited to produce selective radiosensitization and cytotoxicity of human tumor cells compared to normal human fibroblasts. This hypothesis was tested using two human melanoma cell lines and two normal fibroblast cell lines. Either CldCyd or BrdCyd alone caused both cytotoxicity and radiosensitization of tumor and normal cells. The addition of the cytidine deaminase inhibitor tetrahydrouridine (H4U) significantly protected the normal cells but had relatively little effect on the tumor cells. These data indicate that it may be possible to exploit differences between the pyrimidine metabolism of normal cells and melanoma cells to improve the therapeutic index of halogenated pyrimidines both as radiosensitizers and as cytotoxic agents.

Antineoplastic Agents↗

PubMed1989

Radiosensitization by nicotinamide in tumors and normal tissues: the importance of tissue oxygenation status.

Nicotinamide induced radiosensitization of tumors has been suggested to be a consequence of a reduction in tumor hypoxia. We have investigated the possibility that nicotinamide may produce significant radiosensitization in a normal tissue in which the radiation response is also influenced by hypoxia. The normal tissue studied was testis and radiation damage was assessed by measuring survival of spermatogonial stem cells. The radiosensitizing action of nicotinamide in testis was compared to that observed in a C3H mammary carcinoma when assayed by both regrowth delay and local tumor control. Our results show that nicotinamide (1000 mg/kg; i.p.) enhanced radiation damage in both tissue types when the radiation was given up to at least 3 hr after drug injection. Enhancement ratios obtained when the drug and radiation were separated by a 1 hr time interval were between 1.1 to 1.2 for the testis and 1.0 to 1.5 for the tumor. The results suggest that nicotinamide will produce radiosensitization in testis, but the effect is small and less than that observed in tumors.

Animals↗

PubMed1989

Evaluation of nitroimidazole hypoxic cell radiosensitizers in a human tumor cell line high in intracellular glutathione.

Five nitroimidazole hypoxic cell radiosensitizers were evaluated in a human lung adenocarcinoma cell line (A549) whose GSH level was 8-fold higher than Chinese hamster V79 cells. One millimolar concentrations of Misonidazole (MISO), SR-2508, RSU-1164, RSU-1172, and Ro-03-8799 sensitized hypoxic A549 cells to radiation, with Ro-03-8799 giving the highest sensitizer enhancement ration (SER) (2.3). However, MISO, SR-2508 and Ro-03-8799 were less effective in this cell line than in V79 cells, presumably due to higher GSH content of the A549 cells. Increased hypoxic radiosensitization was seen with 0.1 mM Ro-03-8799 after GSH depletion by BSO as compared to 0.1 mM Ro-03-8799 alone (SER-1.8 vs 1.3). The combination of GSH depletion and 0.1 mM Ro-03-8799 was considerably more toxic than 0.1 mM or 1.0 mM Ro-03-8799 alone. This sensitivity was much greater than has been observed for SR-2508. These data show that Ro-03-8799 was the most efficient hypoxic cell radiosensitizer in a human tumor cell line considerably higher in GSH than the rodent cell lines often used in hypoxic radiosensitization studies. Thus, Ro-03-8799 may be a more effective hypoxic cell sensitizer in human tumors that are high in GSH.

Cell Line↗

PubMed1990

Aerobic radiosensitization by SR 4233 in vitro and in vivo.

During the past 3 years, our laboratory has identified and characterized the drug SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) as the lead compound in a series of benzotriazine di-N-oxides that are both potent and selective killers of hypoxic cells in vitro and in rodent tumors in vivo. Recently, we have identified a novel property of SR 4233: the ability of a pre- or post-irradiation drug treatment under hypoxic conditions to radiosensitize aerobic cells in culture. For the mouse cell lines RIF-1 and SCC VII in vitro, this radiosensitization took the form of a steepening of the slope of the acute dose radiation survival curve, although there was also reduced survival in the "shoulder region" of the curve. For both cell lines, the sensitization occurred whether the hypoxic drug exposure was given immediately before or after the irradiation under aerobic conditions. To determine whether radiosensitization could be demonstrated for RIF-1 and SCC VII mouse tumors in vivo, tumor-bearing animals were exposed to 4 daily dose fractions of 5 Gy of X rays either alone, or followed immediately by injections of SR 4233 and the vasoactive agent hydralazine, which increases tumor hypoxia and therefore can potentiate the effect of such hypoxiaspecific drugs. Although treatment with the SR 4233/hydralazine combination after each dose fraction reduced tumor cell survival to between 10(-5) and 10(-6), near the limits of resolution of the clonogenic survival assay, the effect appeared to be strictly additive, suggesting that with this fractionated protocol, aerobic radiosensitization could not be detected. This is likely to be a consequence of the exquisite direct cytotoxicity of the SR 4233 and hydralazine combination toward the hypoxic cells in tumors.

Animals↗

PubMed1990

The dependence of halogenated pyrimidine incorporation and radiosensitization on the duration of drug exposure.

The influence of the duration of exposure to the halogenated pyrimidines iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd) on incorporation into DNA and the resulting radiosensitization was studied in cultured human colon cancer cells. Cells were incubated with either 10 microM BrdUrd or IdUrd for periods up to 7 days. They were also assessed for up to 4 days after removal of drug from the medium. Replacement of thymidine by fraudulent bases was measured using a sensitive gas chromatographic, mass spectrometric (GC/MS) assay. Incorporation of BrdUrd and IdUrd plateaued at 35% and 30%, respectively, after 4 days of exposure. Prolonging the time of exposure to 7 days increased cytotoxicity without affecting either incorporation or radiosensitization. Incorporation remained constant for 1-2 days after removal of drug from the medium. Radiosensitization was linearly related to incorporation throughout the range of conditions assessed. These data suggest that it may be possible to develop a predictive assay for radiosensitization based on measurements of halogenated pyrimidine incorporation in a tumor biopsy specimen. They also suggest that a clinical approach based on repeated short exposures to halogenated pyrimidines may present certain advantages over the current practice of prolonged continuous exposure. A Phase I/II trial using IdUrd and external beam irradiation for the treatment of patients with poor prognosis soft tissue sarcomas has been initiated based on this concept.

Bromodeoxyuridine↗

PubMed1990

Gamma-irradiation response of cocultivated bone marrow stromal cell lines of differing intrinsic radiosensitivity.

There is evidence for differences in the gamma-irradiation response of different cellular lineages within the bone marrow microenvironment. We previously reported that heterogeneity is demonstrable in the gamma-irradiation response of five clonal stromal cell lines, derived from one human bone marrow specimen, despite morphological, histochemical, cytogenetic, and functional similarity. In the present study we tested whether one stromal cell line could affect the intrinsic radiosensitivity of another. Two clonal stromal cell lines, which display distinct gamma-irradiation responses relative to dose rate were used: KM 101, which shows the same radiosensitivity at a low dose rate of 5 cGy/min (LDR) and a high dose rate of 120 cGy/min (HDR) and KM 104 which shows significant gamma-irradiation resistance at LDR. To facilitate the study of the gamma-irradiation response of each cell line during cocultivation, we derived stable subclones of each, expressing the transfected neomycin resistance (neo-r) gene, which confers resistance to the neomycin analog: G 418. Introduction of the neo-r gene did not alter cell lines radiosensitivity. The results show that cocultivation of stromal cell lines before, during, and after gamma-irradiation induces changes in repair of radiation-induced damage, with a dominant effect of a resistant cell line at LDR. In fact, the radiation survival curves of cocultivated stromal cell lines were always characteristic of KM 104, and a dose rate effect was observed, even when KM 101 was present in large excess. Moreover, our results are consistent with preferential killing of the more radiosensitive stromal cell line: both LDR and HDR Do values of the neo-r KM 101, cocultivated with the parent KM 104 for 24 hr before, and during gamma irradiation were significantly lower compared to the neo-r subclone irradiated alone. The LDR Do value of the neo-r KM 104 cocultivated for 24 hr before, and during gamma irradiation with excess of parent KM 101, was significantly higher, compared to the neo-r cells irradiated alone.

Bone Marrow↗

PubMed1991

Oral (po) dosing with RSU 1069 or RB 6145 maintains their potency as hypoxic cell radiosensitizers and cytotoxins but reduces systemic toxicity compared with parenteral (ip) administration in mice.

RB 6145 is a pro-drug of the hypoxic cell radiosensitizer RSU 1069 with reduced systemic toxicity. The maximum tolerated dose (MTD) of RSU 1069 for C3H/He mice was 80 mg/kg (0.38 mmol/kg) ip but 320 mg/kg (1.5 mmol/kg) following po administration. The MTD values of RB 6145 were 350 mg/kg (0.94 mmol/kg) ip and 1 g/kg (2.67 mmol/kg) po. Toxicity of RSU 1069 toward bone marrow stem cells was also less after po administration than after ip administration; 0.1 mmol/kg ip RSU 1069 and 0.38 mmol/kg po RSU 1069 both reduced the surviving fraction of clonogenic CFU-A cells by 50%. Oral administration of RSU 1069 resulted in lower spermatogenic toxicity. No loss of intestinal crypts was detected after ip or po administration of RSU 1069. Some nephrotoxicity was observed in half of the mice given the highest po dose of 1.5 mmol/kg of RSU 1069; this was not observed following the highest ip dose of drug. For RSU 1069 and RB 6145, administered by either route, the maximum hypoxic cell radiosensitization in murine KHT sarcomas, occurred when the drugs were given 45-60 min before 10 Gy of X rays. The degree of radiosensitization produced by a particular dose of either compound was largely independent of the route of administration. Preliminary pharmacokinetic studies, using 3H-RSU 1069, suggested that anti-tumor efficacy correlated with peak blood level of label and concentration in the tumor at the time of irradiation, which were not reduced by po compared with ip administration. Normal tissue toxicity tended to correlate with total exposure over time, which was reduced approximately two-fold by po administration. Oral administration of RSU 1069 or RB 6145, as well as being convenient, may give therapeutic benefit since dose-limiting toxicity in mice was reduced compared with parenteral administration, whereas radiosensitizing activity was less affected.

Administration, Oral↗

PubMed1992

Radiosensitivity testing of human primary brain tumor specimens.

The inherent radiosensitivity of early passage cells derived from 22 patients with tumors of glial origin has been determined using a clonogenic assay system. The mean (+/- SD) surviving fraction at 2 Gy was 0.37 +/- 0.22 (range = 0.02-0.87). No correlation between inherent radiosensitivity and tumor cell plating efficiency or intracellular glutathione was observed. Tumor cells that were both resistant to nitrosoureas and expressed the Mer+ phenotype did not differ significantly in their radiosensitivity as compared to cells that were repair deficient (Mer-) and sensitive to nitrosoureas. Initial clinical follow-up suggests that factors in addition to inherent tumor cell radiosensitivity, such as performance status and age, continue to be the most important determinants of the response of patients with primary brain tumors to radiotherapy.

Astrocytoma↗

PubMed1993

Malignant epidural spinal cord compression associated with a paravertebral mass: its radiotherapeutic outcome on radiosensitivity.

PURPOSE: To evaluate clinical characteristics and functional outcome of malignant epidural spinal cord compression associated with a paravertebral mass. METHODS AND MATERIALS: Between 1987 and 1990, 136 patients with epidural spinal cord compression were treated with irradiation. Of these, 25 patients (18%) had epidural spinal cord compression associated with a paravertebral mass. This report is based on analysis of these 25 patients. Fourteen patients received 3000 cGy in 10 fractions. Seven received 4000 cGy in 16 fractions. Four received 2000 cGy in 5 fractions. Motor function was evaluated by five grades. RESULTS: Lung cancer accounted for the majority of epidural spinal cord compression with a paravertebral mass (60%) followed by lymphoma (8%) and kidney tumor (8%). This pattern of epidural spinal cord compression has a longer duration of pain before developing neurologic symptoms and has a high propensity of the upper thoracic spine involvement by an apical lung cancers. The functional outcome of radiation treatment reveals a significant difference between moderately radiosensitive tumors (lung, prostate, cervix, esophagus) and very radiosensitive tumor (lymphoma). None of the nonambulatory patients became ambulatory following radiotherapy except for the very radiosensitive tumors. Higher doses of radiation treatment (4000 cGy in 16 fractions) did not improve functional outcome. CONCLUSION: Due to the larger tumor burden, radiation treatment for epidural spinal cord compression associated with a paravertebral mass is not as effective as treatment of epidural spinal cord compression without a paravertebral mass except for the very radiosensitive tumor. Therefore, combined treatment modality might be beneficial for improving functional outcome.

Female↗

PubMed1994

The toxic effects, GSH depletion and radiosensitivity by BSO on retinoblastoma.

Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity of BSO on retinoblastoma cells are reported in this paper. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is 2.7 +/- 1.3 x 1.0(-12) mmol/cell, 1.4 +/- 0.2 x 1.0(-12) mmol/cell, and 2.8 +/- 1.2 mumol/g, respectively. The ID50 of BSO on Y-79 and So-Rb50 in air for 3 h exposure is 2.5 mM and 0.2 mM, respectively. GSH depletion by 0.1 mM BSO for 24 h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma-bearing nude mice after BSO administration is differential. GSH depletion after BSO exposure in Y-79 cells in vitro decreases the Do value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under the hypoxic condition is 1.21 and 1.36, respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of cell line and that BSO can increase hypoxic retinoblastoma cells' radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenograft is needed.

Animals↗

PubMed1994

In vivo radiosensitizing effect of nitroimidazole derivative KIN-804.

PURPOSE: In vivo characteristics of 2-nitroimidazole-1-methylacetohydroxamate (KIN-804), which is a newly developed hypoxic cell radiosensitizer, are presented. METHODS AND MATERIALS: The toxicity, pharmacokinetics, and radiosensitizing effect of KIN-804 were studied by in vivo experiments using C3H/He mice bearing the SCC-VII tumor. Results were compared with misonidazole (MISO). RESULTS: LD50(7) of KIN-804 and MISO were 3200 mg/kg and 2000 mg/kg, respectively. The peak of concentrations of KIN-804 in the tumor occurred 20 min after intraperitoneal injection and reached about 62% of the maximum concentration in the blood. The concentrations in brain and sciatic nerve were very low and clearance from sciatic nerve was rapid. Enhancement ratios of KIN-804 calculated using the growth delay method were 1.22, 1.50 and 1.71 at doses of 50, 100, and 200 mg/kg, respectively, compared with 1.36 for MISO at a dose of 100 mg/kg. In the TCD50 assay, enhancement ratios at a dose of 200 mg/kg were 1.69 for KIN-804 and 1.52 for MISO, respectively. CONCLUSION: KIN-804 is a promising radiosensitizer since it shows less toxicity and higher radiosensitizing activity than MISO.

Animals↗

PubMed2006

Selective radiosensitization by nitric oxide in tumor cell lines.

The radiosensitizing effect of nitric oxide (NO) on mouse and human tumor cells with different degrees of malignancy was evaluated. Cells pre-treated with the NO donor diethylenetriamine-NO (DETA-NO), were irradiated with gamma rays. Survival curves were obtained by clonogenicity and fitted to the linear-quadratic model. Results demonstrated an association between radiosensitization and degree of malignancy. The more malignant the cell line, the higher the degree of radiosensitization by DETA-NO. In conclusion, the differential radiosensitizing effect of DETA-NO shown here is of great interest for the potential use of NO in radiotherapy, due to an enhanced radiation effect on tumor vs. normal tissue.

Animals↗

PubMed2006

The effect of p21 antisense oligodeoxynucleotides on the radiosensitivity of nasopharyngeal carcinoma cells with normal p53 function.

OBJECTIVE: p21(WAF1/CIP1) is transcriptionally activated by p53 and is required for G1 to S phase progression. p21 plays a critical role in DNA repair after DNA damage. Thus, cells with defective p21 may result in an enhancement of radiation induced apoptosis and improved radiosensitivity. We tested the hypothesis that p21 antisense oligodeoxynucleotides (p21 AS ODNs) can be used to reduce p21 expression level and increase radiosensitivity in CNE-1-wtp53 nasopharyngeal carcinoma cell line with normal p53 function. METHODS AND MATERIALS: The p21 antisense oligodeoxynucleotides (p21 AS ODNs) and the random control oligodeoxynucleotides (p21 RD ODNs) were synthesized. p21 AS ODNs sequence: 5'-TGTCATGCTGGTCTGCCGCC-3'; p21 RD ODNs sequence: 5'-CCGGTGAACGAGCGAGCACA-3'. p21 AS ODNs and p21 RD ODNs were transfected into CNE-1-wtp53 nasopharyngeal carcinoma cell line. The protein expression levels of P21 were evaluated using Western blotting analysis. Cell cycle progression and apoptotic cells were assessed by flow cytometric analysis. The clonogenic survival assay was performed to determine the survival fraction. The parameters D0, Dq, and N for the single-hit multitarget model and the parameters alpha, beta, alpha/beta, and SF2 for the linear-quadratic model were calculated. BALB/c nude mice were used to investigate the effect of p21 AS ODNs on the radiosensitivity of nasopharyngeal xenografts in vivo. RESULTS: p21 AS ODNs were detected mainly in plasma with fluorescence microscopy investigation. P21 protein level dramatically decreased and the amount of apoptotic cells increased in p21 AS ODNs transfected cells than in p21 RD ODNs transfected cells after irradiation. The percentage of G1 arrest decreased in p21 AS ODNs transfected cells 24 h after radiation, then G2 arrest decreased 48 h after radiation. The values of D0, Dq, SF2 decreased and alpha value increased in p21 AS ODNs transfected cells than in control cells. The inhibition rate in tumor xenografts exposed to X ray of 10 Gy alone was 39.1%, while it was 51.4% in xenografts injected with p21 AS ODNs before exposure to radiation. Unfortunately, there was no significant difference between these two groups (P < 0.05). CONCLUSION: p21 Antisense oligodeoxynucleotides led to inhibition of P21 protein expression, loss of G1 arrest, increase of apoptosis in CNE-1-wtp53 nasopharyngeal carcinoma cell line in vitro and inhibited tumor growth in vivo. Antisense oligodeoxynucleotides may become a promising strategy to enhance radiosensitivity in nasopharyngeal carcinoma cells with normal p53 function.

Animals↗

PubMed2005

Radical mediators and mitogen-activated protein kinase signaling in oxygen-dependent radiosensitivity of human tumor cell lines.

Oxygen enhancement of tumor radiosensitivity is attributed to DNA damage by reactive oxygen species. The mechanism remains unclear but may involve mitochondria as major sources of oxygen and nitrogen radicals as well as central effectors of energy homeostasis and apoptosis. Here we used dihydrorhodamine and 2',7'-dichlorodihydrofluorescein to compare mitochondrial and total cell generation, respectively, of reactive oxygen or nitrogen species in cells irradiated at 5 Gy. Irradiation in the presence of oxygen selectively stimulated mitochondrial radical production in HeLa and MeWo cells, but in MCF7 cells radical production was more generalized. In all three cell lines oxygen impaired cell proliferation as measured by resazurin reduction 7 days after irradiation. Antioxidants N-acetylcysteine, ascorbic acid, and melatonin largely prevented dye oxidation during normoxic irradiation yet had no effect on oxygen-dependent irradiation injury. However, NO synthase inhibitor N(G)-monomethyl-L-arginine protected HeLa and MCF7 though not MeWo cells, consistent with their different levels of constitutive NO generation. SB203580 inhibition of p38 MAPK appreciably protected HeLa and marginally protected MCF7 cells against oxygen-dependent irradiation injury, while the less specific JNK/SAPK inhibitor SP600125 and ERK inhibitor U0126 had no effect. None of the inhibitors affected MeWo radiosensitivity. Therefore oxygen-enhanced radiosensitivity in these tumor cell lines does not depend on extensive production of oxygen radicals and is cell-type dependent. NO mediates oxygen-dependent injury in HeLa and MCF7 cells, by p38-dependent and MAPK-independent mechanisms, respectively. In MeWo cells this oxygen-enhanced radiosensitivity is independent of both NO and MAPK signaling.

Acetylcysteine↗

PubMed2004

Susceptibility and radiosensitization of human glioblastoma cells to trichostatin A, a histone deacetylase inhibitor.

PURPOSE: Histone deacetylase inhibitors (HDAC-Is) show in vitro and in vivo antitumor activity in various types of cancer cells and are being studied in clinical trials. However, studies addressing the combination of HDAC-I and radiation are lacking. The purpose of this study was to assess the effect of trichostatin A (TSA), an HDAC-I, on the radiosensitivity of U373MG and U87MG (human glioblastoma) cell lines. METHODS AND MATERIALS: Intrinsic TSA toxicity was determined by measuring survival in exponentially growing cells treated with 0-200 nM TSA for 0-24 h. To assay the radiosensitizing effect of TSA, cells were exposed to 0-200 nM TSA for 18 h before irradiation, and radiation survival curves were obtained. Radiation survival of TSA-treated cells was determined by clonogenic assay. RESULTS: The human glioblastoma cells showed a dose-dependent reduction in survival and radiosensitization with TSA treatment in the range of 50-200 nM. Exposure to 200 nM TSA resulted in reduced survival of both cell lines, and survival was further reduced with time. Exposure of these cells to TSA before irradiation led to dose-dependent radiosensitization. CONCLUSIONS: These results suggest that HDAC-Is may be a useful adjunct in the treatment of glioblastoma and merit further investigation. Given the limited efficacy of standard treatments for patients afflicted with glioblastoma, the results reported here provide support for clinical trials integrating HDAC-I with radiation therapy.

Apoptosis↗

PubMed2005

Adenoviral-E2F-1 radiosensitizes p53wild-type and p53null human prostate cancer cells.

PURPOSE: E2F-1 is a transcription factor that enhances the radiosensitivity of various cell lines by inducing apoptosis. However, there are conflicting data concerning whether this enhancement is mediated via p53 dependent pathways. Additionally, the role of E2F-1 in the response of human prostate cancer to radiation has not been well characterized. In this study, we investigated the effect of Adenoviral-E2F-1 (Ad-E2F-1) on the radiosensitivity of p53wild-type (LNCaP) and p53null (PC3) prostate cancer cell lines. METHODS AND MATERIALS: LNCaP and PC3 cells were transduced with Ad-E2F-1, Adenoviral-Luciferase (Ad-Luc) control vector, or Adenoviral-p53 (Ad-p53). Expression of E2F-1 and p53 was examined by Western blot analysis. Annexin V and caspase 3 + 7 assays were performed to estimate the levels of apoptosis. Clonogenic survival assays were used to determine overall cell death. Statistical significance was determined by analysis of variance, using the Bonferroni method to correct for multiple comparisons. RESULTS: Western blot analysis confirmed the efficacy of transductions with Ad-E2F-1 and Ad-p53. Ad-E2F-1 transduction significantly enhanced apoptosis and decreased clonogenic survival in both cell lines. These effects were compounded by the addition of RT. Although E2F-1-mediated radiosensitization was independent of p53 status, this effect was more pronounced in p53wild-type LNCaP cells. When PC3 cells were treated with Ad-p53 in combination with RT and Ad-E2F-1, there was at least an additive reduction in clonogenic survival. CONCLUSIONS: Our results suggest that Ad-E2F-1 significantly enhances the response of p53wild-type and p53null prostate cancer cells to radiation therapy, although radiosensitization is more pronounced in the presence of p53. Ad-E2F-1 may be a useful adjunct to radiation therapy in the treatment of prostate cancer.

Adenoviridae↗

PubMed2004

Endothelial cells increase the radiosensitivity of oropharyngeal squamous carcinoma cells in collagen gel.

We assessed the radiosensitivity of human HSCO oropharyngeal squamous carcinoma cells in the presence of paracrine factors produced by human HECV umbilical vein endothelial cells. To this end the cells were embedded in separate collagen gels at the density of 1 x 10(6) cells/ml each, and the two gels were placed in a well of a six-well plate, sharing the same medium but without physical contact (two-gel model). The medium was not changed during the observation period to ensure the accumulation of soluble factors. On day 2 of culture the gels were irradiated with 0, 0.5, 1, 2 and 8 Gray (Gy) and on day 7 of culture they were disaggregated and cell survival evaluated by the MTT assay. Results were compared with proper untreated and irradiated control groups. Under these experimental conditions it was found that: (1) HSCO and HECV cells influenced reciprocally their behaviour in the two-gel model, in terms that cell survival was enhanced and inhibited, respectively; (2) as expected, HSCO cells were more radioresistant in collagen gel than in monolayer; (3) on the average the survival of HECV cells was enhanced at low radiation doses, irrespective of whether they were cultured alone or with HSCO cells in the two-gel model and (4) HSCO cells displayed a high radioresistance when irradiated alone at doses from 0.5 to 8 Gy. However, when co-cultured with HECV cells in the two-gel model, they become highly radiosensitive already at the dose of 2 Gy, while none of them survived at the dose of 8 Gy. This radiosensitizing effect was specifically induced by paracrine factors circulating in the medium, supporting the notion that stromal endothelial cells may be essential components of a metabolic circuitry supplying solid tumors with radiosensitizing factors.

Carcinoma, Squamous Cell↗