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PubMed2003

Histone H2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy.

Based on the role of phosphorylation of the histone H2A variant H2AX in recruitment of DNA repair and checkpoint proteins to the sites of DNA damage, we have investigated gammaH2AX as a reporter of tumor radiosensitivity and a potential target to enhance the effectiveness of radiation therapy. Clinically relevant ionizing radiation (IR) doses induced similar patterns of gammaH2AX focus formation or immunoreactivity in radiosensitive and radioresistant human tumor cell lines and xenografted tumors. However, radiosensitive tumor cells and xenografts retained gammaH2AX for a greater duration than radioresistant cells and tumors. These results suggest that persistence of gammaH2AX after IR may predict tumor response to radiotherapy. We synthesized peptide mimics of the H2AX carboxyl-terminal tail to test whether antagonizing H2AX function affects tumor cell survival following IR. The peptides did not alter the viability of unirradiated tumor cells, but both blocked induction of gammaH2AX foci by IR and enhanced cell death in irradiated radioresistant tumor cells. These results suggest that H2AX is a potential molecular target to enhance the effects of radiotherapy.

Animals↗

PubMed2004

Is DNA polymerase beta important in thermal radiosensitization?

Thermal radiosensitization was tested in a pair of mouse cells (MB+ wild-type and MB-, DNA polymerase beta knockout cells) and in human breast carcinoma cells (MCF7 wild-type and C716 transfected to give elevated DNA polymerase beta expression). Results showed that neither reducing DNA polymerase beta (involved in base excision repair) nor increasing it had any significant effect on thermal radiosensitization. The data indicated that polymerase beta was not involved in thermal radiosensitization, and since hyperthermia is known as a radiation damage repair inhibitor, other repair pathways might be involved and need to be explored.

Animals↗

PubMed2004

Modelling heat-induced radiosensitization: clinical implications.

Clinically achievable minimum tumour temperatures are in the order of about 41 degrees C. Therefore, it is important to evaluate mechanisms by which temperatures in this range might enhance cytotoxicity. Previous in vitro studies have demonstrated that 1-4 h (depending on the sequencing of modalities) of heating at 41 degrees C produces substantial heat-induced radiosensitization with little or no cell killing by heat alone. The increased radiation sensitivity is best modelled as a change in the single hit, alpha, parameter (with no significant effect on the two-hit parameter, beta) of the cell survival curve. The implications of heat-induced radiosensitization being mediated by a change in alpha on the traditional thermal enhancement ratio (for various radiation doses/fraction and alpha/beta) are reviewed. Response rates for a cohort of 60 patients enrolled on a prospective thermal dose escalation study are modelled assuming that the thermal dose dependence of heat-induced radiosensitization is modulated by a heat-induced delta alpha. The clinical data are fitted with delta alpha about 0.05-0.1 Gy-1. Randomized trials reported in the literature and the implication for the design of future prospective trials are reviewed in light of these observations.

Animals↗

PubMed2005

In vitro radiosensitization by oxaliplatin and 5-fluorouracil in a human colon cancer cell line.

The current study was designed to compare the radiosensitizing effects of oxaliplatin and 5-fluorouracil (5FU) in a human colon cancer cell line. A human colon cancer cell line (S1) was treated with various doses of oxaliplatin, 5FU, radiation, and combinations thereof. Various clinically used schedules were mimicked. 5FU was either incubated during 1 h ("bolus") or 24 h ("continuous infusion"). When combining oxaliplatin and 5FU, an isobologram analysis revealed synergistic effects, regardless of 5FU schedule. The IC(10) and IC(50)-doses for the drugs where then combined with radiotherapy. With equitoxic drug doses (IC(50)), radiosensitization was observed in the following order: oxaliplatin > 5FU 24 h > 5FU 1 h exposure. The degree of potentiation corresponded to approximately 0.8 Gy, 0.7 Gy, and 0.2 Gy, respectively. In this experimental setting, oxaliplatin seemed to be a better radiosensitizer than 5FU, and longer incubation time with 5FU was better than short exposure.

Antineoplastic Agents↗

PubMed2001

Hyperthermic radiosensitization: mode of action and clinical relevance.

PURPOSE: To provide an update on the recent knowledge about the molecular mechanisms of thermal radiosensitization and its possible relevance to thermoradiotherapy. SUMMARY: Hyperthermia is probably the most potent cellular radiosensitizer known to date. Heat interacts with radiation and potentiates the cellular action of radiation by interfering with the cells' capability to deal with radiation-induced DNA damage. For ionizing irradiation, heat inhibits the repair of all types of DNA damage. Genetic and biochemical data suggest that the main pathways for DNA double-strand break (DSB) rejoining, non-homologous end-joining and homologous recombination, are not the likely primary targets for heat-induced radiosensitization. Rather, heat is suggested to affect primarily the religation step of base excision repair. Subsequently additional DSB arise during the DNA repair process in irradiated and heated cells and these additional DSB are all repaired with slow kinetics, the repair of which is highly error prone. Both mis- and non-rejoined DSB lead to an elevated number of lethal chromosome aberrations, finally causing additional cell killing. Heat-induced inhibition of DNA repair is considered not to result from altered signalling or enzyme inactivation but rather from alterations in higher-order chromatin structure. Although, the detailed mechanisms are not yet known, a substantial body of indirect and correlative data suggests that heat-induced protein aggregation at the level of attachment of looped DNA to the nuclear matrix impairs the accessibility of the damaged DNA for the repair machinery or impairs the processivity of the repair machinery itself. CONCLUSION: Since recent phase III clinical trials have shown significant benefit of adding hyperthermia to radiotherapy regimens for a number of malignancies, it will become more important again to determine the molecular effects underlying this success. Such information could eventually also improve treatment quality in terms of patient selection, improved sequencing of the heat and radiation treatments, the number of heat treatments, and multimodality treatments (i.e. thermochemoradiotherapy).

Chromatin↗

PubMed2000

The role of G2-block abrogation, DNA double-strand break repair and apoptosis in the radiosensitization of melanoma and squamous cell carcinoma cell lines by pentoxifylline.

PURPOSE: To examine the role of G2-block abrogation, DNA repair inhibition and apoptosis in the enhancement of radiotoxicity by pentoxifylline. MATERIALS AND METHODS: The influence of pentoxifylline on radiotoxicity was assessed by colony assay in TP53 wild-type Bell and mutant MeWo melanoma, and in TP53 wild-type 4197 and mutant 4451 squamous cell carcinoma (SCC) cell lines. G2-block abrogation was assessed by flow cytometry. Induction of DNA damage and repair was measured over a dose range of 0-100 Gy by constant field gel electrophoresis (CFGE). The Annexin-V binding assay was used to identify apoptotic cells. RESULTS: Pentoxifylline, when combined with irradiation, significantly increased radiotoxicity in the TP53 mutant MeWo and 4451 cell lines by radiotoxicity enhancement factors of 3 and 14.5 respectively. No radiosensitization was seen in the TP53 wild-type Be11 and 4197 cells. When the drug was added after irradiation at the time of maximum G2-block expression, no radiosensitization was seen in any of the four cell lines. CFGE analyses showed that pentoxifylline effectively suppressed DNA double-strand break (DSB) repair in all four cell lines, as indicated by 20 h repair inhibition factors of 1.4-2.4. Pentoxifylline did not increase apoptosis in any of the four cell lines. CONCLUSION: These data suggest that radiosensitization by pentoxifylline is not a consequence of G2-block abrogation alone, but that inhibition of DSB repair plays a role in certain cell types.

Apoptosis↗

PubMed2001

Investigation of G2-phase chromosomal radiosensitivity in hereditary non-polyposis colorectal cancer cells.

PURPOSE: To investigate whether cells from hereditary nonpolyposis colorectal cancer (HNPCC) patients, a genetic condition characterized by constitutional mutations in DNA mismatch repair genes and associated with predisposition to colorectal carcinoma (CRC), could present a higher G2 chromosomal radiosensitivity. It is generally hypothesized that cancer predisposition in HNPCC is associated with the loss of the wild-type allele in somatic cells, resulting in defective DNA mismatch repair but, to date, no data on G2 radiosensitivity have been reported for HNPCC. MATERIALS AND METHODS: Lymphoblastoid cell lines derived from six HNPCC patients heterozygous for MLH1, one HNPCC patient carrying a mutant MSH2 allele and three healthy controls were treated with 50 cGy of X-rays and sampled at various harvesting times, monitoring cell-cycle progression by 5-bromo-2-deoxyuridine (BrdUrd) incorporation in order to analyse chromosomal damage in the homogeneous G2 population. RESULTS: There were no differences between lymphoblasts derived from patients in the frequency of G2 chromosomal aberrations induced by X-rays when compared with control cell lines. However, despite the absence of G2 radiosensitivity in HNPCC cells, lymphoblasts from patients heterozygous for MLH1 mutations showed a higher induction of chromatid exchanges. CONCLUSIONS: The observed possible incorrect rejoining of double-strand breaks in MLH1 heterozygotes would be an additional and important factor contributing to loss of heterozygosity in HNPCC patients.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Chromosomal radiosensitivity study of temporary nuclear workers and the support of the adaptive response induced by occupational exposure.

PURPOSE: To study chromosomal radiosensitivity in a population of radiation workers and investigate the possibility of an adaptive response in lymphocytes of workers after short-term occupational exposure to ionizing radiation. MATERIALS AND METHODS: The studied group comprised 41 workers temporarily employed at the Nuclear Power Plant Doel (Belgium) for reactor maintenance. A blood sample was taken before and directly after the exposure period of about 1 month. Chromosomal radiosensitivity was assessed in vitro by the G2 assay and the G0 micronucleus (MN) assay. For the MN assay, a low dose-rate (LDR) in vitro irradiation protocol was applied in addition to high dose-rate (HDR) irradiation of the blood samples in order to determine the dose-rate sparing (DRS) effect. RESULTS: No statistically significant effect of the occupational exposures (up to 10 mSv) on the baseline MN frequencies without in vitro irradiation was observed. A comparison of the number of chromatid aberrations pre- and post-exposure shows no effect of the occupational exposure. On the other hand, the G0-MN assay with the LDR irradiation protocol reveals a systematic reduction in chromosomal radiosensitivity by the exposure, increasing with dose. For workers who received the highest dose (4-10 mSv) a statistically significant (p <0.05) decrease of the in vitro induced MN yields and increase of the dose-rate sparing was observed. CONCLUSIONS: Short-term low-dose occupational exposure may act as an in vivo adaptive dose and stimulate repair in G0 lymphocytes.

Adolescent↗

PubMed2002

Evidence for the involvement of DNA-dependent protein kinase in the phenomena of low dose hyper-radiosensitivity and increased radioresistance.

PURPOSE: To investigate the role of DNA-dependent protein kinase (DNA-PK) in the phenomena of low dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR) using the genetically related M059 cell lines of disparate PRKDC status. MATERIALS AND METHODS: Clonogenic survival was measured for the three cell lines following low doses of X-irradiation using a flowactivated cell sorting (FACS) plating technique. The presence of PRKDC, G22p1 and Xrcc5 proteins was determined by Western blotting and a kinase assay used to measure DNA-PK complex activity. RESULTS: The survival responses for the three cell lines over the 0-0.3Gy dose range were comparable, but differences in radiosensitivity were evident at doses >0.4Gy. M059K and M059J/Fus1 cells (both PRKDC competent) exhibited marked HRS/IRR responses, albeit to different extents. M059J cells (PRKDC incompetent) were extremely radiosensitive exhibiting a linear survival curve with no evidence of IRR. The presence of IRR was coincident with the presence of PRKDC protein and functional DNA-PK activity. CONCLUSIONS: HRS is a response that is independent of DNA-PK activity. In contrast, IRR showed a dependence on the presence of PRKDC protein and functional DNA-PK activity. These data support a role for DNA-PK activity in the IRR response.

Blotting, Western↗

PubMed2004

Role of p53 mutations, protein function and DNA damage for the radiosensitivity of human tumour cells.

PURPOSE: The tumour suppressor protein p53 is considered to have an impact on the radiosensitivity of tumour cells. However, this concept does not easily translate to the tumour sensitivity in the clinics. The aim of the present study was to determine whether a functional or dysfunctional p53 is associated with a sensitive or resistant phenotype. It was further studied whether DNA damage might be an additive factor by which p53 has impact on cell survival. MATERIALS AND METHODS: Nine human tumour cell lines were studied for p53 mutation by direct sequencing of exons 4-9. Regulation of p53 and p21(cip1/waf1) protein was assessed by immunoblotting and cell cycle effects by combining 5-bromodeoxyuridine incorporation and flow cytometry. RESULTS AND CONCLUSION: Three strains (RT112, Du145, SCC4451) were found to have a missense-mutation in the core domain and one did not express p53 at all (HeLa), presumably due to HPV18 infection. Immunoblots of these cells showed neither a regulated p53 nor p21 expression. The cells did not arrest in G1 phase after X-irradiation but did arrest in G2/M. All cells expressing wild-type protein (LNCaP, T47D-B8, MCF-7 and sublines BB and Bus) showed an intact p53 and p21 regulation and a modest arrest in both G1 and G2/M. Thus, in contrast to other studies, all tumour cells investigated showed either a typical p53wt or mutant (mut) pattern. Protein function was compared with cell survival and DNA damage, as assessed previously. p53 wild-type cells were on average 1.3-times (n.s.) more radiosensitive than mutant cells, but there was a considerable overlap between both groups. Further, the 1.3-fold enhanced resistance of cells lacking wild-type p53 was paralleled by a 1.3-fold lower number of induced double-strand breaks. The results suggest that p53 could have impact on chromatin compaction and thus effect DNA damage induction and radiosensitivity of tumour cells.

Adaptation, Physiological↗

PubMed2004

Chromosomal radiosensitivity in secondary-progressive multiple sclerosis patients.

PURPOSE: To investigate chromosomal radiosensitivity of secondary progressive (SP) multiple sclerosis (MS) patients in comparison to a group of healthy individuals. MATERIAL AND METHODS: Chromosomal radiosensitivity was assessed in vitro with the G2 assay and the G0-micronucleus (MN) assay. For the G2 assay phytohaemagglutinin (PHA) stimulated blood cultures were irradiated with a dose of 0.4 Gy 60Co gamma rays in the G2 phase of the cell cycle. For the MN assay unstimulated diluted blood samples were exposed to 3.5 Gy 60Co gamma rays delivered at a high dose-rate (HDR = 1 Gy/min) or low dose-rate (LDR = 4 mGy/min). RESULTS: No significant differences in the number of chromatid breaks were observed between MS patients and healthy individuals. With the G0-MN assay a higher spontaneous MN yield was found in MS patients. At HDR irradiation no significant differences were shown, while at LDR irradiation, MS patients were found less sensitive than healthy controls. The dose-rate sparing index was higher for MS patients, pointing to a better repair capacity. CONCLUSIONS: MS patients are not characterised by an enhanced in vitro chromosomal radiosensitivity. The radioresistant response, which was only observed with the MN assay after LDR irradiation, may point to an adaptive response induced by in vivo oxidative stress in SPMS patients.

Adult↗

PubMed2005

Huge differences in cellular radiosensitivity due to only very small variations in double-strand break repair capacity.

The DNA double-strand break (DSB) repair capacity of normal human fibroblasts was compared with that of cell lines with different genetic alterations. These cell lines are affected either in non-homologous end-joining (180BR), homology directed repair (C2352, C2395), base excision repair (CS1TAN, 46BR) or signalling (AT3, AT2BE, LFS2675, LFS2800, 95P558). Cellular radiosensitivity was determined by colony formation assay, DSB by constant-field gel electrophoresis and apoptosis was detected by caspase3 activity. For the mutated cell lines, the survival fraction at 2 Gy (SF2) varied between 0.013 and 0.49 in contrast to a variation of only 0.15-0.53 for normal fibroblasts. There was no variation in the number of initial DSB and only a small variation in the number of DSB remaining 24 h after irradiation. At 100 Gy, the latter number varied between 2 and 5 Gy-equivalents for normal fibroblasts and only between 3 and 7 Gy-equivalents for the mutated cell lines, corresponding to repair capacities of 95-98 and 93-97%, respectively. There were, however, two outliers (LFS2800, 180BR) where the number of remaining DSB was much higher with 22 and 30 Gy-equivalents, respectively. This elevated number resulted from a delayed repair and apoptotic cells. For all but these two cell lines, the relationship between the number of DSB remaining 24 h after irradiation and SF2 could be described by an identical correlation (r2 = 0.86, p < 0.0001). This result indicates that the relationship between DSB repair capacity and cellular radiosensitivity appears to be the same for normal and mutated cell lines, and that in both cases huge differences in cellular radiosensitivity result from only a very small variation in DSB repair capacity.

Apoptosis↗

PubMed2005

No correlation between radiosensitivity or double-strand break repair capacity of normal fibroblasts and acute normal tissue reaction after radiotherapy of breast cancer patients.

The aim was to study the relationship between cellular radiosensitivity or double-strand break (dsb) repair capacity of skin fibroblasts and the extent of acute reaction after radiotherapy for breast cancer. The study was performed with 25 breast cancer patients submitted to the radiotherapy unit of the Egyptian National Cancer Institute after conserving surgery. Dermal fibroblasts, established from skin biopsies, were used to determine the cellular radiosensitivity via colony assay and the capacity of dsb repair by constant-field gel electrophoresis. Acute reactions were scored using the Radiation Therapy Oncology Group (RTOG) classification. The spectrum of acute reactions varied from grade 1 to 4, whereby most patients developed a grade 1 reaction after total doses ranging between 46 and 70 Gy. Skin fibroblasts showed a pronounced variation in both cellular radiosensitivity expressed as the mean inactivation dose (Dbar) (coefficient of variation, CV=25%) as well as in the number of residual dsb (CV=33%) with no significant correlation between these two endpoints (r2=0.20, p=0.14). Both parameters did not correlate with the extent of acute reaction of the respective patient. The data obtained indicate that the sensitivity of fibroblasts measured either by colony assay or by dsb repair capacity is not a major parameter determining the extent of acute reaction after radiotherapy of breast cancer patients.

Adult↗

PubMed2006

Radiation-induced effects on telomerase in gynecological cancer cell lines with different radiosensitivity and repair capacity.

PURPOSE: Telomerase activation in response to irradiation might enhance the radioresistance of cells. Thus, we have investigated radiation-induced effects on telomerase in six gynecological cancer cell lines, with different intrinsic radiosensitivity and capacity for sublethal damage repair (SLDR). MATERIALS AND METHODS: Three endometrial adenocarcinoma (UM-EC-1, UT-EC-2B and UT-EC-3) and three vulvar squamous cell carcinoma (A431, UM-SCV-2 and UM-SCV-7) cell lines were irradiated with doses of 5, 10 and 25 Gy and the effects on telomerase were evaluated at 0.5, 6, 24 and 48 h post-irradiation. Telomerase activity was quantitatively measured by SYBR Green real-time telomeric repeat amplification protocol. RESULTS: The most radioresistant cell line A431 had the strongest stimulatory effects (approximately 2.0 - 2.5-fold) on telomerase activity 24 and 48 h post-irradiation with the highest radiation doses. In contrast to that, telomerase activities in the highly radiosensitive cell line UT-EC-2B remained below the basal level throughout the 48-h period of post-irradiation with the highest doses, and even a decline to approximately 50% of the basal level was found 24 h after exposure. In other cell lines being either moderately or highly radiation resistant, telomerase activity levels in response to irradiation remained mainly at the basal level or gradually increased. CONCLUSIONS: The present findings indicate that there might be a connection between the radiation-induced telomerase response and radiosensitivity. However, no correlation was found between the radiation-induced effects on telomerase and the sublethal damage repair capacity of the cells.

Cell Line, Tumor↗

PubMed1975

Radiosensitization of cultured mammalian cells by 5-iodouridine.

Radiosensitization of cultured mammalian cells was studied with halogenated pyrimidines, such as 5-iodouridine or 6-chloropurine, which have been shown to promote bacterial cell lethality when combined with gamma-irradiation. When Chinese hamster cells were exposed to gamma-rays to acidic pH values and the number of colonies was scored after 6 to 11 days of incubation, many more cells were inactivated in the presence of the drug than in its absence. This may be due to radiation-induced cytotoxic iodine radicals from the reagent in the case of 5-iodouridine, because the cells were inactivated efficiently only be contact with the previously-irradiated drug solution. The toxicity of the irradiated drug solution increased remarkably when the pH shifted to acidic side. The radiosensitization and the cytotoxic effects of gamma-irradiated drug solution were not found with 6-chloropurine. This may be the first observation on the lethal effect of chemical radicals on mammalian cells, and it is concluded that radiosensitization with 5-iodouridine does not require the drug incorporation into cellular DNA, at least under the conditions adopted in the present studies.

Animals↗

PubMed1976

Gamma radiolysis of thymine in oxygen-free aqueous solution in the presence of electron affinic radiosensitizers: identification of stable products.

Radiosensitizers react with nucleic radicals by addition and by electron transfer reactions. We report the steady-state gamma radiolysis of 1 mM thymine in oxygen-free aqueous solutions containing different classes of radiosensitizing drugs: N-oxyl-free radicals (TAN and TMPN), quinones (menadione and naphtoquinone), nitroheterocyclic compounds (metronidazole and 5-nitro-2-furoic acid) and N-ethylmaleimide. Two classes of thymine degradation products were isolated by thin-layer chromatography and characterized by spectroscopic measurements. The main products, irrespective of radiosensitizers, resulting from oxidation reaction were identified as the cis and trans isomers of 5,6-dihydroxy-5,6-dihydrothymine, N-pyruvyl-N'-formylurea, 6-hydroxy-5,6-dihydrothymine and 5-hydroxy-5,6-dihydrothymine. In the experimental conditions used only N-oxyls and to a lesser extent NEM reacted with 5-hydroxy-5,6-dihydrothymin-6-yl radical, giving stable covalently-bonded addition products with a high yield. TAN showed a higher binding ability with respect to TMPN, which is in good agreement with the rate-constants previously reported for these bimolecular reactions.

Cyclic N-Oxides↗

PubMed1977

Bacterial radiosensitization by 8-methoxypsoralen.

8-Methoxypsoralen has been shown to act as a radiosensitizer of hypoxic bacterial cells with uvrA, recA and uvrB and/or lexA mutations. No effect of the drug on the radiosensitivity of oxic bacteria with these mutations was observed. This drug differs from O2 and electron-affinic radiosensitizers in that its effect is not purely dose-modifying and can exceed the oxygen effect in certain mutants.

Dose-Response Relationship, Radiation↗

PubMed1978

Effect of salt solutions on the radiosensitivity of mammalian cells. IV. Treatment with NaCl solutions containing ouabain, NEM, PNAP, cysteamine or DMSO.

The effects of a wide concentration range of NaCl solutions containing either ouabain, ethanol, para-nitroacetophenone (PNAP), N-ethylmaleimide (NEM), cysteamine or dimethyl sulphoxide (DMSO) on cellular radiosensitivity have been examined. Ouabain and NEM treatment increased the radiosensitivity of V79 Chinese hamster cells, but the action of these chemicals did not depend on the concentration of NaCl. PNAP increased cellular radiosensitivity with increasing NaCl concentration reaching a maximum effect at 0.6 to 0.7 M NaCl. The radioprotective properties of cysteamine, DMSO and ethanol were all strongly dependent on the NaCl concentration in a complex but qualitatively similar manner. DMSO (2.0 M) increased radiation survival of cells after a 1380 rad dose by a factor of about 10(4) when present in 0.075 M NaCl and by a factor of 8.7 when present in 1.2 M NaCl.

Acetophenones↗