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Results for “Radiosensitivity”

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PubMed1987

Radiosensitization in vitro by cis-diammine (1,1-cyclobutanedicarboxylato) platinum(II) (carboplatin, JM8) and ethylenediammine-malonatoplatinum(II) (JM40).

The radiosensitizing ability of two analogues of cisplatin have been tested in vitro. The analogues, CBDCA (JM8) and EDMP (JM40), are currently undergoing clinical tests in the search for an active but less toxic cancer chemotherapeutic agent than cisplatin. The compounds were cytotoxic to log phase RIF1 cells in culture, but at higher concentrations than the parent compound. Both analogues were radiosensitizers of oxic cells when given as 1 h exposures beginning either 3 h before, 1 h before or 2 h after irradiation, giving modest enhancements of approximately 1.2. Each drug caused an inhibition of the repair of sublethal damage which was greatest after CBDCA treatment. Although neither analogue was as good a radiosensitizer as cisplatin, CBDCA appears to show promise as a potential radioenhancing platinum compound.

Carboplatin↗

PubMed1998

The radiosensitivity of recurrent clones of an irradiated murine squamous cell carcinoma in the in vitro megacolony system.

PURPOSE: To measure changes in spontaneous growth rate and radiation response in the progeny of irradiated squamous cell carcinoma cells. MATERIALS AND METHODS: Murine SCC cells of the line AT478 were grown as epithelial megacolonies in vitro, using both the original line and two subsequent passages derived from a clone that had recurred after a high radiation dose. Radiosensitivity was evaluated in terms of local control following single dose irradiation of standard size megacolonies (0.8 cm2). In addition, original megacolonies were given a priming dose of 20 Gy and the recurrent clones arising in situ were retreated at three dose levels for analysis of curability. RESULTS: A marked increase in radiosensitivity was observed in the megacolonies grown from irradiated progeny as compared to original megacolonies, reflected in a shift of the TCD50 from 24.5 to 16.5 Gy. Direct parameter estimation from the cure data suggested that the underlying change was a lowered number of clonogenic 'stem' cells rather than increased cellular sensitivity. A similar decrease in clonogen density was also apparent for the recurrent clones in situ. The change in megacolony curability was paralleled by a substantial growth retardation. CONCLUSION: The data demonstrate persistent changes in the progeny of irradiated SCC tumour cells that affect both growth and radiosensitivity and are compatible with the expression of delayed reproductive death.

Animals↗

PubMed1997

The impact of complex chromosomal rearrangements on the detection of radiosensitivity in cancer patients.

BACKGROUND AND PURPOSE: Lymphocytes of a small fraction of cancer patients responded to in vitro irradiation with an extreme chromosomal reaction. A large portion of the observed chromosome aberrations were complex chromosomal rearrangements (CCR). The present study is an attempt to define the impact of CCR on the predictive detection of an intrinsic clinical radiosensitivity in cancer patients in more detail. MATERIALS AND METHODS: A three-colour 'FISH-painting' technique (chromosome in situ suppression (CISS) hybridization) was used for the detection of chromosomal rearrangements, induced by in vitro irradiation, in 81 samples of peripheral blood lymphocytes from 66 cancer patients. Thirty-three of those were assigned for radiation therapy, the others having just undergone radiation therapy. Seven healthy individuals served as controls. RESULTS: CCRs are a very rare event in non-irradiated cells. Lymphocytes of patients who had just undergone therapeutic irradiation, however, not only exhibited high basic frequencies of CCR but also responded to in vitro irradiation with a more drastic increase of CCR than did the lymphocytes of non-exposed patients. A high inter-individual variability of the reaction to in vitro irradiation could be generally stated. The lymphocytes of patients with clinical signs of an outstanding radiosensitivity responded with an unusually high frequency of CCR. The total number of CCRs detected by CISS was found to be dependent on the interval from a previous radiation therapy and was slightly influenced by previous cytostatic therapy. Irrespective of these influences, patients with clinically defined radiation hypersensitivity were those with the highest radiosensitivity also in cytogenetic terms (including CCR). CONCLUSION: The successful use of FISH-painting for the detection of CCR, in addition to the general breakage frequency, highlights its suitability in the identification of individual hypersensitivity to ionizing radiation. The time-consuming cytogenetic examination can be considerably reduced by its use.

Chromosome Aberrations↗

PubMed1998

Testing for mutations of the ataxia telangiectasia gene in radiosensitive breast cancer patients.

BACKGROUND AND PURPOSE: To determine if clinical radiosensitivity in breast cancer patients is related to mutations of the ataxia telangiectasia gene (ATM). MATERIALS AND METHODS: Fifteen patients who had developed a severe late reaction to a standard radiotherapy schedule were examined for evidence of increased in vitro radiosensitivity using the MTT assay. Mutation analysis was performed using a protein truncation assay. RESULTS: No mutations were detected in the 15 patients despite evidence of increased in vitro radiosensitivity. CONCLUSIONS: Testing for the ATM gene is unlikely to be useful for predicting clinical response to radiotherapy in breast cancer patients.

Ataxia Telangiectasia↗

PubMed1998

Radiosensitivity and oxidative signalling in ataxia telangiectasia: an update.

Radiosensitivity is a major hallmark of the human genetic disorder ataxia telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vivo after exposure of patients to therapeutic doses of radiation and in cells in culture. Clearly an understanding of the nature of the molecular defect in ataxia telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas, the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia telangiectasia (A-T)? As outlined above, since radiosensitivity is a universal characteristic of A-T, understanding the mechanism of action of ATM will provide additional information on radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM-controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense cDNA constructs into tumours to achieve the same end-point.

Animals↗

PubMed1999

Acute and late toxicity, tumour control and intrinsic radiosensitivity of primary fibroblasts in vitro of patients with advanced head and neck cancer after concomitant boost radiochemotherapy.

BACKGROUND AND PURPOSE: The existence of hereditary factors influencing the cellular response to ionising radiation has led to the hypothesis that the inter-patient variability of clinical radiation reactions may, at least in part, be attributable to an individual, or intrinsic, radiosensitivity. Considerable effort has been spent in the development of test systems that would determine individual radiosensitivity before or early during radiotherapy to possibly predict treatment outcome, but the results are still conflicting. The present explorative study was therefore aimed at the detection of associations between acute and late radiation effects, tumour control and in vitro radiosensitivity of primary normal tissue fibroblasts. PATIENTS AND METHODS: Sixty-eight patients with squamous cell carcinoma of the head and neck (93% UICC stage IV) were treated with a simultaneous concomitant boost radiochemotherapy with Carboplatin as part of a prospective non-randomised multicenter study at the University of Heidelberg. Primary fibroblasts were obtained from skin biopsies prior to treatment from 25 unselected patients of this study and the SF2 was determined using the colony forming assay and high dose-rate irradiation. The median follow-up was 21 months (range 2.5-81 months). RESULTS: The locoregional control rate at three years was 32%. No significant association between acute (mucosa reaction grade 1 or 2 vs. grade 3 and 4), late radiation effects (subcutaneous fibrosis, osteonecrosis, larynx oedema), locoregional tumour control and SF2 of primary fibroblasts was found using Cox proportional hazards regression analysis, log-rank test and Mann-Whitney U-test. Although a steep dose-response relationship was observed for the radiation-induced severe larynx oedema, Cox proportional hazards regression analysis could not fully explain the occurrence of severe radiation-induced larynx oedema with the dose to the larynx (P = 0.09). In the subgroup of twenty-five patients, where the SF2 was determined, bivariate analysis revealed about the same non-significant influence of the dose to the larynx on the larynx oedema (P = 0.1) and no influence of the SF2 (P = 0.5). CONCLUSIONS: In our study of patients with advanced cancer of the head and neck, neither the normal fibroblast SF2 nor the severity of acute radiation effects were able to predict late radiation effects or locoregional tumour control.

Adult↗

PubMed2001

Mechanism of the radiosensitization induced by vinorelbine in human non-small cell lung cancer cells.

Vinorelbine (Navelbine, KW-2307), a semisynthetic vinca alkaloid, is a potent inhibitor of mitotic microtubule polymerization. The aims of this study were to demonstrate radiosensitization produced by vinorelbine in human non-small cell lung cancer (NSCLC) PC-9 cells and to elucidate the cellular mechanism of radiosensitization. A clonogenic assay demonstrated that PC-9 cells were sensitized to radiation by vinorelbine with a maximal sensitizer enhancement ratio at a 10% cell survival level of 1.35 after 24-h exposure to vinorelbine at 20 nM. After 24-h exposure to vinorelbine at 20 nM, the approximately 67% of the cells that had accumulated in the G2/M-phase were cultured in the absence of vinorelbine and then irradiated at a dose of 8 Gy. Flow cytometric analyses showed prolonged G2/M accumulation concomitant with continuous polyploidization, and induction of apoptosis was observed in the cells subjected to the combination of vinorelbine-pretreatment and radiation. Polyploidization and induction of apoptosis were confirmed by morphological examination and a DNA fragmentation assay, respectively. We concluded that vinorelbine at a minimally toxic concentration moderately sensitizes human NSCLC cells to radiation by causing accumulation of cells in the G2/M-phase of the cell cycle. Prolonged G2/M accumulation concomitant with continuous polyploidization and increased susceptibility to induction of apoptosis may be associated with the cellular mechanism of radiosensitization produced by vinorelbine.

Carcinoma, Non-Small-Cell Lung↗

PubMed2001

On the radiosensitivity of man in space.

Astronauts' radiation exposure limits are based on experimental and epidemiological data obtained on Earth. It is assumed that radiation sensitivity remains the same in the extraterrestrial space. However, human radiosensitivity is dependent upon the response of the hematopoietic tissue to the radiation insult. It is well known that the immune system is affected by microgravity. We have developed a mathematical model of radiation-induced myelopoiesis which includes the effect of microgravity on bone marrow kinetics. It is assumed that cellular radiosensitivity is not modified by the space environment, but repopulation rates of stem and stromal cells are reduced as a function of time in weightlessness. A realistic model of the space radiation environment, including the HZE component, is used to simulate the radiation damage. A dedicated computer code was written and applied to solar particle events and to the mission to Mars. The results suggest that altered myelopoiesis and lymphopoiesis in microgravity might increase human radiosensitivity in space.

Aerospace Medicine↗

PubMed2002

N-(4-hydroxyphenyl)retinamide (4-HPR) modulates GADD45 expression in radiosensitive bladder cancer cell lines.

We previously demonstrated that N-(4-hydroxyphenyl)retinamide (4-HPR) and gamma-irradiation, when used in combination, had a synergistic effect in inducing apoptosis in bladder cancer cells, suggesting that 4-HPR may increase radiosensitivity in bladder cancer cells. To unravel molecular correlates in this radiosensitizing effect of 4-HPR, we examined the baseline and 4-HPR-induced expression of GADD45 to elucidate possible mechanisms by which 4-HPR enhanced the effect of gamma-irradiation in three bladder cancer cell lines. To investigate the role of p53 in mediating the radiosensitizing effect of 4-HPR, we also examined mutations in exons 5-9 by using direct sequencing and the levels of p53 expression by using RT-PCR and Western blot, before and after treatment with 4-HPR in these bladder cancer cell lines. Two cell lines had low expression of GADD45, and a dose-dependent increase in GADD45 expression induced by 4-HPR was found in bladder cancer cell lines without p53 mutations in exons 5-9. A combination of gamma-irradiation and 4-HPR showed a significantly greater effect in enhancing GADD45 expression than either agent used alone. The results indicate that the combined treatment with 4-HPR and gamma-irradiation has a stronger effect on GADD45 expression than the treatment with either agent alone, which suggests that the two agents may have an additive/synergistic effect. However, a normal p53 function appears to be necessary for the dose-dependent induction of GADD45 by 4-HPR. Once our results are verified and replicated by other investigators, 4-HPR may have a potential clinical implication in effectively treating bladder cancer in combination with low-gamma-irradiation therapy.

Antineoplastic Agents↗

PubMed1998

Evaluation of radiation-induced DNA damage and DNA repair in human lung cancer cell lines with different radiosensitivity using alkaline and neutral single cell gel electrophoresis.

Using the comet assay, radiation-induced DNA strand breaks were evaluated in human lung cancer cell lines with different radiosensitivity (U-1285, U-1906E, U-1752 and U-1810). Single strand breaks were more sensitive indicators of the radiation-induced damage than double strand breaks. However, there was no consistent pattern in the way the various cell lines responded to 1-5 Gy of gamma-irradiation and all cell lines showed a remarkably efficient DNA repair after 1 h. In a separate study of the repair kinetics of DNA double strand breaks, the radioresistant cell line U-1810 showed a more efficient initial strand rejoining than the radiosensitive cell line U-1285 after irradiation at 2 Gy. The latter finding suggests that the detection of early DNA repair may be useful when monitoring the intrinsic radiosensitivity of human lung cancer cells.

DNA↗

PubMed2001

A low-pH culture condition enhances the radiosensitizing effect of wortmannin.

PURPOSE: The radiosensitizing effect of wortmannin on human tumor cells in a low-pH microenvironment was compared with that in a neutral-pH environment. METHODS AND MATERIALS: A172 human glioblastoma cells, A549 human lung adenocarcinoma cells, and HMV-1 human melanoma cells were treated with 20 microM wortmannin 2 h before irradiation, and cell survival was examined. A low-pH microenvironment was simulated by exposing cells to low-pH culture medium for 24 h before wortmannin treatment. The effects of wortmannin on the repair of DNA double-strand breaks (dsbs) after 50-Gy irradiation in both low- and neutral-pH conditions were measured by pulsed-field gel electrophoresis. Expression of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in low-pH conditions was also compared with that in neutral-pH conditions by Western blot analysis. RESULTS: The radiosensitizing effect of wortmannin was greater in low-pH cultures than in neutral-pH cultures for all cell lines. The fast-rejoining component of DNA dsb repair was inhibited more strongly in low-pH than in neutral-pH conditions, although there was little difference in DNA-PKcs expression between groups. CONCLUSIONS: The low-pH culture condition, which was designed to mimic the microenvironment of the central tumor mass in actively proliferating solid tumors, enhanced the radiosensitizing effect of wortmannin by inhibiting the fast-rejoining component of DNA dsb repair and by prolonging the retention of nonrejoined DNA dsbs.

Adenocarcinoma↗

PubMed2001

The influence of autologous tumor fibroblasts on the radiosensitivity of squamous cell carcinoma megacolonies.

PURPOSE: To study the influence of tumor fibroblasts on radiosensitivity and stem cell fraction of tumor cells in squamous cell carcinoma megacolonies by determining colony cure and clonogen survival. METHODS AND MATERIALS: Murine squamous cell carcinoma cells (AT478c) grown as flat but multilayered megacolonies were co-cultured with pre-irradiated tumor fibroblasts derived from the same carcinoma, and irradiated with 1, 2, 4, or 8 fractions. Recurrent clones and their growth pattern in situ were recorded. From megacolony cure data and clonogen survival data, the clonogen number and the parameters of cellular radiosensitivity were calculated. RESULTS: The curability of the co-cultured megacolonies, as determined by TCD50 values, was significantly increased compared to the megacolonies without fibroblasts (p < 0.01). Both the megacolony cure and clonogen survival data suggested a decrease of the clonogen fraction in the co-cultured megacolonies. CONCLUSIONS: The presence of tumor fibroblasts increases megacolony radiosensitivity. This is due to a decrease in the fraction of clonogens in the tumor megacolony, apparently caused by a downregulation of the stem cell fraction of the tumor cells.

Animals↗

PubMed2001

Five-chlorodeoxycytidine, a tumor-selective enzyme-driven radiosensitizer, effectively controls five advanced human tumors in nude mice.

PURPOSE: The study's goals were as follows: (1) to extend our past findings with rodent tumors to human tumors in nude mice, (2) to determine if the drug protocol could be simplified so that only CldC and one modulator, tetrahydrouridine (H4U), would be sufficient to obtain efficacy, (3) to determine the levels of deoxycytidine kinase and dCMP deaminase in human tumors, compared to adjacent normal tissue, and (4) to determine the effect of CldC on normal tissue radiation damage to the cervical spinal cord of nude mice. METHODS AND MATERIALS: The five human tumors used were as follows: prostate tumors, PC-3 and H-1579; glioblastoma, SF-295; breast tumor, GI-101; and lung tumor, H-165. The duration of treatment was 3-5 weeks, with drugs administered on Days 1-4 and radiation on Days 3-5 of each week. The biomodulators of CldC were N-(Phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartyl transcarbamoylase, 5-fluorodeoxycytidine (FdC), resulting in tumor-directed inhibition of thymidylate synthetase, and H4U, an inhibitor of cytidine deaminase. The total dose of focused irradiation of the tumors was usually 45 Gy in 12 fractions. RESULTS: Marked radiosensitization was obtained with CldC and the three modulators. The average days in tumor regrowth delay for X-ray compared to drugs plus X-ray, respectively, were: PC-3 prostate, 42-97; H-1579 prostate, 29-115; glioblastoma, 5-51; breast, 50-80; lung, 32-123. Comparative studies with PC-3 and H-1579 using CldC coadministered with H4U, showed that both PALA and FdC are dispensable, and the protocol can be simplified with equal and possibly heightened efficacy. For example, PC-3 with X-ray and (1) no drugs, (2) CldC plus the three modulators, (3) a high dose of CldC, and (4) escalating doses of CldC resulted in 0/10, 3/9, 5/10, and 6/9 cures, respectively. The tumor regrowth delay data followed a similar pattern. After treating mice only 11/2 weeks with CldC + H4U, 92% of the PC-3 tumor cells were found to possess CldU in their DNA. The great majority of head-and-neck tumors from patient material had markedly higher levels of dC kinase and dCMP deaminase than found in adjacent normal tissue. Physiologic and histologic studies showed that CldC + H4U combined with X-ray, focused on the cervical spinal cord, did not result in damage to that tissue. CONCLUSIONS: 5-CldC coadministered with only H4U is an effective radiosensitizer of human tumors. Ninety-two percent of PC-3 tumor cells have been shown to take up ClUra derived from CldC in their DNA after only 11/2 weeks and 2 weeks of bolus i.p. injections. Enzymatic alterations that make tumors successful have been exploited for a therapeutic advantage. The great electronegativity, coupled with the relatively small Van der Waal radius of the Cl atom, may result in CldC's possessing the dual advantageous properties of FdC on one hand and BrdU and IdU on the other hand. These advantages include autoenhancing the incorporation of CldUTP into DNA by not only overrunning but also inhibiting the formation of competing TTP pools in tumors. A clinical trial is about to begin, with head-and-neck tumors as a first target of CldC radiosensitization.

Animals↗

PubMed2001

Lack of prostate cancer radiosensitization by androgen deprivation.

PURPOSE: The majority of clinical trials have shown that high-grade prostate cancer patients treated with androgen deprivation (AD) plus radiation (RT) have a survival advantage over those treated with RT alone. One possible mechanism for such a favorable interaction is that AD sensitizes cells to radiation. Animal model studies have provided suggestive evidence that AD sensitizes cells to radiation, but this mechanism is difficult to confirm conclusively in vivo. This question was investigated in LNCaP cells grown in vitro. METHODS AND MATERIALS: LNCaP cells were cultured in vitro in Dulbecco's modified Eagle's medium (DMEM)-F12 medium, containing 10% fetal bovine serum (complete medium [CM]). AD was achieved by culture in charcoal-stripped serum (SS)-containing medium. Replacement of androgen was done by adding the synthetic androgen R1881 at 1 x 10(-10) M to SS. Apoptosis was measured with a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Clonogenic survival was used to determine overall cell death, and the results were corrected for differences in plating efficiency from the various growth conditions. RESULTS: LNCaP cells were grown in CM, SS, or SS + R1881 medium, and cell counts obtained at 3, 4, and 5 days. Cell number increased exponentially in CM, whereas no increase in cell number was observed in SS medium. Cell counts from growth in SS + R1881 were intermediate between these extremes. Apoptosis was measured to determine if the combination of AD + RT in vitro resulted in supra-additive cell death, as has been previously described in an in vivo model system. The cells were cultured for 3 days before RT and apoptosis quantified 24 h after RT. There was a consistent supra-additive increase in apoptosis in cells exposed to AD + RT (2 or 8 Gy), as compared to either treatment given individually. In contrast, significant radiosensitization by AD was not observed by clonogenic survival even when the conditions of AD were varied. No radiosensitization was observed upon incubation in SS medium for 3, 4, or 5 days before RT, or extending AD after RT for 6 h before plating or 24 h after plating. CONCLUSION: The results show that in LNCaP prostate tumor cells supra-additive apoptosis does not translate into radiosensitization by clonogenic survival. Because clonogenic survival is a measure of overall cell death, either the level of apoptosis is too small a component of overall cell death or the increases in apoptosis occurred in a subpopulation that would have been killed by other mechanisms. Although the findings indicate that AD does not act by sensitizing prostate cancer cells to RT, the additive cell death and growth inhibitory effects of AD + RT are clinically meaningful.

Androgens↗

PubMed2002

Increased radiosensitivity with chronic hypoxia in four human tumor cell lines.

PURPOSE: It is well known that the radiosensitivity of tumor cells can be significantly reduced under hypoxic conditions. However, most of the reports in the literature refer to an experimental setup in which the supply of oxygen is kept low for a short period of time only. In tumors, chronic hypoxia would seem to be the more typical situation, because of an insufficient vascularization and the limited diffusion of oxygen into the tissue. Under such conditions, certain changes in the proliferation patterns of tumor cells, in which the cell cycle checkpoint protein p53 seems to play a role, have been shown to occur. We therefore decided to study radiosensitivity and cell cycle progression under conditions of chronic hypoxia in several human tumor cell lines differing in their p53 status. METHODS AND MATERIALS: Four human tumor cell lines (melanomas Be11 and MeWo and squamous carcinomas 4197 and 4451) were incubated for 3 h, 24 h, and 72 h under either oxic or hypoxic conditions and subsequently exposed to graded doses of X-rays. In some cases, cells were kept under hypoxia for the same periods of time, but then reoxygenated immediately before irradiation. Cell survival was assessed with the usual colony formation assay, and cell cycle distributions were determined by two-parameter flow cytometry after labeling with bromodeoxyuridine (BrdU). RESULTS: As expected, the oxygen enhancement ratio at 3 h was 2.0 or more in all cases. Differences, however, became evident with longer incubation times. At 24 h, the sensitivity of cells kept under hypoxic conditions both before and during irradiation was practically unchanged with cell lines Be11, 4197, and 4451, but clearly increased with MeWo. This resulted in an oxygen enhancement ratio of only 1.1 for the latter cell line when the sensitivity of aerated cells was used as reference. Cells kept under hypoxia for 24 h and reoxygenated shortly before irradiation, however, also showed an increase in sensitivity, so that the oxygen enhancement ratio based on differences in irradiation atmosphere alone was still around 2.0. At 72 h, the two p53 wild-type cell lines were not available for experiments, because they quickly degenerated under hypoxic conditions. Both mutant cell lines now showed similar results, the sensitivity being increased with irradiation under continued hypoxia as well as after reoxygenation. The oxygen enhancement ratios with reference to aerated cells were 1.3 and 1.5 for MeWo and 4451, respectively. Flow cytometric measurements after labeling with BrdU revealed that in all cell lines, the fraction of active S-phase cells during incubation tended to decrease under hypoxic conditions. Only in the p53 mutant cell lines, however, was this accompanied by an increase of the percentage of S-phase cells that were not actively incorporating BrdU. CONCLUSIONS: It is suggested that these quiescent cells in the S-phase compartment develop because of a general breakdown of cellular energy metabolism. In the p53 mutant cells, this may lead to a cessation of cell cycle progression in all phases alike, because checkpoint control has been lost; p53 wild-type cells, on the other hand, settle down preferentially in G(1) under the same conditions. Independently of the p53 status, however, energy depletion may be the cause of a decreased ability to cope with radiation damage and thus the cause of the observed increase in radiosensitivity. This would become more easily apparent in the p53 mutant cell lines, because they are less sensitive than the p53 wild types to hypoxia as such.

Carcinoma, Squamous Cell↗

PubMed2003

Clinical significance of atomic inner shell ionization (ISI) and Auger cascade for radiosensitization using IUdR, BUdR, platinum salts, or gadolinium porphyrin compounds.

PURPOSE: Halogenated pyrimidines (iododeoxyuridine [IUdR] and bromodeoxyuridine [BUdR]), platinum salts, and gadolinium porphyrins are heavy atom compounds used as radiosensitizers. For IUdR, it has been hypothesized that iodine inner shell ionizations (ISI) and Auger cascades could be one of the primary radiosensitization mechanisms. The purpose of this paper is to estimate the number of ISI produced per tumor cell and per 2 Gy irradiation in clinically relevant modelings. MATERIALS AND METHODS: ISI were evaluated using a two-step method. Photon-induced ISI were calculated using the MCNP-4C Monte Carlo code, heavy atom concentrations from clinical data published in the literature, and at various depths in a water phantom irradiated with 6-MV, (60)Co, (137)Cs, or (192)Ir sources. Electron knock-on induced ISI on K, L, and M atomic shells were evaluated with an hybrid method, using simulated electron spectra and cross-sections derived from the Møller formalism. Using a biological dose equivalence of 0.05 Gy per cell ISI, relative biological effectiveness (RBE) values were calculated for each situation. RESULTS: For platinum and gadolinium, ISI occurs in far less than 0.1% of the cell, whichever is the configuration. For IUdR and BUdR, ISI occurs in between 45% to 483% of the cell. Due to spectrum degradation, about 3 times more photoelectric ISI are generated at greater than shallower depths, and 10 times more for (192)Ir compared with (60)Co or 6-MV X-rays. Photoelectric ISI are about 3 times more frequent for iodine than bromine, but electron knock-on ISI are more frequent on bromine, and at the end about the same number of ISI are generated for both elements. RBEs were found to be between 1.01 and 1.12 for clinically relevant irradiation settings. CONCLUSIONS: The mechanisms of radiosensitization for platinum and gadolinium are clearly not related to an Auger cascade. For halogenated pyrimidines, however, clinically relevant numbers of ISI are generated within each cell. For IUdR, ISI appears to be strongly tied to the photon spectra. Halogenated pyrimidines should be evaluated again clinically, but using lower energy photons like a (192)Ir implant.

Bromodeoxyuridine↗

PubMed2003

Lipid a radiosensitizes hypoxic EMT-6 tumor cells: role of the NF-kappaB signaling pathway.

PURPOSE: Lipid A has shown promising immunostimulatory effects in both experimental tumor models and advanced stage cancer patients. This study examines whether lipid A may directly modulate the radioresponse of tumor cells by activating inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2) through nuclear factor-kappaB (NF-kappaB) signaling. METHODS AND MATERIALS: Hypoxic EMT-6 tumor cells were exposed to lipid A and analyzed for the level of COX-2 and iNOS by Western blotting and enzymatic assays. The hypoxic radioresponse of EMT-6 cells was estimated by clonogenic survival. The activation of NF-kappaB was examined by immunostaining of its p65 subunit and by luciferase reporter gene assay. RESULTS: Lipid A dose-dependently increased the expression and activity of iNOS with a maximal effect at plasma achievable concentrations of 3-30 micro g/mL. The COX-2 mediated production of prostaglandin E2 was constitutively high and further upregulated by lipid A. The radiosensitivity of hypoxic EMT-6 cells was increased up to 2.5 times and counteracted by the iNOS inhibitor aminoguanidine but not by the COX-2 inhibitor NS-398. The mechanism of radiosensitization was linked to NF-kappaB signaling, because its inhibition by phenylarsine oxide impaired both iNOS activation and radioresponse. CONCLUSION: Lipid A is an efficient hypoxic cell radiosensitizer at plasma relevant concentrations, which provides a rationale to combine lipid A with radiotherapy in further studies.

Cell Hypoxia↗

PubMed2003

NS 398 radiosensitizes an HNSCC cell line by possibly inhibiting radiation-induced expression of COX-2.

PURPOSE: Cyclooxygenase-2 (COX-2) protein is frequently elevated in squamous cell carcinoma of the head and neck (HNSCC). The aim of this study was to determine if COX-2 inhibitors have radiosensitizing effects in HNSCC and understand the mechanism by which this occurs. MATERIALS AND METHODS: The radiosensitizing effects of a selective COX-2 inhibitor, NS398, on a HNSCC cell line HEp3, were determined using clonogenic survival assay. Cells were pretreated with the dose of NS398 at which 50% growth inhibition occurred (IC(50)) and then irradiated. COX-2 protein and mRNA were then determined in the presence and absence of NS398. RESULTS: NS398 significantly decreased (p < 0.0001) the calculated survival fraction (SF) for all radiation doses (0.79 to 0.41 at 2 Gy). A significant increase in COX-2 protein of 2.8 fold for 2 Gy and 3.5 fold for 6 Gy was noted 48 h after radiation. Interestingly, the upregulation of COX-2 protein with radiation was suppressed when cells were pretreated with NS398. Quantitative reverse transcriptase polymerase chain reaction showed no significant corresponding increase in COX-2 mRNA at 48 h with ionizing radiation. CONCLUSIONS: The radiosensitizing effect of NS398 could be due to inhibition of radiation-induced COX-2 upregulation by this drug. NS398, known as an inhibitor of COX-2 enzyme activity, down-regulated COX-2 protein expression, which may indicate that NS398 can act upstream of COX-2, and this change appears to be post-transcriptional.

Carcinoma, Squamous Cell↗