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Results for “Radiosensitivity”

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PubMed1991

A comparison of radiosensitization by etanidazole and pimonidazole in mouse tumors.

Radiosensitization by pimonidazole (Ro 03-8799) was tested in three murine tumors, EMT6/SF using the excision assay, SCC-VII/SF using the excision and growth delay assays, and MDAH-MCa-4 using TCD50 assays with both single doses and 6 fractions of radiation with a 24-hr interfraction interval. Results were compared with those using etanidazole (SR-2508), both at equitoxic doses and at doses giving tumor concentrations similar to those achievable in the clinic. In excision assays with EMT6/SF and SCC-VII/SF tumors, pimonidazole and etanidazole gave similar radiosensitization at similar concentrations in the tumors. Pimonidazole, however, did not demonstrate radiosensitization in SCC-VII/SF tumors in the growth delay assay, despite tumor concentrations that gave maximum sensitization in the excision assay. Furthermore, pimonidazole gave less than expected sensitization in single dose and 6-fraction TCD50 assays with MDAH-MCa-4 tumors, and less sensitization than comparable levels of etanidazole in this tumor line. When the concentration of pimonidazole in the tumors was approximately 0.36 mumoles/g the dose modification factor (DMF = dose without sensitizer/dose with sensitizer to give an isoeffect) was 1.56 (1.40-1.74, 95% c.l.) in single dose TCD50 assays. Etanidazole, however, gave a DMF of 1.92 (1.59-2.32) with a tumor concentration of approximately 0.32 mumoles/g and 1.69 (1.46-1.96) with a tumor concentration of approximately 0.21 mumoles/g. Thus, etanidazole gave more consistent sensitization for different tumors and different endpoints than did pimonidazole. The results appear to confirm the disappointing performance of pimonidazole in the clinic.

Animals↗

PubMed1992

The prediction of human tumor radiosensitivity in situ: an approach using chromosome aberrations detected by fluorescence in situ hybridization.

No method of predicting the radiation sensitivity of individual human tumors is presently available, and recently published data show that other factors, in addition to the intrinsic radiosensitivity of the tumor cells, may play a role in the in vivo response of human tumors. Since these factors likely involve the tumor milieu (e.g., cell-cell contact and tumor hypoxia), an in situ assay of radiosensitivity is required. Although an analysis based on chromosome damage is the only suitable assay that would fit the requirements of sensitivity and speed of analysis, conventional examination of chromosome damage is impractical. By allowing the visualization of chromosomes in interphase cells, the technique of premature chromosome condensation (PCC) overcomes the need to culture the tumor cells in vitro, but the technical problem remains of counting a small excess number of breaks over the often large pretreatment chromosome number. We demonstrate here that the combination of fluorescence in situ hybridization (FISH) with PCC enormously simplifies the problem by focusing the analysis on a single chromosome. It also allows exchange aberrations to be scored easily. We demonstrate that the FISH technology may also be used to estimate radiation sensitivity from stable reciprocal translocations in metaphase identified by combining whole chromosome painting with a second color hybridization to the repeat sequences common to the centromeres. Since the frequency of stable translocations should correlate with initial chromosome damage, and since these translocations are not preferentially lost from the irradiated tumor cell population by cell death, an estimate of tumor cell killing following 1-5 dose fractions should be possible. Each of these two methods has its advantages, and a careful study of the two should establish which is superior for routine use to determine tumor radiosensitivity in situ.

Chromosome Aberrations↗

PubMed1992

NLA-1: a 2-nitroimidazole radiosensitizer targeted to DNA by intercalation.

Targeting of electron affinic radiosensitizers to DNA via reversible non-covalent intercalative binding has potential for increasing sensitizer concentrations locally at the DNA target while decreasing accessibility to reductases responsible for bioactivation and cytotoxicity. We have prepared an DNA-targeted acridine-linked 2-nitroimidazole (NLA-1) as an example of such a compound. NLA-1 binds reversibly to DNA with an affinity similar to 9-aminoacridine, and is approximately 1000 times more potent than MISO as a cytotoxin, despite a similar reduction potential. It shows less enhancement of cytotoxicity under hypoxia (5- to 6-fold) than does MISO (approximately 11-fold), but is a potent hypoxia-selective radiosensitizer in AA8 cells with a concentration for an enhancement ratio of 1.6 (C1.6) of 9 microM. The mean intracellular concentration at the C1.6 is 400 microM, on which basis its potency is about twice that of MISO. The in vitro therapeutic index (aerobic cytotoxic potency/hypoxic C1.6) of NLA-1 is approximately 6-fold lower than that for MISO. NLA-1 lacks radiosensitizing activity against SCCVII or EMT6 tumors in vivo at the maximum tolerated dose (MTD) of 100 mumol.kg-1.

Aminoacridines↗

PubMed1994

Bromodeoxyuridine-mediated radiosensitization in human glioma: the effect of concentration, duration, and fluoropyrimidine modulation.

PURPOSE: To define the relative influence of duration of exposure, concentration, and modulation by fluorodeoxyuridines (FdUrd) on the incorporation of 5-bromo-2-deoxyuridine (BrdUrd) into DNA of a human malignant glioma line (D-54) in vitro and in vivo. MATERIALS AND METHODS IN VITRO STUDIES: an established human malignant glioma line (D-54) was exposed to a clinically achievable concentration of BrdUrd to model intravenous (1 microM BrdUrd) and intraarterial (4 microM BrdUrd) conditions. The influence of modulation was assessed using 1 nM FdUrd. Incorporation of BrdUrd, radiosensitization, and cytotoxicity were determined after 24, 72, and 120 h drug exposures. In Vivo studies: nude mice bearing D-54 xenografts were infused with BrdUrd at 100 mg/kg/day for 7 and 14 days or BrdUrd at 400 mg/kg/day for 5 days. The influence of modulation was assessed by combining 100 mg/kg/day of BrdUrd with 0.1, 0.3, and 1 mg/kg/day FdUrd for 7 days. Incorporation of BrdUrd into the DNA of tumor, gut, and marrow were determined. RESULTS: In Vitro: thymidine replacement and radiosensitization were a function of concentration, and incorporation began to plateau after 2 to 3 population doublings. Modulation with 1 nM FdUrd significantly increased incorporation. Radiosensitization was a linear function of thymidine replacement under all conditions tested. In Vivo: infusion with 400 mg/kg/day for 5 days resulted in greater tumor incorporation (10.3 +/- 0.4% thymidine replaced) than treatment with 100 mg/kg/day for 14 days (6.0 +/- 0.6% of thymidine replaced). Infusion of FdUrd with BrdUrd increased normal tissue incorporation of BrdUrd, but failed to increase BrdUrd incorporation in tumor cells. CONCLUSION: These results suggest that relatively short, high dose rate infusions may be preferable to long, low dose rate infusions. The potential benefit of FdUrd modulation demonstrated in vitro may be difficult to realize using continuous systemic infusions.

Animals↗

PubMed1994

Hyperthermia radiosensitization in human glioma cells comparison of recovery of polymerase activity, survival, and potentially lethal damage repair.

PURPOSE: DNA polymerase inactivation is compared to thermal radiosensitization and inhibition of damage recovery in human glioma cells. METHODS AND MATERIALS: Two human glioma cell lines (U87MG and U373MG) were exposed to hyperthermia and irradiation. Hyperthermia was given at 43 degrees C and 45 degrees C and DNA polymerase alpha + delta + epsilon and beta activities were measured. Hyperthermia was given at various times before irradiation and the degree of radiosensitization and polymerase activity was assessed at various times after heating. In addition the ability of cells to undergo repair of potentially lethal radiation damage was assessed for cells irradiated at various times after heating. RESULTS: Polymerase alpha + delta + epsilon and polymerase beta both recovered after heating but polymerase beta was faster and was complete in U373MG but not in the U87MG cell lines after 48 h incubation after heating (45 degrees C, 60 min). Incubation, between hyperthermia and irradiation resulted in a loss of radiosensitization and a loss of inhibition of repair of potentially lethal damage. These changes correlated well with recovery of polymerase beta but not with polymerase alpha + delta + epsilon. CONCLUSION: The correlation of polymerase beta activity and thermoradiosensitization and its recovery indicate that polymerase beta may be one of the mechanisms involved in thermoradiosensitization.

Cell Survival↗

PubMed1994

The radiosensitivity of quiescent cell populations in murine solid tumors in irradiation with fast neutrons.

PURPOSE: We analyzed the characteristics of radiosensitivity and potentially lethal damage repair in the quiescent cell populations of murine SCC VII solid tumors irradiated with fast neutrons, in comparison with those irradiated with 10 MV X rays. METHODS AND MATERIALS: SCC VII tumor-bearing C3H/He mice were irradiated with 30 MeV fast neutrons or 10 MV X rays after receiving 10 injections of 5-bromo-2'-deoxyuridine (BUdR) to label all proliferating tumor cells. Immediately or 24 h after irradiation, the tumors were excised and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus frequency in cells without BUdR labeling was determined using immunofluorescence staining to BUdR. This micronucleus frequency was then used to calculate the surviving fraction of unlabeled cells from the regression line for the relation between micronucleus frequency and the surviving fraction of all tumor cells. Thus, a cell survival curve could be determined for the cells not labeled by BUdR, which can be regarded as the quiescent cells for all practical purposes. RESULTS: The difference in intrinsic radiosensitivity between all tumor and quiescent cells became smaller by using fast neutrons, compared with X rays, especially when large radiation doses were given. Potentially lethal damage repair by quiescent cells was less evident following irradiation with fast neutrons than with X rays, especially when large doses were delivered. CONCLUSION: By using fast neutrons in clinical radiotherapy, the radiosensitivity of solid tumors is thought to depend on their heterogeneity less critically than for X rays.

Animals↗

PubMed1994

Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice.

PURPOSE: In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined. METHODS AND MATERIALS: The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions x three fractions/48 h or 5 Gy/fractions x five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three or four times at 2-h intervals. RESULTS: At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter. CONCLUSION: Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity.

Animals↗

PubMed1995

The spectrum of in vitro radiosensitivity in four human melanoma cell lines is not accounted for by differential induction or rejoining of DNA double strand breaks.

PURPOSE: Radioresistance is a significant clinical problem in advanced malignant melanoma and many melanoma cell lines show a radioresistant acute x-ray survival response in vitro. Given that the DNA double strand break is the lesion most closely correlated with x-ray induced cell lethality, differences in the induction and rejoining of these lesions may account for the radioresistance of some human melanoma cell lines. METHODS AND MATERIALS: The above hypothesis was tested using pulsed field gel electrophoresis to measure x-ray induced DNA double strand break induction and rejoining in four human melanoma cell lines: MM138, MM170, MM96-L and HT 144. RESULTS: The MM138, MM170 and MM96-L cell lines were characterized in vitro by low alpha/beta ratios and broad x-ray survival curve shoulders. MM138 and MM170 were the most radioresistant and MM96-L had intermediate sensitivity. In contrast, HT144 was markedly x-ray sensitive, despite retaining a shoulder and like the other lines, having a low alpha/beta ratio. There were no significant differences in DNA double strand break induction between the cell lines, and thus no correlation existed between DNA double strand break induction and radiosensitivity. Consistent with the shoulders on the x-ray survival curves, all four cell lines showed efficient DNA double strand break rejoining. Highly efficient DNA double strand break rejoining could account for the radioresistance of one of the melanoma lines (MM138). For example, MM138 had rejoined 50% of the induced DNA double strand breaks by 5.5 min compared to 13-17 min for the other three cell lines. The development of postirradiation apoptosis was effectively excluded as the cause of the marked radiosensitivity of the HT144 cell line. CONCLUSION: Other factors (such as lesion repair fidelity or differential lesion tolerance) underlie the differences in the intrinsic radiosensitivity between these melanoma cell lines.

Apoptosis↗

PubMed1995

Optical isomers of a new 2-nitroimidazole nucleoside analog (PR-350 series): radiosensitization efficiency and toxicity.

PURPOSE: A new 2-nitroimidazole nucleoside radiosensitizer, PR-350 (1-[1',3',4'-trihydroxy-2'-butoxy]-methyl-2-nitroimidazole), has been reported to be as efficient as and less toxic than etanidazole. This compound is racemic, and it was recently optically resolved into two isomers, PR-68 (2'R,3'S type) and PR-69 (2'S,3'R type). The other two isomers, PR-28 (2'S,3'S type) and PR-44 (2'R,3'R type), were asymmetrically synthesized. In the present study, we investigated the properties, sensitizing activity, and toxicity of PR-350 and the four optical isomers in comparison with those of other 2-nitroimidazole hypoxic cell radiosensitizers, etanidazole, KU-2285, KIN-804, and RP-170. Because PR-350 and PR-28 can be industrially synthesized, we evaluated whether either of these two drugs are suitable for further investigation. METHODS AND MATERIALS: In an in vitro study, EMT-6 cells were irradiated at a dose of 1-3 Gy under hypoxic conditions in the presence of the drugs at a concentration of 1 mM. A combined cytokinesis-block micronucleus and chromosomal aberration assay was performed. To assess the in vivo effects, colony assay and growth delay assay were performing using SCCVII tumor-bearing C3H mice. The mice received 16-24 GY 10-40 min after administration of 50-200 mg/kg of the drugs. Toxicity and pharmacokinetics in mice were also investigated. RESULTS: The sensitizer enhancement ratio (SER) in the in vitro cytokinesis-block micronucleus assay increased in the following order: PR-69 (1.27) approximately equal to PR-28 (1.31) approximately equal to PR-44 (1.38) approximately equal to PR-350 (1.41) approximately equal to PR-68 (1.47) < etanidazole (1.79) < KIN-804 (2.03) approximately equal to KU-2285 (2.30). The SER at a dose of 200 mg/kg and at an interval of 20 min (optimal interval) in the in vivo-in vitro colony assay increased as follows: PR-44 (1.26) approximately equal to PR-28 (1.29) < PR-69 (1.34) approximately equal to etanidazole (1.35) approximately equal to PR-350 (1.36) < RP-170 (1.41) approximately equal to PR-68 (1.41) < KU-2285 (1.49). The growth delay assay also showed that PR-350 was less efficient than KU-2285 and more efficient than PR-28. PR-350 and the four isomers had similar reduction potentials, but PR-28 and PR-44 were more hydrophilic than PR-68 and PR-69. The LD50 in mice were 5.8 g/kg for PR-350, approximately 7 g/kg for PR-28, 4 g/kg for PR-68, and 6 g/kg for PR-44 and PR-69. The concentration of PR-28 in the murine sciatic nerve was lower than that of PR-350. CONCLUSION: In vivo radiosensitizing activity differed among the four optical isomers, which appeared to be due, at least in part, to differences in lipophilicity. Although PR-28 was the least toxic, its low sensitization efficiency does not warrant clinical trials. Among the PR compounds, PR-68 appears to be most efficient, but optical resolution of PR-68 from PR-350 is expensive, and asymmetrical synthesis of PR-68 is not established. Therefore, PR-350 seems to be most suitable for further investigation among the PR-350 series compounds, considering its higher efficiency compared with PR-28 and PR-44, and established synthesis.

Animals↗

PubMed1995

Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer.

PURPOSE/OBJECTIVE: To determine if the radiosensitivity of normal human skin fibroblasts, measured in early passage cultures, is significantly correlated with the degree of acute or late normal skin damage in patients treated for breast cancer with radiotherapy. METHODS AND MATERIALS: In the 1970s, a series of breast cancer patients was treated at the Department of Oncology in Gothenburg, Sweden with postoperative irradiation to the parasternal region. Patients were treated bilaterally using different fractionation schedules and doses to the right and left fields. Peak acute reactions were scored on a six-point scale, and skin erythema was measured by reflectance spectrophotometry. Telangiectasia was graded over time on a six-point scale. In April 1992, two small skin biopsies were obtained from 22 patients in two treatment groups (i.e., four dose-fractionation schedules) and, using either delayed or immediate plating, fibroblast radiosensitivity was measured in early passage cultures by clonogenic survival, after high and low dose-rate irradiations. Survival at 2.0 Gy (SF2) was calculated from complete survival curves. RESULTS: To test assay reproducibility, SF2 values derived from paired biopsies of the same patient (12 cases) were compared. A reasonably good correlation (p = 0.075) was obtained for SF2s determined by high dose-rate irradiations with immediate plating, but not for delayed plating or low dose-rate treatments. The median coefficient of variation in the replicate SF2s after high dose-rate treatment and immediate plating was 13%, suggesting that the poor correlation in paired SF2 values is due to the magnitude of the uncertainty in SF2 relative to the overall spread in SF2 values between patients (CV = 28%). Individual SF2 values and averaged values from patients with data from two biopsies were compared with the acute and late clinical reactions. A significant negative correlation was found between SF2 and relative clinical response, but only when averaged high dose-rate SF2 values and telangiectasia scores were compared. There was no significant correlation between average SF2 values and acute responses or between individual SF2 measurements and either the acute or late clinical response. CONCLUSION: The results of this study suggest that the degree of late telangiectasia is at least partially dependent upon the intrinsic cellular radiosensitivity of normal fibroblasts, but the relationship is not clear cut. Multiple replicate assays are necessary to obtain reliable estimates of fibroblast SF2 values using current techniques.

Biopsy↗

PubMed1996

Modulation of clonogenicity, growth, and radiosensitivity of three human epidermoid tumor cell lines by a fibroblastic environment.

PURPOSE: To develop a model vitro system to examine the influence of fibroblasts on the growth and survival of human tumor cells after exposure to ionizing radiation. METHODS AND MATERIALS: The cell system of three epidermoid carcinoma cell lines derived from head and neck tumors having differing growth potentials and intrinsic radiosensitivities, as well as a low passage skin fibroblast strain from a normal human donor. The tumor cells were seeded for five days prior to exposure to radiation: (a) in the presence of different numbers of fibroblasts, (b) in conditioned medium from stationary fibroblast cultures, and (c) on an extracted fibroblastic matrix. RESULTS: When grown with fibroblasts, all three tumor cell lines showed increased clonogenicity and increased radioresistance. The radioprotective effect was maximal at a density of approximately 10(5) fibroblasts/100 mm Petri dish, and was greatest in the intrinsically radiosensitive tumor cell line. On the other hand, the effects of incubation with conditioned medium or on a fibroblastic matrix varied among the tumor cell lines. Thus, the protective effect afforded by coculture with fibroblasts must involve several cellular factors related to the fibroblast itself. CONCLUSIONS: These observations emphasize the importance of cultural conditions on the apparent radiosensitivity of human tumor cell lines, and suggest that the fibroblastic connective tissue enveloping the malignant cells should be considered when the aim is to establish a radiopredictive assay from surgical tumor fragments.

Carcinoma, Squamous Cell↗

PubMed1992

Inhibition of glutathione reductase activity by a carbamoylating nitrosourea: effect on cellular radiosensitivity.

Nitrosoureas inactivate cellular glutathione reductase. N,'N'1,3-bis(trans-4-hydroxycyclohexyl)-N'-nitrosoureas (BCyNU), a nitrosourea reported to selectively inhibit glutathione reductase (GR) activity, was examined to determine if it could be used as a means to inhibit cellular levels of this enzyme in radiobiology studies. Confirmation of drug-induced inhibition of GR activity was demonstrated using a cell-free model system employing purified GR. Cellular studies with Chinese hamster V79A03 showed that BCyNU decreased cellular glutathione content concomitant with an inhibition of specific GR activity. Under relatively nontoxic conditions, cellular exposure to BCyNU (25 microM, 0.25 h) either before or after radiation treatment, increased cellular radiosensitivity with the optimum time for drug addition being immediately following radiation. At a BCyNU dosage which produced less than or equal to 5% cell toxicity, a marked decrease in radioresistance was characterized as a reduction in both Dq (24 +/- 1.5%) and Do (8 +/- 0.5%) concomitant with a 25 +/- 2% decrease in cellular glutathione reductase (GR) activity. At cytotoxic drug dosages (25 microM, 1 h; cell survival 79 +/- 7%), a marked radiosensitization manifested by a 1.25 +/- .07-fold reduction in the Dq was observed concomitant with a 49 +/- 4% decrease in GR activity. Using cells enriched in different stages of the cell cycle, BCyNU caused cell-age dependent cytotoxicity with preferential killing of cells in the radioresistant late-S-phase, a likely explanation for its radiosensitizing capabilities at high drug dosages. Data obtained at nontoxic drug dosages suggest that GR-inactivation may be an important component of cellular response to free-radical induced damage.

Animals↗

PubMed1991

Heterogeneity in Alzheimer's disease: evidence from cellular radiosensitivity and complementation of this phenotype.

Radiosensitivity was studied in a series of Alzheimer's disease (AD) patients and normal controls by examining clonogenic survival and radiation-induced chromosome aberrations in lymphoblastoid cell lines. D0 values based on colony survival for AD and normals following exposure to gamma-rays were 0.86 +/- 0.04 and 1.14 +/- 0.03 Gy respectively. However, 2 of the AD cell lines had D0 values in the normal range. This increased radiosensitivity in AD cells was confirmed by an increased number of gamma-ray-induced chromosome aberrations in these cells. Cell fusion was employed to investigate the presence of different complementation groups for the radiosensitive phenotype in AD using frequency of radiation-induced chromosome aberrations as a means of distinguishing different groups. Four complementation groups were found among 5 AD cell lines. These findings provide additional experimental evidence in support of heterogeneity in AD.

Aged↗

PubMed1992

Evidence for individual differences in the radiosensitivity of human skin.

Previously published clinical data have been re-analysed to investigate individual differences in the radiosensitivity of human skin. In the clinical studies, acute and late skin reactions were recorded for 254 breast cancer patients receiving radiotherapy to the internal mammary nodes following simple or modified radical mastectomy. Each patient was treated bilaterally with different fractionation schedules to the right and left fields. Patients were assigned prospectively to 10 different treatment groups of 11-35 patients each, with all patients in a group receiving the same pair of fractionation schedules to the right and left fields. In the present study, correlations between the skin reactions in the two treatment fields per patient were investigated. For each of three different endpoints--peak reflectance measure of erythema, peak acute skin reaction score, and a ranking measure of the progression rate of telangiectasia--significant correlations were found between the levels of skin injury to the right and left treatment fields of the patients in most treatment groups. Although there were correlations between the absorbed doses in the right and left fields, statistical analyses indicated that dose effects were not sufficient to explain fully the patient-to-patient differences in skin response. Thus, these data provide evidence for the existence of individual differences in the radiation response of human skin, both for early and late effects. Whether these differences are dominated by heterogeneity in intrinsic cell radiosensitivity or by other factors has yet to be determined. However, there was no clear evidence of a correlation between the acute and late endpoints, suggesting that the individual differences in radiosensitivity are not dominated by a common genetic component expressed equally in all cells.

Breast Neoplasms↗

PubMed1994

Radiosensitivity of new and established human melanoma cell lines: comparison of [3H]thymidine incorporation and soft agar clonogenic assays.

Seven new low-passage melanoma lines were developed in this laboratory from clinical melanoma specimens and characterised for chromosome complement, DNA ploidy and S-phase content. The radiosensitivity of these lines was compared with that of eight established melanoma cell lines, FME, MM-96, SK-MEL-5, SK-MEL-28, SK-MEL-2, MALME-3M, M19-MEL and LOX-IMVI, using a 96-well microculture assay technique. Dose-response curves were determined using a 5-day incubation period and 6-h terminal [3H]thymidine-labelling period. Radiation (60Co source) was carried out under a lead wedge to provide a radiation dose range of 0-10 Gy, or by irradiating part of the plate (radiation dose 0 or 2 Gy). Data for a range of cell densities in a single 96-well plate were combined into a single regression equation incorporating linear quadratic terms for radiation dose and cell density. SF2 values were defined as the amount of thymidine incorporated following a radiation dose of 2 Gy, expressed as a fraction of that of unirradiated cells, and varied from 0.36 to 0.93. The reproducibility in repeat assays, as defined by the standard error of determinations at different passage numbers, was +/- 0.04. The newly developed lines exhibited a similar range of radiosensitivity to that of the established lines, and melanin content did not correlate with resistance. For nine of the lines, radiation parameters were also determined using a modified Courtenay clonogenic soft agar assay technique, and the results compared with the thymidine incorporation results, and a significant linear correlation was found between SF2 and SF2' (r = 0.89). The linear (alpha) and quadratic (beta) terms of the best-fit linear quadratic dose-response curves, were significantly correlated between the two assays. It is concluded for this series of human melanoma lines that proliferation assays in 96-well plates provide radiosensitivity parameters comparable to those using clonogenic assays.

Adult↗

PubMed2003

Photofrin as a radiosensitizer in an in vitro cell survival assay.

Chemical modifiers (radiosensitizers) are used in order to increase the efficacy of radiotherapy. The use of Photodynamic Therapy for tumor treatment, especially with Photofrin II, is also known. At present, no chemical modifier has been found to act as a selective radiosensitizer. Experiments using several series of cell lines were performed; human bladder cancer cell line (RT4), colon adenocarcinoma cells (HT-29), and the glioblastoma cells (U-373 MG) were investigated, with and without incubation with Photofrin II, before irradiation. The irradiation was performed using doses ranging from 0 to 8Gy. Colony forming tests were applied to determine the efficiency of Photofrin II as a radiation sensitizer in comparison to irradiation alone. Two of the cell lines tested, cultures of the RT4 and U-373 MG, treated with Photofrin II prior to radiation, showed cell survival lower than cultures untreated with Photofrin II but irradiated under identical conditions. For the HT-29 cells, the results did not differ between the two groups (with and without Photofrin). The results of this study showed that Photofrin II can act, under certain conditions as a tumor radiosensitizer.

Adenocarcinoma↗

PubMed2007

Radiosensitization effect of zidovudine on human malignant glioma cells.

Telomeres are shortened with each cell division and play an important role in maintaining chromosomal integrity and function. Telomerase, responsible for telomere synthesis, is activated in 90% of human tumor cells but seldom in normal somatic cells. Zidovudine (AZT) is a reverse transcriptase inhibitor. In this study, we have investigated the effects of gamma-radiation in combination with AZT on telomerase activity (TA), telomere length, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and the changes in radiosensitivity of human malignant glioma cell line U251. The results showed that the TA was suppressed by AZT but enhanced by irradiation, resulting in a deceleration of restored rate of shortened telomere, decreased repair rate of DNA strand breaks, and increased radiosensitivity of U251 cells. Our results suggested that telomerase activity and telomere length may serve as markers for estimating the efficacy of cancer radiotherapy and reverse transcriptase inhibitors, such as AZT, may be used clinically as a new radiosensitizer in cancer radiotherapy.

Cell Line, Tumor↗

PubMed2004

Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazole hypoxic cell radiosensitizers.

(R)- and (S)-Epichlorohydrins were used to prepare the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazoles that function as hypoxic cell radiosensitizers. The synthetic design allowed for introduction of a side chain of varying bulk that permitted an examination of the steric effects on enantio-discrimination in biological assay systems. The single stereocenter also connected the two pharmacophores--a 2-nitroimidazole moiety critical to hypoxic cell radiosensitization, and a haloacetylcarbamoyl group to function as an anti-angiogenesis pharmacophore. In the chick embryo chorioallantoic membrane (CAM) assay, the R-enantiomers possessing the bulky p-tert-butylphenyl group showed higher anti-angiogenic activity than the corresponding S-enantiomers, while there were no differences in the activity between the enantiomers containing the less bulky methyl and tert-butyl groups. Among the compounds we report, R-p-tert-butylphenyl-bromoacetylcarbamoyl-2-nitroimidazole, TX-1898, was found to be the most promising candidate for further development of as anti-angiogenic hypoxic cell radiosensitizer.

Angiogenesis Inhibitors↗