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Results for “Radiosensitivity”

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PubMed1998

TX-1877: design, synthesis, and biological activities as a BRM-functional hypoxic cell radiosensitizer.

PURPOSE: 2-Nitroimidazole acetamide TX-1877 and its derivatives (TX-1877 analogs) were designed, synthesized, and evaluated by their in vitro and in vivo radiosensitization, tumor growth control, suppression of lung metastasis, and immunopotentiation, as biological response modifier (BRM)-functional hypoxic cell radiosensitizers. MATERIALS AND METHODS: TX-1877 analogs were designed and synthesized in our laboratory. In vitro radiosensitizing ability was estimated using EMT6/KU cells under hypoxic conditions. In vivo radiosensitization, antimetastasis, and immunopotentiation were evaluated using female C3H/He mice bearing the SCCVII tumor. Days (15 or 10) after the inoculation of 10(5) SCCVII tumor cells into the hinder thigh, a drug (0.4 mg/g) was administered i.p. and local irradiation of 30 Gy was given at 30 min after its administration. Tumor growth was observed for 20 days and mice were euthanized to count the number of metastatic nodules on the surface of the lungs. Tumor tissues were extirpated and stained by the ABC method at 1, 2, and 3 weeks after treatment for immunological evaluation. RESULTS: Novel types of bifunctional radiosensitizers, TX-1877 and its analogs possessing BRM-functions (i.e., antimetastatic and immunopotentiation effects) were developed. In vitro radiosensitizing abilities of TX-1877 and its analogs, with their partition coefficient values of more than 0.050, were comparable to misonidazole (MISO) at their doses of 1 mM. Tumor regrowth was suppressed evidently 20 days after the treatment in the irradiated group with TX-1877 (TX-1877 plus R) and with KIN-806 (KIN-806 plus R). The former group reduced markedly the mean number of metastatic lung nodules regardless of radiation therapy. TX-1877 and KIN-806 plus R induced helper T lymphocytes. The TX-1877, TX-1877 plus R, KIN-806, and KIN-806 plus R enhanced macrophage infiltration for 3 weeks after treatment. CONCLUSION: TX-1877 is an excellent BRM-functional hypoxic cell radiosensitizer, expected to be useful for clinical use.

Animals↗

PubMed1997

Design, synthesis, and biological activity of anti-angiogenic hypoxic cell radiosensitizer haloacetylcarbamoyl-2-nitroimidazoles.

We designed, synthesized, and evaluated haloacetylcarbamoyl-2-nitroimidazoles, including chloro (KIN-1800, TX-1835, and TX-1836) and bromo derivatives (TX-1844, TX-1845, and TX-1846), as potential hypoxic cell radiosensitizers with antiangiogenic activities. To establish biological function owing to the haloacetylcarbamoyl group in the side-chain, we compared their in vitro radiosensitizing activities with those of their parent 2-nitroimidazoles without haloacetylcarbamoyl groups: misonidazole (MISO), TX-1831, and TX-1832, respectively. Both tert-butoxy substituted derivatives. TX-1835 and TX-1845, were more potent radiosensitizers than TX-1831. The p-tert-butylphenoxy-substituted derivatives, TX-1836 and TX-1846, and the methoxysubstituted derivatives, KIN-1800 and TX-1844, were stronger radiosensitizers than TX-1832 and MISO. We examined the anti-angiogenic activities of these 2-nitroimidazole derivatives containing haloacetylcarbamoyl group by the rat lung endothelial (RLE) cell proliferation assay and chick embryo chorioallantoic membrane (chick CAM) angiogenesis assay and showed that haloacetylcarbamoyl-2-nitroimidazoles were more potent angiogenic inhibitors than the corresponding desacetylcarbamoyl-2-nitroimidazoles. The in vivo chick CAM angiogenesis assay showed that the strong bromoacetylcarbamoyl-2-nitroimidazole radiosensitizers, such as TX-1845 and TX-1846, were the strongest angiogenic inhibitors among them. We concluded that the bromoacetylcarbamoyl-2-nitroimidazole radiosensitizers, such as TX-1845 and TX-1846, are promising as anti-angiogenic hypoxic cell radiosensitizers.

Adenosine Triphosphate↗

PubMed1991

Synthesis and evaluation of a series of 3,5-disubstituted benzisoxazole-4,7-diones. Potent radiosensitizers in vitro.

A series of 3,5-disubstituted-2,1-benzisoxazole-4,7-diones was synthesized and evaluated as radiosensitizers both in vitro and in vivo. These compounds were designed as non-nitro electron-affinic agents in an effort to alleviate some of the toxicities seen with the 2-nitroimidazole radiosensitizers evaluated in the clinic. Several compounds in this series were potent radiosensitizers in vitro, with sensitizer enhancement ratios of 2.0-2.3 at concentrations less than 0.5 mM. Compounds with potent in vitro activity were also evaluated in vivo. However, none of these compounds showed radiosensitizing activity in vivo. The reduction potentials of these compounds were determined by cyclic voltammetry and compared to other electron-affinic radiosensitizers. In general, the reduction potentials of this series of compounds was slightly more positive than the 2-nitroimidazoles, but they fell within the range postulated as acceptable to yield in vivo activity. The results suggest that factors other than reduction potential may be responsible for the lack of in vivo radiosensitizing activity observed for this class of radiosensitizers.

Animals↗

PubMed2002

Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition.

The chromosomal radiosensitivity of breast cancer patients with a known or putative genetic predisposition was investigated and compared to a group of healthy women. The chromosomal radiosensitivity was assessed with the G2 and the G0-micronucleus assay. For the G2 assay lymphocytes were irradiated in vitro with a dose of 0.4 Gy (60)Co gamma-rays after 71 h incubation, and chromatid breaks were scored in 50 metaphases. For the micronucleus assay lymphocytes were exposed in vitro to 3.5 Gy (60)Co gamma-rays at a high dose rate or low dose rate. 70 h post-irradiation cultures were arrested and micronuclei were scored in 1000 binucleate cells. The results demonstrated that the group of breast cancer patients with a known or putative genetic predisposition was on the average more radiosensitive than a population of healthy women, and this with the G2 as well as with the high dose rate and low dose rate micronucleus assay. With the G2 assay 43% of the patients were found to be radiosensitive. A higher proportion of the patients were radiosensitive with the micronucleus assay (45% with high dose rate and 61% with low dose rate). No correlation was found between the G2 and the G0-micronucleus chromosomal radiosensitivity. Out of the different subgroups considered, the group of the young breast cancer patients without family history showed the highest percentage of radiosensitive cases in the G2 (50%) as well as in the micronucleus assay (75-78%).

Adult↗

PubMed2000

Comparison of the radiosensitivity of normal-tissue cells with normal-tissue reactions after radiotherapy.

PURPOSE: To investigate whether the in vitro radiosensitivity of normal lymphocytes and fibroblasts evaluated by the micronucleus (MN) assay predicts acute and late reactions after radio-therapy in cancer patients. MATERIALS AND METHODS: Studies were performed on blood samples from 31 cervical and head and neck cancer patients and on skin fibroblasts from eight of the cancer patients. The radiosensitivity of lymphocytes and of fibroblasts was also assessed in 24 and five healthy donors, respectively. Radiosensitivity was measured after in vitro irradiation with doses ranging from 2 to 5 Gy using micronucleus frequency (the number of micronuclei per single binucleated (BN) cell) and the percentage of BN cells with micronuclei. The in vitro results were compared with the maximum grade of acute and late reactions. RESULTS: There was no significant difference in cellular radiosensitivity between cancer patients and healthy donors. Although cancer patients differed considerably in normal-cell radiosensitivity, no correlation was found between radiosensitivity, either of lymphocytes or fibroblasts, and acute and late clinically observed side effects. In addition, no relationship was observed between the radiosensitivity of lymphocytes and fibroblasts derived from the same donors. CONCLUSION: The data do not support the usefulness of the MN assay in predicting normal-tissue response to radiotherapy in cancer patients.

Adult↗

PubMed1987

Hypoxia-selective radiosensitization of mammalian cells by nitracrine, an electron-affinic DNA intercalator.

The radiosensitizing ability of the 1-nitroacridine nitracrine (NC) is of interest since it is an example of a DNA intercalating agent with an electron-affinic nitro group. NC radiosensitization was evaluated in Chinese hamster ovary cell (AA8) cultures at 4 degrees C in order to suppress the rapid metabolism and potent cytotoxicity of the drug. Under hypoxic conditions, submicromolar concentrations of NC resulted in sensitization (SER = 1.6 at 1 mumol dm-3). Sensitization was also seen under aerobic conditions but a concentration more than 10-fold higher was required. In aerobic cultures NC radiosensitization was independent of whether cells were exposed before and during, or after, irradiation. Postirradiation sensitization was not observed under hypoxic conditions. The time dependence of NC uptake and the development of radiosensitization were similar (maximal at 30 min at 4 degrees C under hypoxia) suggesting that sensitization, unlike cytotoxicity, is due to unmetabolized drug. NC is about 1700 times more potent as a radiosensitizer than misonidazole. This high potency is adequately accounted for by the electron affinity of NC (E(1) value at pH7 of -275 mV versus NHE) and by its accumulation in cells to give intracellular concentrations approximately 30 times greater than in the medium. However, concentrations of free NC appear to be low in AA8 cells, presumably because of DNA binding. If radiosensitization by NC is due to bound rather than free drug, it suggests that intercalated NC can interact very efficiently with DNA target radicals. This is despite a binding ratio in the cell estimated as less than 1 NC molecule/400 base pairs under conditions providing efficient sensitization. This work suggests a new approach in the search for more effective clinical radiosensitizers, and poses questions on the means by which intercalated drugs can interact with DNA damage.

Aminoacridines↗

PubMed1985

Radiosensitizers as probes of DNA damage and cell killing.

Cell killing and other deleterious biological effects of ionizing radiation are the result of chemical changes to critical targets, initiated at the time of exposure. Electron-affinic radiosensitizers act, primarily, by chemically modifying this radiation damage and its consequent biological expression, and such changes can be used to probe the nature of the cellular radiation target. According to a redox hypothesis of radiation modification, the molecular mechanism of electronic-affinic radiosensitization involves an oxidative interaction of the sensitizer with reactive, potentially damaging target radicals, which competes with reductive processes that restore the target to its undamaged state. The effects have been compared of a series of hypoxic cell radiosensitizers on radiation-induced DNA damage and mammalian cell killing, in order to ascertain the nature of the critical radiation target site(s) involved. Sensitizer efficacy is determined by the ability to oxidize the radiation target and is found to increase exponentially with increasing electron affinity. The threshold redox potential, below which no sensitization occurs, corresponds to the oxidation potential of the target bioradical involved, and is characteristic, and useful in identification, of the particular radiation target. Model product analysis studies of DNA base damage, inorganic phosphate release, single-strand breaks and incorporation of radioactively labelled sensitizer into DNA show a correspondence between the electronic-affinic radiosensitization of DNA damage and cell killing. A careful comparison of the radiosensitization of different DNA sites and cell killing indicates that the sugar-phosphate backbone of DNA, not the heterocyclic bases, is the DNA target site which mimics cell killing in its threshold redox potential and overall radiosensitization response. These results suggest that the enhancement by electron-affinic drugs of radiation damage to the DNA backbone (strand breaks) correlates strongly with, and is the most likely cause of, the radiosensitization of hypoxic cell killing.

Animals↗

PubMed1991

Influence of the 100% w/v perfluorooctyl bromide (PFOB) emulsion dose on tumour radiosensitivity.

The radiosensitizing effect of a 100% w/v emulsion of a fluorocarbon, PFOB, which carries 4 times more oxygen than does Fluosol-DA 20% emulsion, was studied on two human tumour xenografts (HRT18 and HT29) and the murine tumour EMT6. This effect was compared with that obtained with carbogen alone. The fluorocrit (amount of fluorocarbon in the blood) and haematocrit remained unchanged from 7 to 65 min post-injection of the emulsion (8 ml/kg). Tumour-bearing mice were pretreated with 100% w/v PFOB emulsion doses ranging from 2 to 15 ml/kg in the presence of carbogen for 30 min prior to and during irradiation. The fluorocrit increased from 1.5% to 9.5% as the dose of 100% w/v PFOB emulsion increased from 2 to 15 ml/kg. The haematocrit remained the same for all the fluorocarbon emulsion doses used. Tumour radiosensitization varied with the fluorocarbon emulsion dose. Clinically relevant doses (2-4 ml/kg) of the 100% w/v PFOB emulsion plus carbogen produced significantly more radiosensitization than carbogen alone, with sensitizing enhancement ratios of 1.4 for EMT6 and 1.7 for HRT18. The radiosensitivity of HRT18 cells was thus very close to that obtained with normally oxygenated cells. For higher doses (8-15 ml/kg) the radiosensitizing effect of 100% w/v PFOB emulsion plus carbogen becomes comparable to that of carbogen alone. These experiments show that clinically useful doses of 100% w/v PFOB plus carbogen produced tumour radiosensitization only at relatively low fluorocrits. Thus the fluorocrit, and hence the fluorocarbon's oxygen-carrying capacity, is not the only factor involved in radiosensitizing tumour cells by oxygen-carrying fluorocarbon emulsions.

Adenocarcinoma↗

PubMed1991

Structure-activity relationships for tumour radiosensitization by analogues of nicotinamide and benzamide.

Nicotinamide has been shown in our laboratory and those of other investigators to be an effective radiosensitizer of a variety of mouse tumours, while producing little or no radiosensitization of normal tissues. Its mechanism of action is different from classical electron-affinic compounds and appears to be the result of improved tumour oxygenation. In this study we have synthesized 29 analogues of nicotinamide and benzamide and characterized them for their tumour radiosensitization and acute toxicity in mice. The data show that a wide range of additions to the nicotinamide and benzamide ring produce tumour radiosensitization similar to that produced by equimolar doses of misonidazole, but that substitutions of the amide tend to reduce radiosensitization. Other structure-activity relationships are evident. Although some compounds produce similar tumour radiosensitization to nicotinamide at equimolar doses, and are comparably low in acute toxicity, none appears sufficiently superior to supplant nicotinamide itself as a candidate for clinical trials. Thus these data provide evidence that nicotinamide, because of the extensive experience with its use in man, is likely to be the best drug in the benzamide-nicotinamide series for development as a radiosensitizer of human tumours.

Animals↗

PubMed1993

Thermal radiosensitization in heat- and radiation-sensitive mutants of CHO cells.

Recently, it has been hypothesized (Iliakis and Seaner 1990) that DNA double-strand break (dsb) repair proficiency is a prerequisite for heat radiosensitization on the basis of the finding that the radiosensitive and dsb-repair-deficient mutant xrs-5 cell line shows no significant heat-induced radiosensitization (not even for severe heat doses), whereas their wildtype counterpart (CHO) did show such an effect. In the current study, the extent of hyperthermic radiosensitization in a new gamma-radiation-sensitive cell line, irs-20, recently isolated by Stackhouse and Bedford (1991) and a heat-sensitive mutant hs-36 (Harvey and Bedford 1988) was compared with the radiosensitization of their mutual parent CHO 10B12 cell line. The irs-20 and CHO 10B12 cells have comparable heat (43.5 degrees C) sensitivities, whereas hs-36 and CHO 10B12 show a similar sensitivity to gamma- and X-rays. Radiosensitization due to pre-exposure to 43.5 degrees C heating of plateau phase cultures was found for all three cell lines, even after relatively mild heat treatment killing < 20% of cells. Experiments using CHEF electrophoresis confirmed the dsb repair deficiency of the irs-20 cells (Stackhouse and Bedford 1992) and showed that heat inhibited dsb repair in all three cells lines. These data indicate that DNA repair deficiency (overall dsb repair) per se does not imply an absence of the ability for heat radiosensitization.

Animals↗

PubMed1995

Heat-induced intranuclear protein aggregation and thermal radiosensitization.

In the current study, the hypothesis that thermal radiosensitization is (indirectly) caused by heat-induced denaturation and aggregation of nuclear proteins is further investigated. Thermotolerant rodent cells showed a reduced intranuclear protein aggregation as compared with non-tolerant cells immediately after a heat treatment. This was reflected in the extent of radiosensitization when the cells were X-irradiated immediately after a heat treatment. When heat and radiation were separated in time, a faster disaggregation was found in thermotolerant cells, which was paralleled by a more rapid decline of radiosensitization. Cells transfected with hsp72 showed protection against heat-induced nuclear protein aggregation and reduced thermal radiosensitization. Transfection with hsp27 resulted in an accelerated nuclear protein disaggregation and accelerated decline of thermal radiosensitization. Despite a significant overall correlation between TER and nuclear protein aggregation, the slopes of the correlation curves for the individual cell lines deviated significantly. Yet, the experiments support the hypothesis that radiosensitization is primarily caused by inhibition of DNA repair as a result of the presence of denatured and aggregated proteins in the cell nucleus. Expression of hsps (e.g. in thermotolerant cells), by affecting nuclear protein aggregation, can have an impact on thermal radiosensitization.

Animals↗

PubMed1997

Intrinsic radiosensitivity of healthy donors and cancer patients as determined by the lymphocyte micronucleus assay.

The purpose of the study was to evaluate the usefulness of the cytokinesis-block micronucleus (MN) assay in assessment of radiosensitivity of lymphocytes in cancer patients. Lymphocytes from 15 cervical cancer patients, 21 head and neck cancer patients, seven lung cancer patients and 19 healthy donors were analysed using MN assay. The proportion of binucleate cells (BC) in cancer patients ranged from 22 to 56% and was significantly lower than in the control group (38-68%). MN frequency assessed five times over 6 months in four healthy donors showed that the interindividual variation was significantly higher than intraindividual. Before (0 Gy) and after irradiation (2 and 4 Gy) no statistical differences in the mean number of MN/BC were observed between healthy donors and cancer patient groups. Nevertheless, statistical cluster analysis allowed each group of donors to be divided into radioresistant and radiosensitive subgroups of patients. They showed significantly different dose response. Separate comparison of the mean MN frequency within all examined radioresistant and radiosensitive subgroups, showed statistically significant differences only after a dose of 4 Gy. At this dose, the lung cancer patients and cervical cancer patients from radiosensitive subgroups presented significantly higher radiosensitivity than the healthy donors. However, healthy donors from radioresistant subgroup did not differ significantly from cancer patients. This work has shown a high variation in interindividual radiosensitivity of donors and suggests the possibility of identifying radiosensitive patients on the basis of MN assay performed on lymphocytes.

Adult↗

PubMed1999

Relationships between colony forming efficiency and parameters of intrinsic radiosensitivity.

PURPOSE: In an attempt to determine whether radiosensitivity is correlated with colony forming efficiency (CFE), a large amount of data have been analysed from the literature. MATERIALS AND METHODS: The survival curves of 446 human cell lines irradiated in exponentially growing phase in vitro are included in this study. Technical factors such as culture type and the use of feeder cells were considered cofactors in addition to the genetic and histological origin of the cells. Intrinsic radiosensitivity is expressed in terms of the parameters of the linear quadratic model and the single-hit multitarget model. RESULTS: It is shown that low CFE is characteristic of cells plated in agar and cells from primary biopsies. Cells plated in the presence of feeder cells have, in general, higher CFE than cells plated without feeder cells. A positive correlation is observed between intrinsic radiosensitivity and CFE: the higher the CFE, the more resistant the cell line. This relationship is particularly obvious when radiosensitivity is expressed in terms of alpha, S2 or D, parameters which essentially characterize the initial part of the survival curve. The correlation is also found within histological or genetic groups of cell lines. However, for a given cell line, there is no relationship between CFE and radiosensitivity among different experiments. Cells irradiated in the presence of feeder cells are less subject to this behaviour. CONCLUSIONS: CFE as well as radiosensitivity are intrinsic properties of a cell line. Experimental conditions determine the quality of the correlation between radiosensitivity and CFE.

Cell Line↗

PubMed1999

Caffeine-increased radiosensitivity is not dependent on a loss of G2/M arrest or apoptosis in bladder cancer cell lines.

PURPOSE: Bladder cancer cell lines UCRU-BL-13, UCRU-BL-17/2 and UCRU-BL-28, with differing p53 status and molecular responses to irradiation, were used to investigate possible mechanisms for caffeine-induced radiosensitization. MATERIALS AND METHODS: After treatment with caffeine and exposure to X-radiation, radiosensitivity was determined by clonogenic assay. Cell-cycle arrest and apoptosis were measured by flow cytometry. RESULTS: Both BL-13 and BL-28 cells (each expressing p53 with a wild-type sequence) fail to arrest at the G2 checkpoint after radiation, but nevertheless caffeine did induce radiosensitization. In contrast, in BL-17/2 cells (expressing p53 with a point mutation in codon 280), caffeine treatment abrogated the radiation-induced G2 arrest but was not accompanied by radiosensitization. No effects on radiosensitivity were seen in RT112 cells (expressing a functionally defective p53) at low caffeine doses (2 mM), but at higher doses (4 mM and 10 mM) caffeine caused both abrogation of radiation-induced G2 arrest and radiosensitization. In none of the cell lines examined did caffeine treatment and/or irradiation result in apoptosis. CONCLUSIONS: In contrast with previous studies, the data suggest that radiosensitization induced by caffeine is not dependent on abrogation of G2 arrest or the induction of apoptosis, and is not selective for cells expressing p53 proteins with mutations.

Apoptosis↗

PubMed2005

Ku86 modulates DNA topoisomerase I-mediated radiosensitization, but not cytotoxicity, in mammalian cells.

Ku86 is an integral component of the nonhomologous end-joining (NHEJ) pathway of cellular double-strand break repair. In the current study, we investigated the role of Ku86 in DNA topoisomerase I-mediated radiosensitization induced by camptothecin in mammalian cells. Interestingly, as examined by clonogenic survival assay, a 30-minute camptothecin treatment induced significantly higher levels of radiosensitization in the Ku86-deficient Chinese hamster ovary xrs-6 cells than in the hamster Ku86-complemented xrs-6+hamKu86 cells, albeit exhibiting similar drug toxicity in these two cell lines. To confirm these findings, similar studies were conducted in two pairs of transfectant sublines established from the Ku86-deficient Chinese hamster lung fibroblast XR-V15B cells. Compared with the vector-alone sublines, radiation resistance was restored in the human Ku86-complemented sublines without alteration of cell cycle distributions. Again, significantly higher levels of camptothecin-induced radiosensitization were observed in the vector-alone sublines than in the Ku86-complemented XR-V15B sublines. In contrast, camptothecin treatments, ranging from 0.5 to 24 hours, induced similar cytotoxicities in both vector-alone and Ku86-complemented sublines. Because neither the DNA-damaging etoposide and cisplatin nor the tubulin-binder vinblastine induced enhanced levels of radiosensitization in the Ku86-deficient cells, Ku86 seems to uniquely affect topoisomerase I-mediated radiosensitization induced by camptothecin. Furthermore, cotreatment with DNA replication inhibitor aphidicolin abolished both camptothecin-induced cytotoxicity and radiosensitization in the vector-alone, as well as the Ku86-complemented subline cells, indicating both events are initiated by replication-dependent topoisomerase I-mediated DNA damages. Taken together, our data show a novel role of Ku86 in modulating topoisomerase I-mediated radiosensitization, but not cytotoxicity, in mammalian cells.

Animals↗

PubMed2004

Differential radiosensitization in DNA mismatch repair-proficient and -deficient human colon cancer xenografts with 5-iodo-2-pyrimidinone-2'-deoxyribose.

PURPOSE: 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a pyrimidinone nucleoside prodrug of 5-iododeoxyuridine (IUdR) under investigation as an orally administered radiosensitizer. We previously reported that the mismatch repair (MMR) proteins (both hMSH2 and hMLH1) impact on the extent (percentage) of IUdR-DNA incorporation and subsequent in vitro IUdR-mediated radiosensitization in human tumor cell lines. In this study, we used oral IPdR to assess in vivo radiosensitization in MMR-proficient (MMR+) and -deficient (MMR-) human colon cancer xenografts. EXPERIMENTAL DESIGN: We tested whether oral IPdR treatment (1 g/kg/d for 14 days) can result in differential IUdR incorporation in tumor cell DNA and subsequent radiosensitization after a short course (every day for 4 days) of fractionated radiation therapy, by using athymic nude mice with an isogenic pair of human colon cancer xenografts, HCT116 (MMR-, hMLH1-) and HCT116/3-6 (MMR+, hMLH1+). A tumor regrowth assay was used to assess radiosensitization. Systemic toxicity was assessed by daily body weights and by percentage of IUdR-DNA incorporation in normal bone marrow and intestine. RESULTS: After a 14-day once-daily IPdR treatment by gastric gavage, significantly higher IUdR-DNA incorporation was found in HCT116 (MMR-) tumor xenografts compared with HCT116/3-6 (MMR+) tumor xenografts. Using a tumor regrowth assay after the 14-day drug treatment and a 4-day radiation therapy course (days 11-14 of IPdR), we found substantial radiosensitization in both HCT116 and HCT116/3-6 tumor xenografts. However, the sensitizer enhancement ratio (SER) was substantially higher in HCT116 (MMR-) tumor xenografts (1.48 at 2 Gy per fraction, 1.41 at 4 Gy per fraction), compared with HCT116/3-6 (MMR+) tumor xenografts (1.21 at 2 Gy per fraction, 1.20 at 4 Gy per fraction). No substantial systemic toxicity was found in the treatment groups. CONCLUSIONS: These results suggest that IPdR-mediated radiosensitization can be an effective in vivo approach to treat "drug-resistant" MMR-deficient tumors as well as MMR-proficient tumors.

Animals↗

PubMed2006

In vitro and in vivo radiosensitization induced by the ribonucleotide reductase inhibitor Triapine (3-aminopyridine-2-carboxaldehyde-thiosemicarbazone).

PURPOSE: Because ribonucleotide reductase (RR) plays a role in DNA repair, it may serve as a molecular target for radiosensitization. Unlike previously investigated RR inhibitors, Triapine potently inhibits both RR holoenzymes. Therefore, the effects of Triapine on tumor cell radiosensitivity were investigated. EXPERIMENTAL DESIGN: The effects of Triapine on the in vitro radiosensitivity of three human tumor cell lines and one normal cell line were evaluated using a clonogenic assay. Growth delay was used to evaluate the effects of Triapine on in vivo tumor radiosensitivity. The levels of the RR subunits were determined using immunoblot analysis and DNA damage and repair were evaluated using gammaH2AX foci. RESULTS: Exposure of the tumor cell lines to Triapine before or immediately after irradiation resulted in an increase in radiosensitivity. In contrast, Triapine enhanced the radiosensitivity of the normal fibroblast cell line only when the exposure was before irradiation. There were no consistent differences between cell lines with respect to the expression of the RR subunits. Whereas Triapine had no effect on radiation-induced gammaH2AX foci at 1 hour, the number of gammaH2AX foci per cell was significantly greater in the Triapine-treated cells at 24 hours after irradiation, suggesting the presence of unrepaired DNA damage. Triapine administration to mice bearing tumor xenografts immediately after irradiation resulted in a greater than additive increase in radiation-induced tumor growth delay. CONCLUSIONS: These results indicate that Triapine can enhance tumor cell radiosensitivity in vitro and in vivo and suggest that this effect involves an inhibition of DNA repair.

Cell Cycle↗

PubMed2006

Inhibition of Akt by the alkylphospholipid perifosine does not enhance the radiosensitivity of human glioma cells.

Akt has been implicated as a molecular determinant of cellular radiosensitivity. Because it is often constitutively activated or overexpressed in malignant gliomas, it has been suggested as a target for brain tumor radiosensitization. To evaluate the role of Akt in glioma radioresponse, we have determined the effects of perifosine, a clinically relevant alkylphospholipid that inhibits Akt activation, on the radiosensitivity of three human glioma cell lines (U87, U251, and LN229). Each of the glioma cell lines expressed clearly detectable levels of phosphorylated Akt indicative of constitutive Akt activity. Exposure to a perifosine concentration that reduced survival by approximately 50% significantly reduced the level of phosphorylated Akt as well as Akt activity. Cell survival analysis using a clonogenic assay, however, revealed that this Akt-inhibiting perifosine treatment did not enhance the radiosensitivity of the glioma cell lines. This evaluation was then extended to an in vivo model using U251 xenografts. Perifosine delivered to mice bearing U251 xenografts substantially reduced tumor phosphorylated Akt levels and inhibited tumor growth rate. However, the combination of perifosine and radiation resulted in a less than additive increase in tumor growth delay. Thus, in vitro and in vivo data indicate that the perifosine-mediated decrease in Akt activity does not enhance the radiosensitivity of three genetically disparate glioma cell lines. These results suggest that, although Akt may influence the radiosensitivity of other tumor types, it does not seem to be a target for glioma cell radiosensitization.

Animals↗