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At least 1,135 records · Page 63Linked to original sources

PubMed1987

Radiosensitivity and sublethal damage repair in human umbilical cord vein endothelial cells.

The assessment of the comparative radiosensitivity of different parenchymal cells is potentially of great importance in clinical radiotherapy. Previous studies from various laboratories using vessel regeneration techniques have demonstrated that endothelial cells are quite radioresistant, having a Do in excess of 250 rads. The present studies were undertaken to investigate the radiosensitivity of human endothelial cells obtained from umbilical cord veins (HEC) using "colony formation" as an endpoint, and to evaluate their ability to repair sublethal radiation damage (SLD). The endothelial origin of the cells in the surviving colonies was demonstrated by their positive staining for factor VIII antigen. The survival curve for HEC has a Do of about 165 rads, with a moderate initial shoulder. Dose fractionation studies demonstrate a moderate capability to repair SLD, comparable to other human cells studied including fibroblasts and other normal diploid cells in vitro. These studies indicate that HEC, being a terminally differentiated cell type with various differentiated markers, may prove useful in radiobiological and radiocarcinogenesis studies.

Cell Survival↗

PubMed1987

Effect of anemia on tumor radiosensitivity under normo and hyperbaric conditions.

The effect of chronic anemia on tumor radiosensitivity in a murine tumor has been investigated. Anemia was induced by bilateral kidney irradiation given several months before tumor implantation. Anemic, anemic transfused, and normal non-anemic age-matched tumor bearing animals were irradiated with X rays (2 F/24 hr) either in air, air plus misonidazole, or under hyperbaric oxygen. The most resistant response was that of tumors grown in normal mice treated in air. Anemia produced an increase in radiosensitivity which was further enhanced by red blood cell replacement. The most sensitive overall response was seen in the anemic-transfused group treated with HBO.

Adenocarcinoma↗

PubMed1987

The effect of GSH depletion on thermal radiosensitization.

Depletion of intracellular glutathione (GSH) increased aerobic thermal radiosensitization in Chinese hamster ovary (CHO) cells gamma irradiated and heated at 42 degrees C. The GSH concentration was decreased to various stable levels by exposure to increasing concentrations of diethylmaleate (DEM). Analysis of dose-response curves indicated that GSH depletion affected thermal sensitization and thermal radiosensitization at 42 degrees when greater than 95% of the GSH had been depleted. GSH depletion also increased the fixation of radiation damage. For example, survival after 10 Gy decreased from 0.012 to 0.006 if CHO cells were incubated in 100 microM DEM at 37 degrees for 2 hrs after irradiation. The results show that GSH might be an important agent for the protection of cells against thermal enhancement of radiation damage.

Animals↗

PubMed1987

Radiosensitization of primary human tumor cell cultures by N-methylformamide.

The effects of the differentiation-inducing agent N-methylformamide (NMF) on the radiation response of ten primary human tumor cell cultures were investigated. Cell survival was determined using an adhesive tumor cell culture system. NMF (1%) was added to cultures on Day 1 and was left for 6 days; cultures were irradiated with graded doses of X rays (1.0-6.0 Gy) on Day 4. Using survival at 2.0 Gy as a comparative endpoint, eight of ten cultures tested exhibited enhanced radiosensitivity upon exposure to NMF. In sensitized cultures, the dose-enhancement factors ranged from 1.3 to 2.5. The NMF-mediated radiosensitization did not appear to be dependent on the histologic cell type. The results presented support previous data obtained from established cell lines and suggest that NMF may offer clinical benefits against a variety of tumor types when used in combination with radiotherapy.

Cell Survival↗

PubMed1988

The multi-dose clinical tolerance and pharmacokinetics of the combined radiosensitizers, Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole).

The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) have differing physico-chemical properties and clinical toxicities. The former is basic, lipophilic and produces an acute but transient central nervous system syndrome; the latter is neutral, hydrophilic and causes cumulative peripheral neuropathy. We therefore investigated the possibility of combining these agents to achieve additive radiosensitization with no enhancement of toxicity, as demonstrated in a rodent tumor model. Following a single dose study which showed a lack of interaction with respect to both toxicity and pharmacokinetics, twenty-one patients have now completed simultaneous drug administration on an escalating, multiple dose schedule. There has been no adverse acute interaction up to 0.75 g/m2 Ro 03-8799 with 2 g/m2 SR 2508 for 15 doses. At this dose-level, however, all patients experienced peripheral neuropathy. There was no adverse pharmacokinetic interaction, or perturbation of plasma pharmacokinetics between initial and final infusions. Tumor concentrations were determined in 48 biopsy samples 0-60 min after administration. Mean values normalized to a dose of 0.75 g/m2 Ro 03-8799 plus 2 g/m2 SR 2508 were 33 micrograms/g Ro 03-8799 and 74 micrograms/g SR 2508. These would be expected to produce a single-dose sensitizer enhancement ratio of around 1.5. The combination is predicted to be around 6.8 times more active than misonidazole, and superior to any single agent tested to date. The current schedules are reaching the limits of clinical tolerance, and an attempt is now being made to define the optimal regimen for use in a randomized clinical trial of the combination.

Adult↗

PubMed1988

Hypoxic cell radiosensitizers in the treatment of high grade gliomas: a new direction using combined Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole).

The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) have been evaluated for their simultaneous penetration into human brain tumors and surrounding normal tissue. Thirteen patients received a dose of 1 g of each agent, infused over a 10 minute period during neurosurgery. Samples of glioma (20), brain (10) and cerebrospinal fluid (1) were obtained at a mean time (+/- SD) of 31 +/- 18 min from the end of infusion. A 24 hr plasma time course was measured in six patients. Nitroimidazole concentrations were determined by HPLC. For a mean dose of 0.55 g/m2 of each agent, the mean tumor concentrations (+/- SD) were 17.0 +/- 12.0 micrograms/g for Ro 03-8799 and 13.5 +/- 10.9 micrograms/g for SR 2508. The tumor/plasma ratios were 279 +/- 230% and 47 +/- 34% respectively. For adjacent 'normal' brain tissue, the radiosensitizer concentrations were 29.9 +/- 13.1 micrograms/g for Ro 03-8799, and 4.0 +/- 1.7 micrograms/g for SR 2508, and the brain/plasma ratios were 430 +/- 29% and 14 +/- 8% respectively. There was a significant trend towards increasing accumulation of both agents with time, in both tumor and normal brain. Concentrations in cerebrospinal fluid were very low. Plasma pharmacokinetics for Ro 03-8799 were similar to previous experience, but for SR 2508 the terminal half-life was greater in this series by a factor of 1.3. The results confirm that Ro 03-8799 is distributed widely in the central nervous system, and demonstrate that SR 2508 can achieve high tumor concentrations when the blood-brain barrier is compromised. The concentrations achieved with the combination are indicative of a significant advantage over metronidazole, misonidazole, or either agent alone, and normalized to the therapeutic dose of 0.75 g/m2 plus 2.0 g/m2 SR 2508 are consistent with those giving additive sensitization in an in vivo mouse tumor model.

Brain Neoplasms↗

PubMed1988

Use of a colorimetric microtiter (MTT) assay in determining the radiosensitivity of cells from murine solid tumors.

We assessed the use of a colorimetric assay for determination of radiosensitivity for cells taken directly from murine solid tumors. The assay uses microtier plates and measures the ability of viable cells to reduce a tetrazolium salt (MTT) to an insoluble form, a formazan salt. We established the dependency of the assay on the cell number and time of assay for two murine tumors (EMT-6 and RIF-1). We compared the MTT assay to the standard clonogenic assay and had good agreement of surviving fraction after radiation doses of 2 and 4 Gy. It is possible, therefore, to adapt the MTT assay for use with cell suspensions prepared directly from fresh murine tumors. This may provide a methodology for the determination of the clinical radiosensitivity of tumors including fresh clinical tumor specimens.

Animals↗

PubMed1988

Radiosensitization produced by iododeoxyuridine with high linear energy transfer heavy ion beams.

Little is known about radiosensitization produced by iododeoxyuridine (IUDR) with high linear energy transfer radiation. Likewise, the effect of IUDR on repair of sublethal or potentially lethal damage is unclear. A series of in vitro experiments was performed examining these aspects of IUDR radiosensitization. Human T1 cells were grown in the presence of 3.0 micromolar IUDR for 72 hours (approximately three doubling times), an exposure which resulted in minimal cytotoxicity to unirradiated cells. As the cells entered plateau phase they were exposed to X rays and a variety of heavy ion beams. Sensitization was found to decrease as linear energy transfer (LET) increased. No sensitization took place in an extremely high LET Lanthanum ion beam (1000 keV/micrometer). However, IUDR produced significant sensitization in the Neon ion beam currently used to treat cancer patients at Lawrence Berkeley Laboratory. Sensitization enhancement ratios at the 40% cell survival level were found to be 1.8 for X rays, 1.5 for the proximal Bragg peak of the clinical Neon beam, and 1.3 for the distal peak of the clinical Neon beam. Cell survival curves fitted to the linear-quadratic model showed IUDR significantly increased the value of the linear component (alpha) in beams with LETs below 40 keV/micron. The value of the quadratic component (beta) was unaffected by IUDR, regardless of LET. Split-dose experiments with both X rays and proximal peak Neon ions revealed IUDR did not affect sublethal damage repair. Similarly, delayed-plating experiments showed IUDR did not affect repair of potentially lethal damage. In contrast to cells unexposed to IUDR, IUDR-treated cells showed near-equal levels of cell killing throughout the extended Bragg peak of the clinical Neon beam. These findings suggest that the addition of IUDR to Neon ion radiotherapy could enhance the therapeutic ratio of the clinical Neon beam.

Cell Survival↗

PubMed1989

Radiosensitization by a new nucleoside analogue: 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole (RP-170).

A new potent hypoxic cell sensitizer, a 2-nitroimidazole nucleoside analogue having methoxyglycerol as a sugar moiety at the N-1 position of the imidazole ring (RP-170), has been synthesized. Its radiosensitizing activities in vitro and in vivo were investigated and compared with those of misonidazole (MISO) and etanidazole (SR-2508). As might be expected from the almost identical electron affinities of the three compounds, they were equally effective against hypoxic EMT6 cells in vitro. The in vivo-in vitro excision analysis showed that RP-170 was also as effective as MISO and etanidazole to radiosensitize solid tumor cells in vivo. An intraperitoneal administration of 200 mg/kg of RP-170 and an intravenous administration of the same dose of etanidazole showed an equal sensitizer-enhancement ratio of 1.51 to solid EMT6/KU tumors. Its effectiveness was also demonstrated by growth delay assay using solid SCCVII tumors. As predicted from the low partition coefficient, RP-170 and etanidazole showed apparently lower toxicity in vivo than MISO; their LD50/14 were 4.3, 4.8, and 1.8 g/kg in our experiment, respectively. Moreover, RP-170 showed fast clearance from serum in mice (t1/2 = 10.24 min) and poor penetration into neural tissues. Although RP-170 does not show any advantages over etanidazole in terms of sensitization or toxicity, RP-170 might be preferable under certain circumstances because it can be given orally.

Animals↗

PubMed1989

Radiosensitivity of different human tumor cells lines grown as multicellular spheroids determined from growth curves and survival data.

Five human tumor cell lines were grown as multicellular tumor spheroids (MTS) to determine whether multicellular tumor spheroids derived from different types of tumors would show tumor-type dependent differences in response to single-dose irradiation, and whether these differences paralleled clinical behavior. Multicellular tumor spheroids of two neuroblastoma, one lung adenocarcinoma, one melanoma, and a squamous cell carcinoma of the oral tongue, were studied in terms of growth delay, calculated cell survival, and spheroid control dose50 (SCD50). Growth delay and cell survival analysis for the tumor cell lines showed sensitivities that correlated well with clinical behavior of the tumor types of origin. Similar to other studies on melanoma multicellular tumor spheroids our spheroid control dose50 results for the melanoma cell line deviated from the general pattern of sensitivity. This might be due to the location of surviving cells, which prohibits proliferation of surviving cells and hence growth of melanoma multicellular tumor spheroids. This study demonstrates that radiosensitivity of human tumor cell lines can be evaluated in terms of growth delay, calculated cell survival, and spheroid control dose50 when grown as multicellular tumor spheroids. The sensitivity established from these evaluations parallels clinical behavior, thus offering a unique tool for the in vitro analysis of human tumor radiosensitivity.

Cell Division↗

PubMed1989

Chlorophenoxy acetic acid derivatives as hemoglobin modifiers and tumor radiosensitizers.

We have studied the influence of the antilipidemia drug, clofibrate, and several structurally related analogs on the binding affinity of hemoglobin for oxygen and the radiation sensitivity of the SCCVII/St carcinoma in the mouse. Several compounds in this class reduced hemoglobin affinity in vivo; and two of these, ML1024 (etophyline clofibrate) and ML1037, were at least as effective as clofibrate at reducing hemoglobin affinity and much less toxic. When given orally at a dose of 4.1 m mole/Kg, 1/2-2 hrs before 20 Gy X rays, clofibrate gave radiosensitization in the SCCVII/St tumor equivalent to a 40-fold reduction in hypoxic fraction. ML1024 and ML1037 at a dose (3.0 m mole/Kg), which had a similar effect on hemoglobin, gave much less sensitization of the tumor. Only ML1024 produced a statistically significant effect, equivalent to a four-fold reduction in hypoxic fraction. We conclude that there are several clofibrate analogs which in relation to their toxicity are much better hemoglobin modifiers than the parent compound. They do not, however, show the same radiosensitizing effects, leading us to believe that mechanisms other than changes in hemoglobin/oxygen binding must also be involved.

Animals↗

PubMed1989

Oncogenic transforming potential of nitroimidazole radiosensitizers.

The oncogenic transforming potentials of a number of hypoxic cell radiosensitizers have been compared including misonidazole, SR-2508, Ro-03-8799, and RSU-1069, using the C3H 10T1/2 cell system. While the dual function bioreductive 2-nitroimidazole RSU-1069 is a particularly potent hypoxic cell radiosensitizer, both in vitro and in vivo, it is also more cytotoxic and has a considerably higher oncogenic transforming potential than the other nitroimidazoles tested. In combination with radiation, RSU-1069 produces a supra-additive transforming response in C3H 10T1/2 cells. For all the other sensitizers tested, the number of transformants produced by drug and radiation combined are simply additive. RB-6145, an analog of RSU-1069 with an equivalent sensitizing efficiency, is substantially less toxic and much less oncogenic than RSU-1069. At doses that produce similar in vitro enhancement ratios, RB-6145 is no more oncogenic than misonidazole and produces an additive transforming incidence in combination with radiation. RB-6145 appears to be a promising substitute for RSU-1069 for future clinical application(s) as a hypoxic cell sensitizer.

Animals↗

PubMed1989

Radiosensitizing activity of 1-alkyl-3-nitropyrrolo-(2,3-b)-pyridine derivative.

Radiosensitization characteristics of a newly synthesized N-(3,N'-morpholinpropyl)-2-[3-nitropyrrolo-(2,3-b)-pyridine -1-yl] ethanoic acid amide and the chemical basis of the action were studied. Partition coefficient, radox potentials for the one electron reduction of the compound were determined. This was confirmed by studies on the radiosensitization effect and cytotoxicity of the compound tested in vitro using Chinese hamster V79 cells. The results show that the sensitizing efficiency for this compound is C1.6 at a concentration of 0.5 mmol dm-3, which is similar to MISO. Its toxicity was not lower than that of MISO or metronidazole.

Animals↗

PubMed1989

Pre- and post-irradiation radiosensitization by SR 4233.

SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a bioreductive agent which exhibits highly selective killing of hypoxic cells in a variety of mammalian cell lines in vitro and in murine tumors in vivo. The selective toxicity of the drug results from its one-electron reduction under hypoxic conditions to form a free radical intermediate capable of damaging DNA, through the formation of strand breaks. Using the neutral filter elution assay, SR 4233 was found to be more efficient at producing DNA double strand breaks in Chinese hamster ovary (CHO) cells than an equitoxic dose of gamma-rays. Drug and radiation sequencing experiments were also performed, with both cell survival and DNA strand break rejoining used as endpoints. As a result of these studies, we now describe two additional properties of SR 4233: (a) radiosensitization of aerobic cells in culture produced by hypoxic incubation with drug either before or after irradiation, and (b) the inhibition of subsequent rejoining of radiation-induced DNA double strand breaks after hypoxic pretreatment with drug. The magnitude of the radiosensitization produced did not vary for drug treatments which, when given alone, reduced cell survival over a range from 30% to 2%. The extent of DNA repair inhibition increased with increasing severity of the SR 4233 pretreatment, but was quite small for non-lethal drug exposures.

Animals↗

PubMed1989

KIH-802: 2-nitroimidazole-1-acetohydroxamate as a hypoxic cell radiosensitizer.

We have identified potassium 2-nitroimidazole-1-acetohydroxamate (KIH-802) as a hypoxic cell radiosensitizer potentially superior to Miso. The water-soluble acetohydroxamates of 2-nitroimidazole (KIH-802; free acid 801) and 4-nitroimidazole (KIH-852) were designed, synthesized, and evaluated by in vitro and in vivo screening against EMT6 cells. Enhancement ratios of KIH-802 and 801 were 1.92 and 1.68, respectively, compared with 1.58 for MISO all at 1 mM. These acetohydroxamates are also expected to be more effective in vitro than SR-2508 based on our previous experiments. In vivo ERs of KIH-802, 801, and 852 were 1.75, 1.50, and 1.35, respectively, compared with 1.57 for MISO all at the same dose of 200 mg/kg. The data clearly show that the addition of an acetohydroxamic acid moiety to the 2-nitroimidazole skeleton can enhance radiosensitizing ability.

Animals↗

PubMed1989

NLP-1: a DNA intercalating hypoxic cell radiosensitizer and cytotoxin.

The 2-nitroimidazole linked phenanthridine, NLP-1 (5-[3-(2-nitro-1-imidazoyl)-propyl]-phenanthridinium bromide), was synthesized with the rationale of targeting the nitroimidazole to DNA via the phenanthridine ring. The drug is soluble in aqueous solution (greater than 25 mM) and stable at room temperature. It binds to DNA with a binding constant 1/30 that of ethidium bromide. At a concentration of 0.5 mM, NLP-1 is 8 times more toxic to hypoxic than aerobic cells at 37 degrees C. This concentration is 40 times less than the concentration of misonidazole, a non-intercalating 2-nitroimidazole, required for the same degree of hypoxic cell toxicity. The toxicity of NLP-1 is reduced at least 10-fold at 0 degrees C. Its ability to radiosensitize hypoxic cells is similar to misonidazole at 0 degrees C. Thus the putative targeting of the 2-nitroimidazole, NLP-1, to DNA, via its phenanthridine group, enhances its hypoxic toxicity, but not its radiosensitizing ability under the present test conditions. NLP-1 represents a lead compound for intercalating 2-nitroimidazoles with selective toxicity for hypoxic cells.

Animals↗

PubMed1989

Characteristics of fluorinated nitroazoles as hypoxic cell radiosensitizers.

Types of 2-nitroimidazoles and 3-nitro-1,2,4-triazoles bearing one or two fluorine atoms on their side chains were synthesized to evaluate their physicochemical properties, radiosensitizing effects, and toxicity. The reduction potential of the compounds containing one fluorine was similar to that of misonidazole (MISO), whereas that of the difluorinated compounds was slightly higher. Both mono- and difluorinated compounds had an in vitro sensitizing activity comparable to or slightly higher than that of MISO. The fluorinated 3-nitrotriazoles were almost as efficient as the 2-nitroimidazoles with the same substituent. In vivo, some of the compounds were up to twice more efficient than MISO, whereas others were as efficient as MISO. Toxicity in terms of LD50/7 in mice was quite variable depending on the side-chain structure; the amide derivatives were less toxic than MISO, whereas the alcohol and ether derivatives were more toxic. In view of the radiosensitizing effect and toxicity in vivo, at least one compound, KU-2285 (a 2-nitroimidazole with an N1-substituent of: CH2CF2CONHCH2CH2OH) has been found to be as useful a hypoxic cell sensitizer as SR-2508.

Animals↗

PubMed1989

High efficiency of ferricenium salts as radiosensitizers of V79 cells in vitro and the KHT tumor in vivo.

Ferricenium salts (Fc+X-) can act as radiosensitizers of hypoxic cells in vitro and of KHT tumor cells in vivo. Sensitization is manifest by a removal of the shoulder of the hypoxic radiation survival curve in vitro. This results in a dose modification factor (DMF) of 2.0 when measured at a surviving fraction of 0.1, for 10 mumol dm-3 FcPF6. In comparison, little sensitization is seen in air. The toxicity of these metal complexes, but not their radiosensitizing ability, can be decreased by including protein (Bovine serum albumin) in the medium. This may be related to the fact that the ferricenium complexes react readily with nucleophiles to generate OH radicals. Ferricenium trichloracetate, when given at a dose of 200 mg/kg to mice with the KHT tumor gives an enhancement ratio of 1.3.

Animals↗