SEARCH · PubMed Health

Results for “Radiosensitivity”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,117 records · Page 62Linked to original sources

PubMed1989

In vitro chemosensitivity of four new carcinoma of the cervix cell lines: relationship to radiosensitivity.

Using a clonogenic cell survival assay, the chemosensitivity of four recently established cervix carcinoma cell lines to four drugs used in the treatment of this disease (bleomycin, cisplatin, etoposide and methotrexate) has been determined. Exposure was for 1 h except for methotrexate where 24 h was used. Results showed that, on a molar basis, bleomycin was most cytotoxic against each cell line (doses to produce 10% cell survival from 10 to 40 mciroM). However, if the clinical area under the curve (AUC) values are taken into consideration, the cell lines appeared to be relatively resistant to cisplatin (surviving fraction range of 0.9-0.6) and methotrexate but sensitive to bleomycin and etoposide (surviving fraction range of 0.18-0.012). Among this small group of lines, there was some evidence to suggest a positive correlation between chemo- and radiosensitivity; the HX/151c line was significantly more radiosensitive than the other three lines (P = 0.03) and clearly more chemosensitive, particularly against bleomycin (correlation coefficient of 0.81) and etoposide (correlation coefficient of 0.80).

Antineoplastic Agents↗

PubMed1984

Daily variation in radiosensitivity of circulating blood cells and bone marrow cellularity of mice.

Random bred, nocturnal, male Mus musculus (DUB-ICR), on a 12/12 light/dark cycle with lights on at 6 a.m., were exposed to 100 R or 200 R of X-radiation at either noon or midnight to study diurnal radiosensitivity in circulating blood cells and bone marrow cellularity. Hematocrits, reticulocyte and white blood cell counts, daily white blood cell rhythm, and bone marrow cellularity indicate that these mice are more radiosensitive at night. At low doses it is possible that diurnal rhythms in natural, biological radioprotectors such as corticosterone may have more influence on radiation sensitivity than mitotic activity.

Animals↗

PubMed1988

Radiosensitizing effect of camphor on transplantable mammary adenocarcinoma in mice.

The comparative radiosensitizing effects of camphor and metronidazole on murine transplantable mammary adenocarcinoma are reported. Male C3H/Jax mice bearing transplanted mammary tumours were treated with camphor (0.5 microM/body wt) or metronidazole (0.5 microM/g body wt) 45 min before subjecting to local X-irradiation at the dose levels of 30, 80, 100 or 120 Gy. Sequential in situ measurement of the tumour volumes during the follow-up period of 45 days revealed that the maximum enhancement ratios of tumour growth delay for camphor and metronidazole were 4.8 and 2.5, respectively. This suggests that camphor can be a potential radiosensitizing agent in cancer radiotherapy.

Adenocarcinoma↗

PubMed1990

pSV3neo transfection and radiosensitivity of human cancer cell lines.

Immortalisation of human fibroblasts by transfection with a plasmid, pSV3neo, results in an increase in their radioresistance. The change in radiosensitivity may either be a consequence of transformation or due to expression of the SV40 T-antigen in pSV3neo. To investigate these two possibilities, we transfected pSV3neo into cells already transformed and immortalised. The radiosensitivities of three human bladder cancer cell lines were unaltered in clones expressing T-antigen, indicating that the changes observed in fibroblasts probably are a consequence of transformation, and not the presence of SV40 T-antigen.

Antigens, Viral, Tumor↗

PubMed1995

Adaptation and cross-resistance: an explanation for the existence of different radiosensitivities among malignant melanoma cells.

A hypothesis is presented to explain the apparent difference in the radioresponsiveness of melanoma lesions whether they are located on the skin or in other parts of the body. The hypothesis states that the radiosensitivity of a cell may change when the cell adapts to live and grow in a different environment. The most important environmental factor that affects the radiosensitivity of cutaneous melanoma cells appears to be the partial pressure of oxygen in their immediate environment. By virtue of adapting to grow in an environment having a high partial pressure of oxygen, the melanoma cells located on the skin may have developed a better antioxidant defense mechanism than cells that metastasize to, and grow in, other parts of the body having lower partial pressures of oxygen such as lymph nodes, brain and viscera. Because some of the cell-damaging effects of both oxygen and ionizing radiation are mediated through a similar mechanism, the melanoma cells on the skin become cross-resistant to ionizing radiation because of their higher tolerance to oxygen toxicity.

Adaptation, Physiological↗

PubMed1982

A comparison of the cytological effects of three hypoxic cell radiosensitizers.

Misonidazole has entered Phase III clinical trials as a hypoxic cell radiosensitizer. Neurotoxocity is the major dose-limiting factor and has prompted the development of two further compounds with reduced lipophilicity and shorter half-life in vivo. Aside from the short-term problem of neurotoxocity, other potential long-term consequences should be considered. Such is the purpose of this investigation where the cytological effects of three radiosensitizers upon oxic and hypoxic Chinese hamster V-79 cells have been examined. Two newer compounds, desmethylmisonidazole and Stanford Research compound 2508, were compared with their clinically used predecessor, misonidazole. Under aerated conditions, cell killing was increased with SR-2508 in a concentration and time dependent manner, so as to exceed by more than three times the level produced by the other two drugs at 5 mM for 72 hours. Cell progression into mitosis was also markedly reduced by as much as 1/10,000 of control values. However, as the three compounds induced similar frequencies of sister chromatid exchange (SCE) and chromosome aberration, the enhanced cytotoxic effect of SR-2508 appears to be mediated via an interphase rather than a post-mitotic cell death. Cells were made hypoxic and treated with the three drugs for 4 hr, then mitoses sequentially collected for 16 hr. The three compounds produced similar levels of cell killing, slowing of cell cycle progression, SCE's and chromosome aberrations, with cycle-specific effect on S and G-1 phase cells for SCE induction. These results indicate that desmethylmisonidazole and misonidazole have similar cytotoxic and clastogenic properties under oxic and hypoxic conditions. SR-2508 is relatively more toxic to aerated cells and may deserve close clinical observation for toxicity to normal tissues; further, all three agents may enhance DNA damage and mutagenesis in tissues that are normally hypoxic.

Animals↗

PubMedDate not supplied

The development of an oral prodrug, SR-2545, of the 2-nitroimidazole radiosensitizer SR-2508.

SR-2508, a 2-nitroimidazole radiosensitizer, is expected to be clinically superior to desmethylmisonidazole or misonidazole because of its lower lipophilicity with subsequent lower drug levels in neural tissue and more rapid plasma elimination. The intravenous route of administration will be optimal but oral drugs may be necessary. Since decreased lipophilicity will decrease oral absorption we have synthesized, and tested in mice, SR-2545, an acetate ester prodrug of SR-2508. In the liver there is complete first pass metabolism to parent drug with no prodrug detectable in the blood. Compared to an equal dose of oral SR-2508, the prodrug yields a more rapid, reproducible, plasma peak with twice the bioavailability, peak plasma concentration and radiosensitization. If oral preparations of SR-2508 are to be used in the clinic the prodrug, SR-2545, is likely to be superior to oral SR-2508.

Administration, Oral↗

PubMedDate not supplied

The pharmacokinetics in mice and dogs of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole.

We have examined the pharmacokinetic properties of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole (MISO). In dogs, 2 analogues showed comparable peak plasma concentrations with considerably shorter half-lives (t1/2) and reduced areas under curves (AUC). Benznidazole (Ro 07-1051) had a much longer t1/2, a higher AUC, and somewhat higher peak concentrations. In mice tumor/plasma, brain/plasma, and tumor/brain ratios were generally similar to MISO, as was penetration of brain and peripheral nerve by benznidazole in dogs. Selection of lipophilic analogues with appropriate pharmacokinetic properties may facilitate accommodation of the potentially different requirements for improved radiosensitization or chemosensitization.

Animals↗

PubMedDate not supplied

Radiosensitization of the RIF-1 murine flank tumor by desmethylmisonidazole (Ro 05 9963) during interstitial brachytherapy.

We have investigated the interaction of the nitroimidazole radiosensitizer desmethylmisonidazole (Ro 05 9963) with interstitial radiation using a clonogenic cell assay as the endpoint. Removable I-125 sources were implanted at right angles to the outer surface of globular RIF-1 tumors grown in the flanks of C3H/He mice. Desmethylmisonidazole was administered by continuous intraperitoneal infusion at a rate of 2.7 mg/gm body weight /24 hr. Tumor and serum drug levels were measured by high performance liquid chromatography. Tumor drug levels of 40--100 mugm/gm tumor tissue were achieved consistently. No appreciable cytotoxicity was produced by desmethylmisonidazole alone, but a radiosensitization effect with a dose modifying factor of 1.6 was found.

Animals↗

PubMed1984

High dose rate radiosensitization: a clinical pilot study of 27 cancer patients.

In laboratory experiments, it was reported by some authors that radiation response increases with the dose rate, although other workers have reported that this relationship does not exist. Up to the present, this problem has remained controversial. The present clinical pilot study was designed with the aim of comparing the effect of high and low dose rates. The study was carried out on 27 patients who suffered from various types of malignancy. Twelve patients with advanced but relatively comparable bilateral metastases in the neck region, and 15 patients with multiple pulmonary metastatic foci were studied. Radiation was given at a high dose rate (1112 rad/min) when irradiating one side of the neck or one of the metastatic lesions in the lung, while radiation was given at a low dose rate (400 rad/min) on the opposite side of the neck or a separate lesion in the lung. All other aspects of radiation, however, were identical for all lesions. The total dose varied from 4000-7000 rad/4-7 wk. Five fractions per week and a daily dose of 200-300 rad was given. It was observed that the high dose rate gave rise to a higher radiosensitivity than the low dose rate. Tumor regression rates were calculated by measuring the dimensions of the lesions. The tumor regression rate in the high dose rate group was universally higher than that in the low dose rate group. The radiation response in the high dose rate group was about 5.2-37.6%, averaging 18%, higher than that in the low dose rate group. In conclusion, a high dose rate of radiation elicits a higher radiosensitivity, and hence, a possible higher cancericidal effect.

Adolescent↗

PubMed1984

Preliminary report on AT1727 as a potential radiosensitizer.

AT1727 is a derivative of ICRF 154. The purpose of this study was to evaluate its "radiosensitizer" properties. From October 1979 until the end of December 1980, 89 patients with radiation resistant cancers such as soft tissue sarcoma, squamous lung cancer (with large lesion, 6-8 cm diameter) and other cancers had been included in trial. Radiation therapy was carried out using CO60 or 8 Mev Linac. Fifty-five patients had a remarkable objective remission rate of 61.8% (55/89). Eighteen of 30 patients with soft tissue sarcomas obtained obvious remission (60%), and 26 of 38 patients with lung cancer had remission (68.4%). Patients with esophageal cancer (5/6) and nasopharyngeal cancer (5/5) also had good remission rates. The side-effects of this treatment were very mild: anorexia and vomiting were noted in 50% and no significant changes were noted in liver and kidney function tests and blood platelet count. Leucopenia was slight in all but one patient. No difference in the lung fibrosis rate was noted between the two randomized groups. From the results of this study we concluded that AT1727 had some effect as a "radiosensitizer" but much more work is needed to confirm this.

Clinical Trials as Topic↗

PubMed1984

Marked radiosensitization of cells in culture to X ray by 5-chlorodeoxycytidine coadministered with tetrahydrouridine, and inhibitors of pyrimidine biosynthesis.

Our approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine), which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC) with tetrahydrouridine (H4U). We propose that CldC, coadministered with H4U, is metabolized in the following manner: CldC----CldCMP----CldUMP---- ----CldUTP----DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In X irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses, we have obtained 3.0 to 3.8 apparent dose enhancement ratios (these represent upper limits) when cells are preincubated with inhibitors of pyrimidine biosynthesis: N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorodeoxyuridine (FdU) or 5-fluorodeoxycytidine (FdC) + H4U. Optimum conditions for radiosensitization are: PALA (0.1 mg/ml) 18-20 hr prior to FdU (0.1 microM) or FdC (0.02 microM) + H4U (0.1 mM) followed 6 hr later by CldC (0.1-0.2 mM) + H4U (0.1 mM) for 56-68 hr. Viabilities of 10 +/- 4% to 15 +/- 1% (+/- S.E.) were obtained for drug-treated unirradiated cells. Enzymatic studies indicate that this toxicity may be tumor selective. CldC + H4U alone (at these concentrations) results in 20% substitution of CldU for thymidine in DNA (determined by HPLC analysis). Preliminary toxicity studies indicate that mice will tolerate treatment protocols involving a single dose of PALA (200 mg/kg) followed by a dose of FdU (50 mg/kg) and 3 cycles of CldC (500 mg/kg) + H4U (100 mg/kg) at 10 hour intervals, with marginal weight loss (4%). In this approach we seek to obtain preferential conversion of CldC to CldUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.

Animals↗

PubMed1985

Intra-arterial infusion of radiosensitizer (BUdR) combined with hypofractionated irradiation and chemotherapy for primary treatment of osteogenic sarcoma.

Combined modality treatment was given in nine patients of osteogenic sarcoma wherein the tumor was unresectable because of location or amputation was refused. This alternative to massive surgery comprised hypofractionated irradiation, intra-arterial infusion of the radiosensitizer 5'-bromodeoxyuridine (BUdR) and adjuvant systemic chemotherapy. Local control was achieved in seven of the nine patients. Four survived, all without evidence of disease at 6, 7.1, 8.8, and 10.5 years after completion of irradiation. Pulmonary metastases developed in six patients--of whom one survives, following high-dose pulmonary irradiation and additional chemotherapy. Significant soft-tissue injury occurred in five patients. On the basis of our experience, we believe that new approaches using modifications of external beam irradiation with different fractionation schedules or better radiosensitizing compounds may hold promise for patients with non-resectable osteosarcoma.

Adolescent↗

PubMed1986

Radiosensitization in vitro and in vivo by 3-nitrotriazoles.

A series of 3-nitro-1,2,4-triazole derivatives bearing various types of side chain (R) at the N1-position (AK-2000 series) were synthesized and their radiosensitizing effect and toxicity in vitro and in vivo were investigated, in comparison with those of Misonidazole (MISO), SR-2508, and RSU-1069. Of the fifteen 3-nitrotriazoles tested, all had sensitizing effects in vitro on hypoxic V79 cells. Also, all but one had definite effects on solid EMT6/KU and SCCVII tumors in vivo. For many of the triazole compounds, the degree of radiosensitization in vitro and in vivo appeared identical. However, they were generally less efficient, both in vitro and in vivo, than the corresponding 2-nitroimidazoles, whereas their aerobic cytotoxicity and toxicity to mice (LD50/7) were comparable to those of the 2-nitroimidazoles. Considering the sensitizing effect and toxicity, AK-2123 (R = CH2CONHC2H4OCH3) may be as useful as MISO, but none of the triazoles have been proved to be superior to SR-2508.

Animals↗

PubMed1986

Analogues of RSU-1069: radiosensitization and toxicity in vitro and in vivo.

A series of nitroimidazoles containing aziridine and alkyl-substituted aziridine functions has been synthesized. The 2-nitroimidazole compounds examined all show greater radiosensitizing efficiency in vitro than misonidazole. The 4- and 5-nitroimidazole analogues are also more efficient than equivalent compounds which do not contain the alkylating aziridine moiety. All the compounds show increased toxicity towards hypoxic cells relative to aerobic cells, but this toxicity is reduced by alkyl-substitution of the aziridine ring. In vivo toxicity can also be reduced by modification of the aziridine function, but such alterations appear to have less effect upon the high radiosensitizing efficiency of these compounds in vivo. As a consequence of this study, compounds of potentially improved therapeutic utility compared to RSU-1069, the first reported member of this class, have been identified.

Animals↗

PubMed1986

Studies on the mechanisms of the radiosensitizing and cytotoxic properties of RSU-1069 and its analogues.

RSU 1069 is a substantially more efficient sensitizer than misonidazole when hypoxic Chinese hamster V79 cells are irradiated in vitro at room temperature; such that for 0.5 mmol dm-3 sensitizer an ER of 3.0 is obtained for RSU 1069 whereas an ER of only 1.6 is obtained for misonidazole. However, when irradiation is done at 4 degrees C, the radiosensitization caused by RSU 1069 is reduced to a level close to that obtained with misonidazole, the action remaining unaltered at the lower temperature. This temperature dependent component of sensitization for RSU 1069 suggests the involvement of a slow biochemical process that has an appreciable activation energy. The RSU 1069 analogue RB 7040 is a more efficient radiosensitizer than RSU 1069 particularly at lower concentrations. This compound has a pKa value of 8.45, in contrast to that of RSU 1069 which is 6.04. Weak bases with pKa values in excess of average intra-cellular pH can be taken up preferentially into cells from medium at pH 7.4. It is shown that RB 7040 has a 4 X higher intracellular concentration than RSU 1069 for a similar extracellular concentration. This will explain, at least in part, the greater sensitizing efficiency of this compound when compared to RSU 1069 in vitro.

Animals↗

PubMed1986

A phase I study of the combination of two hypoxic cell radiosensitizers, Ro 03-8799 and SR-2508: toxicity and pharmacokinetics.

The hypoxic cell radiosensitizer Ro 03-8799 produces acute central nervous system toxicity which limits repeated doses of the drug to 0.75 g/m2, but peripheral neuropathy does not occur. SR-2508 causes no acute effects at doses greater than 3.0 g/m2, but causes peripheral neuropathy at cumulative doses of 30 g/m2. By combining maximum tolerated doses of each agent, it may be possible to increase efficacy, but not toxicity. Escalating single doses of Ro 03-8799 and SR-2508 were administered to 10 patients. The drugs were infused together in 50 ml of 0.9% saline over 10 min, beginning at 0.5 g/m2 of each agent, and proceeding to a fixed dose of 0.75 g/m2 Ro 03-8799 with 0.5, 1.0, 2.0, and 3.0 g/m2 SR-2508. Four patients experienced the expected acute syndrome related to Ro 03-8799, but the incidence was not increased by escalating doses of SR-2508, and no peripheral neuropathy was seen. Plasma and urine pharmacokinetic studies showed that no drug interaction occurred. Six patients have been given a 9-dose regime over a 3 week period, using 0.75 g/m2 Ro 03-8799 and escalating doses of 0.5, 1.0, and 1.5 g/m2 SR-2508. All exhibited the expected acute side effects related to Ro 03-8799, but with no increase at the higher doses of SR-2508. No other toxicity was seen. Plasma pharmacokinetics performed at the beginning and end of the schedule were similar. Biopsies were taken from six superficial tumors following combined radiosensitizer administration. Mean tumor concentrations over the 30 min following the end of infusion were 30 and 72 micrograms/g for Ro 03-8799 and SR-2508, respectively. These values would be expected to translate into an approximate single dose sensitizer enhancement ratio of 1.5 to 1.6, offering a significant gain over the enhancement possible with the drugs given alone. The overall advantage will be determined by the maximum dose levels and number of doses possible; the escalation of both parameters is now in progress.

Adolescent↗

PubMed1986

Combined radiation-protective and radiation-sensitizing agents. III: Radiosensitization by misonidazole as a function of concentrations of endogenous glutathione or exogenous thiols.

Radiosensitization of V79 Chinese hamster fibroblasts by 0.5 mM misonidazole is a smooth function of endogenous glutathione (GSH) levels as modulated upwards by pre-incubation in medium containing cysteamine, or downwards by pre-incubation in medium containing buthionine sulfoximine. The enhancement ratio (radiation sensitivity in nitrogen/radiation sensitivity in nitrogen +/- sensitizer or thiol) varies from 1.3 at 12 mM to 2.25 at less than 0.1 mM endogenous GSH. The enhanced radiosensitivity of thiol-depleted hypoxic cells is reversed when exogenous thiols are added, and for equivalent ER, the exogenous thiol concentrations are much lower than the endogenous GSH concentrations. Measurement of intracellular drug concentrations amplified rather than diminished the above discrepancy, since intracellular concentrations of cysteamine were lower and glutathione much lower than the extracellular concentrations. Three possible explanations are addressed: an external membrane component of damage is involved, long-range protection to DNA target radicals is possible from outside the cell (e.g., donation of electrons), and (c) endogenous glutathione is not in a free or exchangeable state (e.g., bound).

Animals↗