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C Grau

Publications and source records attributed to C Grau.

At least 73 records · Page 4Linked to original sources
PubMed1992

Improving the radiation response in a C3H mouse mammary carcinoma by normobaric oxygen or carbogen breathing.

The limited therapeutic benefit from nitroimidazoles has renewed the interest in normobaric oxygen as a hypoxic cell radiosensitizer. In this experimental study we have tried to modify the oxygenation of a C3H mammary carcinoma by flushing tumor-bearing mice with oxygen or carbogen for 5 min before and during treatment. The response to these treatments was evaluated by the changes in radiation-induced tumor control (TCD50) and by the changes in tumor hypoxic fraction (HF). Irradiation was given either as a large, single dose or as five equal, daily fractions. High levels of oxygen in the inspired air were found to decrease the TCD50 significantly. The enhancement ratios were in the range of 1.2-1.4 (p less than 0.05) for both single dose and fractionated irradiation, which suggests that hypoxic cells may be important even when reoxygenation is believed to be complete between fractions. The change in TCD50 corresponded to a decrease in the fraction of clonogenic hypoxic cells from 12% to 3-4% (p less than 0.05). Tumor blood flow was not significantly influenced by the gas treatment. This study thus shows that normobaric oxygen/carbogen inhalation may significantly improve the local tumor control by reducing the diffusion related hypoxia within tumors.

Administration, Inhalation↗
PubMed1992

Influence of carboxyhemoglobin level on tumor growth, blood flow, and radiation response in an experimental model.

Carboxyhemoglobin (HbCO) is formed when carbon monoxide is bound to hemoglobin. High levels of HbCO are known to reduce the amount of oxygen that can be carried to the tissues. This experimental study focuses on the influence of HbCO on the growth, blood flow, and radiation response of an experimental mouse tumor. The study was designed to mimic the clinical situation where heavy smokers are undergoing radiotherapy while having a high HbCO level. The tumor was a C3H mammary carcinoma grown in the feet of CDF1 mice. Chronic exposure to carbon monoxide, resulting in 10% HbCO, increased the tumor volume doubling time from 2.5 to 3.5 days (p less than 0.05). The acute exposure to carbon monoxide prior to and during irradiation significantly raised the radiation dose required to control the tumor locally. The TCD50 increased from 54 Gy in air breathing mice (HbCO 0-2%) to 57 Gy (HbCO 7-9%) and 61 Gy (HbCO 20-23%). This increase corresponded to an increase in the fraction of clonogenic hypoxic tumor cells from 0.12 in air breathing animals to 0.21 and 0.41, respectively. The tumor blood flow, determined by the 86RbCl extraction technique, decreased to 63% (n.s.) and 50% (p less than 0.05) for low and high HbCO levels, respectively.

Animals↗
PubMed1992

Interaction of misonidazole, hyperthermia, and irradiation in a C3H mammary carcinoma and its surrounding skin in vivo.

The interaction of irradiation, Misonidazole (MISO), and hyperthermia was studied in a C3H mouse mammary carcinoma and its surrounding skin in vivo. MISO (0.5-1.0 mg/g) was injected 30 min before irradiation. Hyperthermia (41.5 degrees-43.5 degrees C for 60 min) was given either simultaneously, 0.5 hr, or 4 hr after X rays. The results were evaluated as the radiation dose to achieve tumor control (TCD50) or moist desquamation of the skin (DD50) in half of the treated animals. A therapeutic gain was found when the enhancement in tumors were greater than that found in skin. The combination of simultaneous heat and irradiation caused great enhancement in radiation response, but with no therapeutic gain. A slightly lower enhancement of the damage in both tissues was found with a 30 min interval between irradiation and hyperthermia, whereas heat 4 hr after X rays gave a small, but significant therapeutic gain. MISO significantly enhanced the response in tumors but not in skin. Combined trimodality treatment with MISO, irradiation, and hyperthermia resulted in enhancement ratios up to 15, dependent on temperature, radiation-heat interval, and to a lesser extent the MISO dose. The enhancement was for all schedules most pronounced in the tumors, resulting in an improved therapeutic effect. The combination of MISO and hyperthermia may be a valuable addition to radiotherapy, especially if heat and irradiation can be applied with close interval and with one of the modalities given selectively to the tumor.

Animals↗
PubMed1992

Effects of age on event-related potentials in chronic alcoholics: a multimodal study.

To test different versions of the premature aging hypothesis in alcoholics, brainstem auditory evoked potentials (BAEPs), long-latency auditory evoked potentials (LAEPs), P3 and visual evoked potentials (VEPs) were recorded in 32 alcoholic subjects. The phenomena in patients' event-related potentials (ERPs) differ from those observed in normal aging subjects and become more pronounced with age. ANOVA showed a significant effect by group (alcoholic patients/controls) on certain parameters of BAEPs (III, III-V, I-V), VEPs (P100 latency) and LAEPs (N1-P2 amplitude and N2 latency) unaffected by age, while age had a significant effect on some parameters of LAEPs (N2-P3 amplitude, P3 latency) unaffected, or less affected by chronic alcohol consumption. At a clinical level, abnormalities in BAEPs and VEPs seem good early trouble indices in alcoholic patients, while alterations in latencies and amplitudes of LAEPs appear in older patients. These data seem to be in favor of a critical age or critical abuse in the action of alcohol, in place of the classical hypothesis of premature aging.

Adult↗
PubMed1991

Interaction of hyperthermia and cis-diamminedichloroplatinum(II) alone or combined with radiation in a C3H mammary carcinoma in vivo.

The interaction between hyperthermia and cis-diamminedichloroplatinum(II) (c-DDP) given in various schedules as an adjuvant to radiation treatment was investigated in a C3H mouse mammary carcinoma in vivo. Both hyperthermia (43.5 degrees C for 60 min) and c-DDP (6 mg/kg i.p.) caused a delay in tumor growth when given individually. When c-DDP was given 4 h prior to hyperthermia, the increase in tumor growth time corresponded to an additive effect, but when the interval was reduced to 15 min, the tumor growth delay was significantly greater than additive. The modifying effect of these schedules on radiation was studied using local tumor control (50% tumor control dose) as the endpoint. c-DDP alone did not result in any enhancement of tumor control, irrespective of whether it was given 15 min or 4 h after irradiation. In contrast, heat treatment at 43.5 degrees C for 60 min given 4 h after irradiation resulted in a significant reduction in the 50% tumor control dose, with an enhancement ratio of 1.8. From a clamped local tumor control assay, it was found that c-DDP selectively killed aerobic cells, whereas hyperthermia was primarily directed toward the hypoxic clonogenic cells in the tumors. Combining the two modalities (simultaneously) resulted in a significant additional increase in the killing of well-oxygenated clonogenic cells, but the destruction of hypoxic cells was not different from that obtained after heat alone.

Animals↗
PubMed1991

The potential of using hyperthermia to eliminate radioresistant hypoxic cells.

It is known that cells in a nutritionally deprived and acidic environment are sensitive to heat. In general these same cells are chronically hypoxic and therefore heat possesses the potential to eliminate (some) of this radioresistant population. A direct radiosensitization is observed when heat is given simultaneously with radiation. This effect occurs to the same extent in both aerobic and hypoxic cells, thus the oxygen enhancement ratio is unchanged. By giving heat several hours after radiation the direct radiosensitization is avoided and the specific heat killing of the acidic, chronically hypoxic, tumor cells may be utilized to improve the therapeutic gain. The current investigation clearly demonstrates this concept in a C3H mammary carcinoma using a local tumor control assay. This effect could be further enhanced by adding hypoxic radiosensitizers (nimorazole, misonidazole) or a blood flow modifier (nicotinamide) which can eliminate acutely hypoxic cells.

Animals↗
PubMed1991

Radiosensitizing and cytotoxic properties of mitomycin C in a C3H mouse mammary carcinoma in vivo.

The radiosensitizing and cytotoxic properties of Mitomycin C (MMC) was investigated in vivo using regrowth delay and tumor control assays. MMC significantly enhanced the radiation-induced growth delay when administered 15 min before irradiation; the slope of the dose response curve significantly increased and corresponded to a Dose Modifying Factor (DMF) of 1.9 (1.5-2.3; p less than 0.001). When MMC was given 4 hr after irradiation, the additional regrowth delay resulted in a parallel shift of the dose response curve, and MMC was not significantly dose modifying (DMF 1.3 (0.9-1.3); p less than 0.05). From isobologram analysis it was found that the preirradiation MMC schedule resulted in supra-additive responses, whereas MMC given after irradiation had an additive effect. The enhancement of radiation-induced tumor control was similarly found to peak when MMC was given 6 hr to 15 min prior to irradiation. At these intervals, the observed TCD50 for the combined treatments relative to radiation alone corresponded to Enhancement Ratios of 1.27 and 1.29, respectively (p less than 0.001). Longer intervals between the modalities reduced the enhancement, but the combined treatments were still significantly better than radiation alone (ER 1.12, 1.16 and 1.17; p less than 0.001). The significant enhancement of tumor control correlated with a substantial drug-induced cytotoxic effect toward hypoxic tumor cells, as determined by clamped TCD50 experiments. A single dose of MMC (3 mg/kg) was found to kill up to 97% of all hypoxic tumor cells.

Animals↗
PubMed1991

Sensori-neural hearing loss in patients treated with irradiation for nasopharyngeal carcinoma.

The present investigation has been carried out to evaluate the sensitivity of the inner ear to irradiation. Cochlear function was tested in a cohort of 22 patients before and 7-84 months after receiving external irradiation for nasopharyngeal carcinoma. The pre-irradiation sensori-neural hearing threshold at 500, 1000, 2000, and 4000 Hz was used as a baseline for the individual patient, and the observed sensori-neural hearing loss (SNHL) was calculated as the difference between pre- and post-irradiation values. The pre-irradiation hearing level or patient age was not correlated with the actual SNHL. In contrast, there was a significant correlation between the total radiation dose to the inner ear and the observed hearing impairment. SNHL was most pronounced in the high frequencies, with values up to 35 dB (4000 Hz) and 25 dB (2000 Hz) in some patients. The latent period for the complication appeared to be 12 months or more. The deleterious effect of irradiation on the hearing should be kept in mind both in treatment planning and in the follow-up after radiotherapy.

Adult↗
PubMed1991

New methods for the assay of 5-isosorbide mononitrate and its validation.

Differential scanning calorimetry (DSC) is a method which has been applied to obtain thermal information about both raw material and the determination of the content of 5-ISMN in dry mixtures with lactose. The main advantage this offers, compared to other methods, is that it is not necessary to use a standard, it only being necessary to know the data of its fusion heat. HPLC and TLC-densitometry are considered for the determination of 5-ISMN: lactose and pharmaceutical dosage forms. Linearity test, repeatability and accuracy were satisfactory in both methods. Recovery data in pharmaceutical formulations (expressed as the percentage of the label claim) from HPLC and TLC did not give any significant difference (P = 95%). The results show that the chromatographic methods are simple, fast and reliable procedures for the determination of 5-ISMN.

Calorimetry, Differential Scanning↗
PubMed1991

Effect of step-down heating on the interaction between heat and radiation in a C3H mammary carcinoma in vivo.

The effect of step-down heating (SDH) on the interaction between heat and radiation was investigated in a C3H mammary carcinoma in vivo. SDH consisted of an initial sensitizing treatment (ST) performed at 44.5 degrees C or 43.5 degrees C followed by a lower temperature test treatment (TT) in the range 41.0-43.0 degrees C. Step-up heating (SUH), i.e. TT followed by ST, and single heating were used as controls. The end-point was the radiation dose needed to control 50% of the tumours (TCD50). The results were evaluated by calculating the thermal enhancement ratio (TER) defined as TER = TCD50 (radiation alone)/TCD50 (radiation and heat). For a simultaneous application of TT and radiation a significant enhancement of direct heat radiosensitization was observed with increasing ST time or ST temperature using SDH. In contrast, only a minor increase was seen with SUH. A comparison between TCD50 values for the corresponding SUH and SDH schedules revealed that the SDH effect was largest at 41.0-42.0 degrees C and decreased with increasing TT temperature. The radiosensitizing effect of SDH also decreased if an interval was allowed between ST and TT or between TT and radiation. However, as a result of an increased cytotoxicity towards hypoxic tumour cells, the TCD50 value for SDH remained significantly smaller than for SUH, even with a sequential combination of radiation and heat.

Animals↗
PubMed1991

Multimodality exploration of event-related potentials in chronic alcoholics.

Short- and long-latency auditory evoked potentials (SAEPs and LAEPs), visual-evoked potentials (VEPs), and contingent negative variation (CNV) were studied in 32 chronic alcoholics and their age-, sex-, and education-matched control subjects. The alcoholics exhibited a delayed SAEP peak V and an increase in the III-V and I-V intervals, increased VEP P100 latency, increased LAEP N2 and P3 latencies and increased LAEP N1-P2 amplitude. The analysis of the anomalies at a clinical level indicates a differential sensitivity of the event-related potentials. The parameters most sensitive to chronic alcohol consumption were (in descending order) P3 latency, peak V latency, the I-V and III-V intervals, and P100 latency.

Adult↗
PubMed1990

Cytotoxic effect of misonidazole and cyclophosphamide on aerobic and hypoxic cells in a C3H mammary carcinoma in vivo.

The chemosensitising effect of the nitroaromatic radiosensitiser misonidazole (MISO) on the alkylating agent cyclophosphamide (CTX) has been investigated in a C3H mammary carcinoma in CDF1 mice. The selective cytotoxicity against aerobic and hypoxic cells was measured indirectly, using a local tumour control (TCD50) assay. The hypoxic fraction was calculated from the dose difference between the TCD50S for tumours irradiated either in air or under clamped conditions. The relative survival of tumour cells after drug therapy was expressed as a surviving fraction (SF). CTX (100 mg kg-1) was found to be considerably more toxic towards hypoxic than aerobic cells (SF 4% versus 52%). MISO (1000 mg kg-1) was almost exclusively toxic to hypoxic cells (SF 22%). When MISO and CTX were administered simultaneously a decrease in the surviving fraction was observed. The effect on aerated cells was found to be 10-fold more than expected from addition of toxicities, suggesting a chemosensitising effect on these cells by MISO when used in combination with CTX. No synergistic effect was found on radiobiologically hypoxic cells. The exact role of hypoxia for the development of chemosensitisation seems to be complex and requires additional research in the future.

Animals↗
PubMed1990

The in vivo response of a C3H mammary carcinoma to treatment with misonidazole, cyclophosphamide and radiation.

The potential chemosensitizing effect of the nitroaromatic radiosensitizer misonidazole (MISO) on the alkylating agent cyclophosphamide (CTX), and the interactions of these agents with radiation, have been investigated in a C3H mammary carcinoma in CDF1 mice. MISO at 1,000 mg/kg caused a small increase in tumour growth time (TGT; time to reach 3 times treatment volume) from 3.6 days to 4.5 days. CTX (100 mg/kg) increased the TGT to 15.7 days. The combined treatment of MISO and CTX given with intervals of either 15 min or 4 h increased the TGT to 23.3 and 23.8 days respectively. The radiation enhancement ratio (ER) was found to be 2.13 and 1.10 for MISO administered before or after x-rays respectively. The corresponding ERs for CTX were 1.16 and 1.22. The two drugs given in combination resulted in significant radiation ERs of 2.68 (both drugs given within 30 min before x-rays), 3.00 (MISO 30 min before and CTX 3 1/2 h after x-rays) and 1.40 (both drugs given after x-rays). In contrast to what has previously been reported, and in contrast to the tumour regrowth delay data, the results of the tumour control experiments were found to reflect no more than an additive action of the two drugs when used together with radiation in vivo.

Animals↗
PubMed1990

[Not Available].

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History, Modern 1601-↗
PubMed1990

The influence of radiation dose on the magnitude and kinetics of reoxygenation in a C3H mammary carcinoma.

The variation in hypoxic fraction as a function of time after various priming doses of radiation has been investigated in a C3H mouse mammary carcinoma in situ. The hypoxic fraction was calculated from data for local tumor control. Untreated tumors were found to contain 4.8% radiobiologically hypoxic cells. Within minutes after a priming dose of 20 Gy given in air, the hypoxic fraction increased to a value not significantly different from 100%. After 4 h, reoxygenation was complete (hypoxic fraction 1.3%), and the hypoxic fraction stabilized at a level significantly below the untreated value. Following a priming dose of 40 Gy the reoxygenation pattern was different: The hypoxic fraction stayed above the pretreatment value for 4 h, and pronounced reoxygenation occurred after 12 h (hypoxic fraction 0.4%). At longer time intervals the hypoxic fraction again increased to--and slightly above--the oxygenation level of untreated tumors. The present findings show that reoxygenation in solid tumors is a function of radiation dose, and the data suggest that mechanisms other than a decrease in tumor cell O2 consumption are involved in tumor reoxygenation.

Animals↗
PubMed1988

Effect of cancer chemotherapy on the hypoxic fraction of a solid tumor measured using a local tumor control assay.

The effect of mitomycin C (MMC), adriamycin (ADM), cyclophosphamide (CTX), cisplatinum (cis-DDP) and bleomycin (BLM) on the aerobic and hypoxic cells of a C3H mammary carcinoma in CDF1 mice was investigated using the tumor control assay. Hypoxic fractions (HF) were calculated by an indirect technique using the horizontal displacement of the TCD50 value from the dose-response curves of tumors irradiated under normal or clamped conditions. The HF and absolute number of tumor cells following a combined treatment was compared to that obtained with radiation alone. MMC, ADM and CTX had a significant enhancing effect on the unclamped TCD50. All three drugs caused a marked reduction in the proportion of hypoxic cells, decreasing the HF from 5.4% to about 1% of the total cell number. The surviving proportion of hypoxic cells were 11.1, 8.9 and 6.5% respectively. Killing of aerobic cells was also observed but the effect was less than that seen on the hypoxic cells, with the survival only being reduced to between 38 and 68% of the total number of aerobic cells. In contrast, cis-DDP and BLM were shown to produce major cell killing in the aerobic compartment but actually showed no cytotoxicity towards hypoxic cells. This would explain the lack of radiation enhancement observed for these two drugs. We conclude that the ability of adjuvant drugs to improve radiation response is dependent on the hypoxic cell killing by the drugs.

Animals↗
PubMed1976

Ultradian rhythms in the mobility and behavior of rhesus monkeys.

The presence of ultradian rhythms in the mobility and behavior of rhesus monkeys was explored in eleven animals equipped with mobility FM transmitters and placed alone or in pairs in laboratory cage situated in a sound proof, temperature controlled room, with food and water ad libitum. After an habituation period of 3 to 7 days, telemetric recordings of the mobility of the animals showed ultradian rhythms with a periodicity of 70 min during the daily 12-h light period. During the corresponding 12-h dark period, there were two dominant cycles of 103-144 min and 48 min respectively. Restriction of food and water to 1h/day did not change the duration of these cycles, and the presence of random noise also had little effect. Spontaneous behavior occurred in regular sequences within each cycle. Social relationships were found to affect rhythmicity of behavior, since pairs of monkeys synchronized their cycles. The lever press response recorded during auto-shaping showed the same rhythmicity found in mobility, demonstrating the influence of ultradian rhythms on learned behavior.

Animals↗