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R Guttenberger

Publications and source records attributed to R Guttenberger.

27 records · Page 2Linked to original sources
PubMed1992

Is the experience with CHART compatible with experimental data? A new model of repair kinetics and computer simulations.

A new incomplete repair model is introduced that differs from previous models of this type by not assuming that repair is complete during long intervals, e.g. "overnight" intervals of 12-24 h. The model was used to assess the risk of myelopathy resulting from continuous hyperfractionated accelerated radiotherapy treatment (CHART) in light of recent experimental data on the rat spinal cord. Model calculations employing biexponential repair kinetics showed that CHART treatments might result in a higher myelopathy risk than an equal dose given in conventional 2-Gy fractions if the parameters obtained from the animal data hold. The probability of observing what has been reported for CHART was determined in computer simulations for different variance scenarios. The chance to observe four myelopathies in the 74 cervical cord patients was estimated to range between 25 and 62%, while the probability to see 0 in 68 thoracic cord patients ranged from 48 to 27%. These numbers were derived from reasonable assumptions about the repair kinetics (e.g. 60% of damage repaired with a half-time of 8 h) so that the over-all probability to observe 4/74 and 0/68 was maximized, and depending on the scenario fell in the range 12-17%. Finally, from these simulations a myelopathy risk of approximately 0.3-1.2% is predicted for the currently employed maximal CHART dose to the spinal cord, i.e. 42 Gy. We conclude that the CHART experience is not compatible with the new experimental data (p < 5%). Incomplete repair is unlikely to be the sole reason for the unexpected toxicity of CHART (p < or = 17%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Impact of spinal cord repair kinetics on the practice of altered fractionation schedules.

The kinetics of repair of sublethal lesions in the spinal cord was assessed in detail using a rodent model. Experiments were designed to obtain the fractionation sensitivity, alpha/beta, and to quantify the kinetics of repair after a clinically relevant fraction size. Pairs of 2-Gy fractions at intervals ranging from 0 to 24 h were given from Monday through Friday, to cumulative doses of 40-84 Gy. In addition, two groups of animals received 1.5 or 1.2 Gy twice a day at 8-h intervals, 5 days a week, to total doses of 66-90 Gy and 67.2-98.4 Gy, respectively. All irradiations were followed by a top-up dose of 16 Gy. Analysis of the experimental data revealed that a bi-exponential repair model fit the experimental data significantly better than did the mono-exponential model (p = 0.002). The repair half times obtained were 0.7 (0.2-1.3) h and 3.8 (2.6-4.9) h, respectively. The proportion of injury repaired by the longer half time was estimated to be 0.62 (0.37-0.86). The data showed that delivering 2 fractions per day at 6- or 8-h intervals instead of one per day led to a 16.5% (11.8-21.1%) and 13.5% (9.1-17.8%) reduction in the tolerance, respectively. Finally, the results indicated that when incomplete repair between fractions was accounted for, the linear-quadratic (LQ) model was valid in describing fractionation response down to 1.2 Gy per fraction.

Animals↗
PubMed1992

Modification of radiation-induced carcinogenesis in mice by misonidazole and WR-2721.

The effects of the radiosensitizer misonidazole (MISO) and the radioprotector WR-2721 on radiation-induced carcinogenesis in C3Hf/Kam mice were investigated. The right hind legs were exposed to graded single doses of gamma-rays. MISO and WR-2721 were given i.p. 30 min before irradiation at a dose of 1 mg/g and 0.4 mg/g, respectively. The RCD50, or radiation dose inducing tumors in 50% of the irradiated legs, was determined 650 days after treatment. The same animals were also checked for the effect of these drugs on hair loss and radiation-induced leg contractures. MISO enhanced radiation carcinogenesis by a factor of 1.43, whereas WR-2721 reduced it by a factor of 1.75. These effects on carcinogenesis correlated well with the modifying effects of the two agents on radiation-induced hair loss (early damage) and leg contractures (late damage).

Amifostine↗
PubMed1991

Changes in TCD50 as a measure of clonogen doubling time in irradiated and unirradiated tumors.

Dose-cure experiments have been carried out on a moderately well differentiated murine mammary carcinoma, designated MCA-4, at different stages of growth after tumor-cell inoculation or after 8 mm established tumors had been exposed to 60 Gy. TCD50 assays were performed at 1, 3, 7, 14, or 21 days after tumor cell inoculation, or when tumors reached a size of 6 or 8 mm. Likewise, TCD50 assays were performed at 0.25, 1, 3, 5, 8, 12, 16, or 21 days after 8 mm tumors had been exposed to a 60 Gy priming dose, or when the recurrent tumors reached 6 or 8 mm. All irradiations were performed under hypoxic conditions. The TCD50 (95% confidence limits) was 64.0 (61.7-68.3) Gy for the 6-mm and 71.9 (70.1-73.9) Gy for the 8 mm tumors, and these values were unaffected by preirradiation. Direct analysis was used for the simultaneous estimation of D0, clonogen number, and clonogen doubling time from the pooled data. There was no significant difference between D0 estimates for the preirradiated and control tumors, and the pooled estimate was 10.6 (9.6-11.8) Gy for tumors assayed at specified time points where the size was unknown. This is clearly higher than in tumors of known size [estimate for 6- and 8-mm tumors: D0 = 5.4 (4.5-6.6) Gy] owing to size and other heterogeneity. The clonogen doubling times (Tclon) were 3.4 (3.0-4.0) days in the preirradiated tumors and 5.8 (4.9-7.1) days in the unirradiated tumors. It is not unreasonable to assume that the systematic error due to heterogeneity was approximately the same for D0 and Tclon (since variable clonogen number is likely the predominant source of heterogeneity), and thus the ratio of D0 for tumors of unknown sizes (10.6 Gy) and D0 for tumors of known sizes (5.4 Gy) can be used to "correct" the Tclon estimates, with the result that Tclon (preirradiated) = 1.7 days and Tclon (unirradiated) = 3.0 days. We conclude that the clonogen doubling time was shorter in tumors exposed to a single high-dose irradiation than in unirradiated controls, which implies the existence of faster cell repopulation in irradiated tumors.

Animals↗
PubMed1991

A nonparametric method for the derivation of alpha/beta ratios from the effect of fractionated irradiations.

Multifractionation isoeffect data are commonly analysed under the assumption that cell survival determines the observed tissue or tumour response, and that it follows a linear-quadratic dose dependence. The analysis is employed to derive the alpha/beta ratios of the linear-quadratic dose dependence, and different methods have been developed for this purpose. A common method uses the so-called Fe plot. A more complex but also more rigorous method has been introduced by Lam et al. (1979). Their method, which is based on numerical optimization procedures, is generalized and somewhat simplified in the present study. Tumour-regrowth data are used to explain the nonparametric procedure which provides alpha/beta ratios without the need to postulate analytical expressions for the relationship between cell survival and regrowth delay.

Animals↗
PubMed1990

Kinetics of recovery from sublethal radiation damage in four murine tumors.

The kinetics of repair of sublethal radiation damage (SLD) was studied in four transplantable C3H mouse tumors, i.e. mammary carcinoma AT17, fibrosarcoma SSK2, and squamous cell carcinomas AT51 and AT478. Tumors were irradiated with 4 fractions of 300 kV X-rays given under local hypoxia at intervals ranging from 0 to 6 h. Radiation response was measured by growth delay, which was directly analyzed using a general curve description based on the extended linear-quadratic model (exponential repair kinetics). In contrast to existing methods all growth delay values were utilized to estimate the alpha/beta ratios and the half-times as well as their confidence limits in a non-linear least squares analysis. The half-times were 42, 44, 54 and 31 min, respectively. It is concluded that repair of SLD is virtually complete after 5 h in these tumors. This is also due to the relatively small proportion of repairable damage in these tumors reflected in their alpha/beta values, which were 38, 30, 54 and 42 Gy, respectively.

Animals↗
PubMed1988

[Intracellular recovery--basis of hyperfractionation].

The radiobiological basis of a hyperfractionated radiation therapy versus conventional fractionation with respect to therapeutic gain, i.e., improved normal tissue sparing for the same level of tumour cell inactivation, will be presented. Data on the recovery potential of various tissues as well as the kinetics of repair will be given. The problem of incomplete repair with short irradiation intervals will be discussed.

Animals↗
PubMedDate not supplied

Is there any correlation between MDR1, GST-pi-expression and CEA?

BACKGROUND: The levels of mRNA-expression of multidrug resistance (MDR1) and glutathione-S-transferase pi (GST-pi) were measured and correlated with the immunohistochemical expressions of tumour markers. MATERIALS AND METHODS: Analysis of total mRNA was performed by Northern and slot blots. The expression of carcinoembryonic antigen (CEA) and other tumour markers was assessed by immunohistochemistry. The tumour panel comprised tumours of different histologies. RESULTS: CEA-positive tumours showed a significantly higher ex-pression of MDR1 and GST-pi than CEA-negative tumours. Wilcoxon-Test: mean rank of the MDR1 expression (14.3 vs. 7.8; p < 0.05) and GST-pi expression (15.3 vs. 5.9; p < 0.001). No other correlation could be found. CONCLUSIONS: The relationship of MDR1 and GST-pi with the tumour marker CEA implies that evaluation of CEA can help in discriminating between tumours with high or low expression of drug resistance. Furthermore, correlation between MDR1, GST-pi and CEA indicates that there might be a common mechanism, regulating drug resistance and expression of CEA.

ATP Binding Cassette Transporter, Subfamily B, Mem↗