Biomedical subjects

B Maurer-Schultze

Publications and source records attributed to B Maurer-Schultze.

At least 19 recordsLinked to original sources

PubMed1996

Prognostic relevance of the intrinsic growth deceleration of the first passage xenografts of human renal cell carcinomas.

BACKGROUND: Although successful xenotransplantation of human tumors in nude mice highly predicts prognosis, little is known regarding the biologic background of this correlation. In this study, the relationship between the macroscopic growth pattern of first-generation xenografts of human renal cell carcinomas in nude mice and prognosis was studied. METHODS: Macroscopic growth patterns of the first-generation xenografts of locally confined renal cell carcinomas were analyzed according to the best-fit Gompertz recursion formulas. RESULTS: The parameter "b" of the growth pattern, the measure of the intensity of growth deceleration as a function of tumor growth, strongly predicted prognosis after nephrectomy as a single factor; faster growth deceleration, i.e., lower b values, predicted better prognosis (mean follow-up, 5.2 years; P = 0.000008 for the disease free period and P = 0.000018 for overall survival). It is also the most significant single prognostic parameter among others (including staging and grading) according to a multivariate analysis. CONCLUSIONS: The parameter expressing the Gompertzian macroscopic growth deceleration of the first-generation xenografts of clinically locally confined renal cell carcinomas in nude mice explains the strong prognostic impact of xenotransplantation.

Animals↗

PubMed1995

Significance of conventional and new prognostic factors for locally confined renal cell carcinoma.

BACKGROUND: The prognosis of patients with locally confined renal cell carcinoma is variable. To improve the prognostic knowledge and select patients at high risk, additional prognostic parameters are needed. METHODS: The significance with respect to survival and tumor recurrence of "classic" and "new" prognostic parameters has been examined by following 41 patients with locally confined renal cell carcinoma after nephrectomy (mean follow-up, 5.2 years). The significance of histologic grade, tumor stage, Ki-67 index, proliferating cell nuclear antigen index, 3H-thymidine labeling index, tumor ploidy status, and tumor growth after xenotransplantation into nude mice (GAX range) was tested using the Kaplan-Meier plots by the log rank test or Tarone's test and also by the Cox multiple hazard regression analysis. RESULTS: Tumor stage (P < 0.0025), histologic grade (P < 0.005), Ki-67 index (P < 0.006), and GAX range (P < 0.00004) were found to be significant prognostic parameters for survival and tumor recurrence using single-factor analysis. Applying the multivariate analysis, the combination of the "new" factors, GAX range and Ki-67 index, resulted in even a higher prognostic relevance than the combination of the "classic" prognostic factors, tumor stage and histologic grade. The calculated prognostic index based on the results of the Cox analysis, which, except for stage and grade, included the Ki-67 index, was shown to be highly correlated with survival (P = 0.00002) and tumor recurrence (P = 0.0004). Its prognostic validity was studied with the receiver operating characteristics procedure and was found to be considerably superior to that of the two conventional prognosticators. CONCLUSIONS: The additional determination of the Ki-67 labeling index increases the prognostic assessment of patients with locally confined renal cell carcinoma.

Animals↗

PubMed1995

Effect of biological response modifiers on growth and cell proliferation of human tumor xenografts in nude mice.

The effect of biological response modifiers on macroscopic tumor growth and on tumor cell proliferation of a human renal cell carcinoma and a squamous cell carcinoma (hypopharynx) in nude mice has been studied. Tumor necrosis factor alpha (TNF-alpha) and interferon alpha (IFN-alpha) as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) were applied either alone or in combination, and TNF-alpha was also combined with etoposide (ETP). TNF-alpha and IFN-alpha alone or in combination did not substantially affect the course of tumor growth, however, they did influence the pattern of tumor growth. There was also only a marginal effect on tumor cell proliferation. However, IFN-alpha protects the animals from tumor growth associated weight loss. ETP and ETP plus TNF-alpha leads to a deceleration of tumor growth, a decrease of the labeling index and to a significant decrease of the animal weight which indicates that the first two effects may be partly due to the toxicity of the treatment. GM-CSF modifies cell proliferation in a dose-dependent manner, i.e. stimulation at low doses and tendency to inhibition at higher doses. Although there is no substantial direct antineoplastic effect of the agents studied, the results make clear that indirect effects of therapeutic agents due to therapy induced cachexia should always be regarded. It is interesting that IFN-alpha has a protective effect against cachexia.

Animals↗

PubMed1993

Treatment of a human renal cell carcinoma in nude mice with recombinant human tumor necrosis factor alpha and etoposide.

The effect of treating a human renal cell adenocarcinoma xenografted into Balb/c-nu/nu (nude) mice with recombinant human tumor necrosis factor alpha (TNF alpha) and the cytostatic agent etoposide (ETP) as monotherapy or combination has been studied. Antitumor effects were evaluated by determining growth of the tumor implants by external caliper measurements and tumor cell proliferation by determining the labelling index (LI) after pulse labelling with 3H-thymidine. The toxicity of the treatment with TNF alpha and/or ETP was also studied by measuring the animal weight. Monotherapy with TNF alpha had no effect on tumor growth or proliferation. Treatment with ETP as a single agent, TNF alpha plus ETP applied concurrently and TNF alpha plus ETP two days later led to a slight inhibition of tumor growth and also to a slight decrease of the LI. In contrast to a monotherapy with TNF alpha, all therapeutic modalities containing ETP showed an increased toxic effect on the animals represented by a distinct weight loss. This suggests that the minute efficacy of the treatment observed could well be due solely to its toxicity. In contrast to two other studies, no additive or synergistic effect of the antineoplastic activity of TNF alpha and/or ETP was found. The intertumoral variation of human renal cell carcinomas could be one reason for the different results with this therapeutic regimen.

Animals↗

PubMed1992

Cell proliferation in human tumours growing in nude mice: renal cell carcinomas, larynx and hypopharynx carcinomas.

Cell proliferation of 51 human renal cell carcinomas and 9 larynx and hypopharynx carcinomas has been studied in vitro and using xenotransplants. The proliferative activity ([3H]thymidine labelling index) increases during the first passages in nude mice and then remains almost constant throughout subsequent passages. A comparison of cell kinetic parameters of 8 human renal cell carcinomas, 1 hypopharynx and 2 larynx carcinomas, with data of xenografts and of human tumours in situ published up to now, shows that the cell kinetic parameters of human tumour xenografts presently studied range between those of human tumours in situ and those of autochthonous or transplantable mouse tumours. S-phase durations and potential doubling times are considerably shorter in xenotransplants than in human tumours in situ, whereas the cycle time is about the same. This means that the growth fraction increases considerably after xenotransplantation. This change of human tumour cell proliferation after transplantation into nude mice should be kept in mind if one wishes to draw conclusions from the nude mouse model on conditions in human beings, particularly with respect to therapeutic regimens, which are frequently tested in the nude mouse model.

Animals↗

PubMed1990

Cell kinetic studies of endothelial cells in the adenocarcinoma EO 771 and the effect of cyclophosphamide.

Cell kinetic studies of endothelial cells in the adenocarcinoma EO 771 growing in C57bl/6j mice and after transplantation into Balb/c-nu/nu mice, as well as of the effect of cyclophosphamide treatment have been carried out. The 3H-thymidine labelling index of endothelial cells decreases from about 8% 3-6 days after tumour inoculation to about 3% at 18 days. This decrease parallels that of the labelling index of tumour cells, i.e. there is a positive correlation between the labelling index of endothelial cells and that of tumour cells. The labelling index of endothelial cells in the tumour periphery is two to three times as high as that in the tumour centre reflecting corresponding differences in the rate of proliferation. There is no difference in the proliferation of endothelial cells whether the tumour grows in C57bl/6j or in Balb/c-nu/nu mice. After treatment with cyclophosphamide the labelling index of endothelial cells decreases within 2 days to 1-2% and remains that low despite regrowth of the tumour with increased tumour cell proliferation, indicating that tumour relapse does not depend on tumour angiogenesis.

Adenocarcinoma↗

PubMed1990

Tracer dose and availability time of thymidine and bromodeoxyuridine: application of bromodeoxyuridine in cell kinetic studies.

The present experiments with [14C]-thymidine (TdR) and [3H]-bromodeoxyuridine (BrdU) using mouse jejunal crypt cells show that the upper limit of the tracer dose of TdR is about 0.5 microgram g body weight-1 and that of BrdU is about 5.0 micrograms g body weight-1. Applying these doses, the proportions of the endogenous DNA synthesis attributed to the exogenous DNA precursor are 2% and 9% respectively. For [3H]-TdR doses commonly used in cell kinetic studies this proportion is only 0.1-1.0%, a negligible quantity that does not influence the endogenous DNA synthesis. The maximum availability time of tracer doses of TdR as well as BrdU is 40 to 60 min, the majority of the precursors being incorporated after 20 min. The availability time is the same for TdR doses exceeding the tracer dose by a factor of 80, whereas it is prolonged in the case of BrdU doses exceeding the tracer dose by a factor of 50. BrdU is suitable to replace radioactively labelled TdR in short term cell kinetic studies, i.e. determination of the labelling index or of the S phase duration by double labelling. However, more studies are needed to elucidate how far BrdU can replace TdR in long term studies as shown by differences between the fraction of labelled mitoses (FLM) curves of a human renal cell carcinoma measured with BrdU and [3H]-TdR.

Animals↗

PubMed1990

Growth and proliferation of a transplantable mouse tumor and of human tumors growing in nude mice.

Growth and proliferation were studied of a transplantable mouse tumor, the adenocarcinoma EO 771 (Adca EO 771) growing in C 57 and in nude mice on the one hand, and of human tumors (renal cell and hypopharynx carcinoma) growing in nude mice on the other. There is almost no difference in tumor growth, histology and proliferation whether the Adca EO 771 grows in C 57 or in nude mice. However, there are great differences in this respect between the transplantable mouse tumor and human tumors. Growth of the Adca EO 771 and C 57 and in nude mice occurs according to the Gompertz function, whereas growth of human tumors in nude mice differs, some tumors grow exponentially and some according to the Gompertz function. The proportion of necrotic tissue strongly increases with increasing tumor size in the case of the Adca EO 771, while it is about constant in human tumors regardless of the tumor size. The tumor cell density of the Adca EO 771 increases considerably with increasing tumor size, however, it remains about constant in human tumors. Concerning tumor cell proliferation an S phase duration was found that is rather similar for the cells of the transplantable mouse tumor as well as of the human tumors suggesting that DNA synthesis might be regulated by the host organism. A quantitative study of the growth of the metastases of the Adca EO 771 exhibited an allometric correlation between the growth of the metastases and that of the primary tumor. This leads to the consequence that metastases might originate later than estimated until now assuming exponential growth of metastases. Treatment of the Adca EO 771 with cyclophosphamide results in the death of almost all tumor cells; however the tumor repopulates. The toxic effect of cyclophosphamide on the mouse organism strongly depends on the size of the tumor at the time of treatment.

Adenocarcinoma↗

PubMed1989

Tumor cell recruitment in the mouse adenocarcinoma EO 771 directly demonstrated by double labeling with [3H]- and [14C] thymidine and flow cytometry.

Tumor cell recruitment in the mouse adenocarcinoma EO 771 after application of 1-beta-D-arabinofuranosylcytosine (AraCyt) has been directly demonstrated by double labeling with [3H]- and [14C]-thymidine. This method enables a quantitative study of the extent and time course of tumor cell recruitment in this solid mouse tumor. The results show that tumor cell recruitment is a continuous process that starts early after AraCyt application (about 4-8 h) and lasts about 1 day with a maximum at about 12 h after Ara-Cyt application. Up to 40% of all cells are recruited at that time. The recruited tumor cells re-enter the resting state after having passed through one cycle.

Adenocarcinoma↗

PubMed1989

Development of the perifollicular capillary network. Autoradiographic and morphometric studies in the rabbit ovary.

The published data give a report on systematic examinations on the development of the perifollicular capillary network in the theca interna in rabbit ovaries. The follicle size and the number of capillaries were investigated by means of morphometric methods. The extent of proliferation of granulosa and endothelial cells was studied autoradiographically by determining the labelling index (LI). The results show that the perifollicular capillary network is initiated only when the stratum granulosum has developed into a multilayered cell population. After that the number of capillaries increases linearly with increasing follicle size, independently of the oestrus cycle. During follicle growth at different times in the oestrus cycle the decrease and increase in the LI of granulosa cells is followed by a corresponding decrease and increase in the LI of endothelial cells several hours later. It should be noted, however, that the proliferation of endothelial cells in follicles with a diameter of 900 microns continues, although the decreasing LI of granulosa cells already indicates a reduced follicle growth. The number of labelled endothelial cells in atretic follicles decreases only after a decrease in proliferation of granulosa cells. In conclusion, it can be noted that the follicle growth and function is not influenced by variations in the number of capillaries in the theca interna. The curve of LI of granulosa and endothelial cells suggests that the granulosa cells have a certain regulatory function with respect to the growth of the capillary network in the theca interna.

Animals↗

PubMed1989

Intracellular localization of the calcium- and calmodulin antagonist fendiline.

Microautoradiograpic studies of mouse heart sections were performed to evaluate intracellular localization of the antianginal drug fendiline (Sensit). 15 microCi 3H-fendiline/g b. w. (0.5 mg/kg b.w.) were injected intravenously. 10 min p.a. the heart was removed and either frozen in acetone/dry ice or, after perfusion in situ with dextran 40 and formaldehyde, fixed in formaldehyde. Frozen, paraffin-embedded, and semithin epoxy resin sections were prepared and coated with Ilford K2 emulsion. After 7 to 30 days exposure and development in amidol silver grains were counted above cells, nuclei and extracellular space. The results show that fendiline is able to enter myocardial cells.

Animals↗

PubMed1988

Fully automated TV-image analysis of the cell-cycle: comparison of the PLM method with determinations of the percentage and the DNA content of labelled cells.

A cell-cycle analysis based on a fully automated TV-image scanning system is proposed to replace the laborious PLM method. To compare the efficiency of the two procedures, cell-cycle parameters were assessed in Ehrlich (diploid and hyperdiploid), L-1210, and JB-1 mouse ascites tumours and in rat jejunal crypts. The percentages of labelled mitoses (PLM) were counted visually on Feulgen-stained autoradiographs obtained at various times after a single 3H-thymidine pulse. The fraction of labelled cells (P) and the DNA ratio of labelled and unlabelled cells were measured by TV-image analysis in the same slides and plotted against time. Within practical limits, TV-image analysis using the P-curve gives the same results as the PLM method. Using the P-curve has the important advantage that its first part, beginning at the time of 3H-thymidine injection and ending at the first maximum, furnishes more information about the cell cycle than the corresponding part of the PLM curve. It can be used to compute tG2M tS and the ratio of the growth faction index to the cell-cycle time (IP/tC) whereas the first part of the PLM-curve reveals only the length of the S-phase (tS). The IP/tC ratio is a readily accessible measure of growth and increases when the cells divide more frequently. Cell death rates may be neglected since the ratio is determined within less than the duration of one cell cycle. Moreover, the data from the first part of the P curve indicate whether there is a large non-growth fraction. If the non-growth fraction is small, i.e. if IP approximately 1, the P curve need only be measured until the first maximum is reached so that fewer samples and animals are required. If the non-growth fraction is large or unknown, the cell-cycle parameters are calculated by reference to the position and size not only of the first minimum and the first maximum, but also of the second minimum of the P curve.

Animals↗

PubMed1988

An in vivo study on the synchronizing effect of hydroxyurea.

The effect of hydroxyurea (HU; 0.5 mg/g body wt) on L 1210 ascites tumor cells has been studied using various cell kinetic methods. In contrast to the general assumption that HU blocks cells at the G1/S boundary [J. Brachet (1985) Molecular Cytology, Vol. I, p. 266, Academic Press, New York], the present results show that the cells are not held at G1/S but enter S at about the normal rate and are accumulated in early S phase due to a dose-dependent inhibiting effect of HU on DNA synthesis. Partial synchronization of the cells demonstrated by a distinct mitotic peak 10 h after HU application is not due to a G1/S block of the cells and their subsequent synchronous passage through the cycle after release from the block but is due to rather complex mechanisms of action of HU: a differential cytocidal effect and an effect on the passage of the cells through the cycle, both depending on the position of the cells throughout the cycle. HU kills S-phase cells, mainly cells in early S phase; i.e., a great portion of the cells "accumulated" in early S phase is killed by the drug, while G1-phase cells are almost not affected by the lethal effect of HU. These G1-phase cells pass through the cycle more rapidly after cessation of the HU effect. The same is true for the surviving cells accumulated in early S phase, while part of the cells in the remaining S phase are delayed in their passage through the cycle. This causes partial synchronization, since a great portion of all cells that survive HU treatment reach mitosis at the same time.

Animals↗

PubMed1988

Tumour cell recruitment of the JB-1 and L 1210 ascites tumour determined directly by double labelling with [14C]- and [3H]-thymidine.

Tumour cell recruitment of the JB-1 and L 1210 ascites tumour has been demonstrated directly by a double-labelling method with [14C]- and [3H]-thymidine (TdR). After [14C]-labelling of all proliferating tumour cells by multiple injections of [14C]TdR, recruitment of resting cells was stimulated by removal of the majority of tumour cells, i.e. by maximum aspiration of ascitic fluid. The number of recruited resting cells in the remaining tumour that re-enter the cell cycle after stimulation was demonstrated directly by a single injection of [3H]TdR given at different times after stimulation. The increase in the percentage of purely [3H]-labelled cells, i.e. recruited cells, with increasing time after stimulation, shows that recruitment is not a synchronous but a continuous process, the maximum of which occurs earlier in the case of the L 1210 than the JB-1 tumour. This suggests that there seems to be a relationship between the time required for maximum recruitment and the corresponding cell cycle parameters of the unperturbed tumour. There is a transitory increase of the growth fraction to about 100% and a considerable shortening of the cycle time at the maximum of recruitment.

Animals↗

PubMed1988

The recursion formula of the Gompertz function: a simple method for the estimation and comparison of tumor growth curves.

A method for analysing tumor growth curves is presented based on regression analysis of the linear relationship between the logarithm of the tumor size at a certain time and of that at a constant time interval earlier. By measuring the tumor size at constant time intervals the Gompertzian growth curve can be transformed into a straight line. This permits both the calculation of best fit Gompertzian curves and the comparison of different growth curves simply based on linear regression analysis. Since this new method includes exponential growth as a special case, it enables a quantitative discrimination between exponential and Gompertzian growth. Furthermore, this method permits the calculation of best fit Gompertz functions based upon individual measurements of tumor collectives without a common time scale (i.e., spontaneous tumors). As an example, it is demonstrated that the growth curves of the transplantable mouse adenocarcinoma EO 771 do not depend on the number of tumor cells inoculated.

Adenocarcinoma↗

PubMed1987

Cytocidal and toxic effect of various cytostatic drugs on three ascites tumors of the mouse.

The cytocidal and toxic effects of four cytotoxic drugs (CY, DDP, VCR, Ara-C) were studied using three types of ascites tumors (L 1210, JB-1, EAT) growing on three different mouse strains (B6D2F1, AKR, NMRI). There were considerable differences in the cytocidal effect of the same dose of each drug on the three tumor cell lines; 100% of the L 1210 ascites tumor-bearing animals were permanently cured by a high dose of CY (300 mg/kg) and 30% by DDP (13 mg/kg), while most of the JB-1 and all EAT-bearing mice died earlier than the untreated control mice. The sensitivity of the animals of the three mouse strains to the toxic effect of the same drug dose also differed. CY was better tolerated than DDP. Ara-C and VCR doses used in the present work were non-toxic and showed little cell killing effect. Furthermore, the present study showed that tumor-bearing mice were more sensitive to the toxic side effects of CY, DDP, and Ara-C than tumor-free animals. The growing tumor itself increased the vulnerability of normal cells to the drug.

Animals↗

PubMed1987

Mechanism of growth retardation of the adenocarcinoma EO 771.

Growth retardation of tumors has been predominantly described by an increase of the "cell loss factor" phi. However, this cell loss factor alone merely reflects the growth deceleration without giving information on the mechanism that causes growth retardation. In the present study a quantitative analysis of the mechanism causing growth retardation of the adenocarcinoma EO 771 has been carried out by determining separately the components of the cell loss factor phi, namely the cell production rate and the cell loss rate of the tumor cell population. For this purpose the alteration of the histology of the tumor (proportion of necrotic tumor tissue, tumor cell density) and the proliferative capacity of the tumor cell population as a function of the tumor size was studied by applying morphometric and cell kinetic methods. The results show that growth deceleration is due to a decrease of the cell production rate kappa p and a simultaneous increase of the cell loss rate kappa l. Both processes contribute to about the same extent to the growth deceleration of the tumor cell population. In early tumor growth deceleration is mainly due to a prolongation of the cycle time of the tumor cells, in later phases of tumor growth to an increasing probability of the tumor cells to decycle leading to a decrease of the growth fraction GF and an increase of the cell loss rate kappa l.

Adenocarcinoma↗

PubMed1987

Re-examination of the effect of beta-adrenergic blocking agents on the proliferation of rat jejunal crypt cells using the stathmokinetic method.

Reports of the effects of beta-adrenergic receptor blocking agents on the proliferative activity of rat jejunal crypt cells are contradictory. According to Tutton and Helme (1974) a single injection of propranolol or practolol (10 mg/kg) increased the mitotic index twofold and shortened the duration of the cell cycle of the crypt cells. However, upon repeating the experiments with double the dose of propranolol, Maurer-Schultze et al. (1986) observed no such effects using cell kinetic methods with 3H-thymidine instead of the stathmokinetic method applied by Tutton and Helme. Since the discrepancy in the results may have been due to methodological differences the same stathmokinetic method used by Tutton and Helme has been applied in the present work. However, the results obtained with this method indicate no influence by propranolol on the proliferation of jejunal crypt cells even with a dose of 20 mg/kg. Consequently we were unable to confirm the stimulant effect of propranolol on crypt cell proliferation. The possible causes of the discrepancy between the present results and those of Tutton and Helme are discussed.

Animals↗