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Biomedical subjects

D Schmähl

Publications and source records attributed to D Schmähl.

At least 19 recordsLinked to original sources
PubMed1992

Influence of reducing luxury calories in the treatment of experimental mammary carcinoma.

The aim of this study was to investigate the influence of dietary calorie intake at three different fat levels on (a) the growth of established methylnitrosourea (MNU)-induced mammary carcinoma, (b) the reappearance of mammary carcinomas after surgical removal, and (c) the growth of manifest lesions in animals treated with the cytostatic agent hexadecylphosphocholine (HPC). A reduction of calories by 30% significantly inhibited tumour growth of manifest mammary carcinomas in rats, without having a negative influence on body weight gain. After chemotherapeutic treatment no significant dietary influence was observed besides the high antineoplastic efficacy of HPC, but when feeding calorically restricted diets to surgically treated animals the number of reappearing tumours was considerably smaller (P = 0.06) than after feeding the diets ad libitum. The fat content of the diets did not influence the growth of manifest mammary carcinomas. No significant dietary effects were exerted on oestradiol or testosterone levels in untreated tumour bearing animals. An elevation of oestradiol levels was observed when animals were subjected to HPC and fed a high calorie diet. An elevation of testosterone levels was assessed after surgical treatment of the rats, irrespective of fat content and calorie level. Our results suggest that a reduction of calories can inhibit growth of manifest mammary carcinomas and has impeding effects on tumour development after surgical removal. After effective chemotherapeutic treatment the additional influence of dietary changes was of less relevance. Furthermore, our data do not establish any association between growth inhibition of mammary tumours, caused by the mild caloric restriction, and altered oestradiol or testosterone production.

Animals↗
PubMed1991

On the long-term toxic risk of dinaline.

The long-term toxic risk of the cytostatic agent dinaline (4-amino-N-(2'-aminophenyl)-benzamide) was assessed in a rat bioassay. Regular administration of 9, 3 and 1 mg/kg for 106 weeks was associated with significantly increased survival of female rats receiving the median and low doses. Dinaline significantly reduced the occurrence of malignant tumors in male rats and prolonged the manifestation time of malignancies in female rats. Unlike malignant tumors, benign neoplasms were increased in male rats and were not significantly different from controls in female rats. Analysis of organ distribution of neoplastic lesions revealed a dose-dependently decreased tumor incidence in the hematopoietic and lymphatic tissue, the mammary gland (females only) and the pituitary gland and a not dose dependently reduced incidence of liver tumors. This contrasted with dose dependently increased tumor incidences in the adrenal gland, the gonads and the vagina. Considering these findings, dinaline has to be assessed as a modulator of carcinogenesis in rats. The observed decreased and increased tumor incidences suggest a hormone-related mechanism of action.

Animals↗
PubMed1991

Effect of dietary calorie and fat restriction on mammary tumor growth and hepatic as well as tumor glutathione in rats.

Effect of dietary calorie restriction and fat reduction on growth of established mammary carcinoma in rats and on glutathione levels in liver and tumor tissue was investigated. Reduced (GSH) and oxidized (GSSG) glutathione were determined enzymatically. Female Sprague-Dawley rats were injected with 25 mg/kg methylnitrosourea (MNU) on day 50 of life for tumor induction, and subsequently fed a diet containing 50 kcal/day with 45% (energy %) fat. When tumors reached approximately 1 cm3, the diet was changed for 10 +/- 2 weeks. Four dietary groups were formed: two high calorie groups (50 kcal/day) with 45% or 25% fat and two calorie restricted groups (35 kcal/day) with 45% or 25% fat, respectively. Tumor growth was significantly inhibited by the 30% calorie restriction, and the inhibition was most effective in the calorie restricted group with low fat level. However, reduction of fat, alone, had no significant inhibitory effect. GSSG levels in both liver and tumor showed no differences among the groups. Hepatic GSH levels tended to be lower in the calorie-restricted groups, and showed no difference between isocaloric groups with different fat levels. In contrast, GSH in tumor tissue tended to be lower in the low fat groups, independently of calorie levels.

Animals↗
PubMed1991

Locoregional administration of 5-fluoro-2'-deoxyuridine (FdUrd) in Novikoff hepatoma in the rat: effects of dose and infusion time on tumor growth and on FdUrd metabolite levels in tumor tissue as determined by 19F-NMR spectroscopy.

The influence of infusion time and dose on the anticancer efficacy of 5-fluoro-2'-deoxyuridine (FdUrd) was investigated using a locoregional therapy model: Novikoff hepatoma transplanted i.m. into the thigh of Wistar rats and FdUrd infusion via a catheter implanted in the femoral artery. In experiment A the FdUrd dose (five daily doses of 12, 19 and 30 mg/kg) and the duration of administration (bolus, 1 h, 5 h, and 24 h) were varied. The change in tumor volume following treatment and the number of rats showing regression vs progression served as indicators of therapy response. The results showed a clear dose dependence, and for each infusion time the 30 mg/kg dose was the most effective, without any signs of general toxicity. At this dose the longest infusion time (24 h) was less effective (regression in three of six rats) compared with 1-h or 5-h treatments (four of five in regression). In experiment B either one or five daily FdUrd doses (15, 30, 60 mg/kg) were administered i.a. for the same infusion times used in experiment A. After treatment, tumors were explanted ex vivo and approximately 1-g tissues samples were immediately frozen in liquid nitrogen for storage. 19F-NMR spectroscopy at 11.7 T was used to quantify FdUrd metabolites [5-fluorouracil (FUra), alpha-fluoro-beta-alanine (F beta Ala), 5-fluorouracil nucleosides and nucleotides (F-Nuc)] in the solid tumor tissue samples (maintained at 4 degrees C) with a detection threshold of about 5 nmol/g. The metabolite signal pattern indicated that FdUrd is first converted to FUra, followed by anabolism primarily to nucleotides in the oxy form (e.g. FUTP). The total amount of fluorine detected in tumor tissue increased with dose and decreased with infusion time. For all treatments FNuc could be detected, even after 24 h infusion, and their levels showed a good linear correlation with the total F. The major catabolite F beta Ala was present in tumor at low levels that correlated poorly with total F, indicating recirculation from other organs (e.g. liver) as the main source. Thus, the NMR method can provide detailed information regarding the efficiency of locoregional treatment (catheter function, drug uptake and metabolism). Initial results of non-invasive in vivo NMR experiments are also presented.

Animals↗
PubMed1991

Treatment of chemically induced autochthonous rat mammary and colorectal carcinomas with interleukin-2.

The antineoplastic efficacy of human interleukin-2 (IL-2) in autochthonous methylnitrosourea-induced mammary carcinoma and in acetoxymethyl-methyl-nitrosamine-induced colorectal carcinoma of Sprague Dawley rats has been investigated. Under the conditions applied, IL-2 was non-toxic. In the mammary carcinoma IL-2 was therapeutically inactive. In the colorectal carcinoma, 1200 U IL-2/day exhibited significant antitumour activity in established tumours as well as in tumours treated "prophylactically" before their manifestation (P less than 0.05). The effect of IL-2 seemed to be more pronounced when given before manifestation of colorectal tumours (T/C = 8.7% vs 17.8% in established tumours). The differential sensitivity of the autochthonous mammary and colorectal carcinoma may be explained by differences in their proliferation rates and differences in volumes at the beginning of IL-2 therapy. IL-2 seems to be preferentially active in small tumours with a low proliferation rate, a feature typical of colon tumours.

Animals↗
PubMed1991

Metabolism of debrisoquine and susceptibility to breast cancer.

There may exist an association between the genetically determined oxidation status of the antihypertensive agent debrisoquine (DEB) and the propensity to develop tumours. The metabolism of DEB is extensive in 90% of healthy subjects (metabolic ratio = MR = 0-12.6; MR = % DEB excreted divided by % 4-hydroxy-DEB excreted) and poor in 10% (MR greater than 12.6). In patients with cancer of the lung, urinary bladder, and gastrointestinum, the percentage of high metabolizers is increased to greater than 98%. The poor metabolizer mode is almost devoid of cancer patients. It was investigated whether breast cancer patients show a similar association with respect to the oxidative status of DEB. 108 breast cancer patients and 123 women with benign gynecologic disorders received 1 tablet of 10 mg DEB orally in the evening. Urine was collected for the subsequent 8 hrs and analysed for its content of DEB and its main urinary metabolite 4-OH-DEB by means of HPLC. No decreased amount of poor metabolizers was seen in the cancer group.

Breast Neoplasms↗
PubMed1991

Relationship between dose and risk reduction: statistical evaluation of a combination experiment with three hepatocarcinogenic N-nitrosamines in rats.

Data from an experiment on the single and combination effects of very low doses of N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR) and N-nitrosodiethanolamine (NDELA) in 1800 male Sprague-Dawley rats were analysed for age-specific incidence (time to death with liver tumour) by Cox's proportional hazards model. The model revealed a linear relationship between daily exposure to low levels of N-nitrosamine and time to death with liver tumour within the dose range investigated: an increase in individual dose resulted in a proportional decrease in liver tumour-free survival. The finding was established for the three individual carcinogens as well as for their combination. NDEA was 40 times more active than NDELA. Extrapolation to N-nitrosamine exposure levels lower than those used in the experiment revealed only a minor reduction in age-specific liver tumour incidence compared to that achieved by an equivalent reduction within the experimental dose range. In rats at advanced age a further reduction in carcinogen-induced liver tumour incidence did not contribute to longer overall survival, due to competitive, probably independent causes of death. The data thus support the idea of a quasi-threshold in terms of a 'no observed effect level'.

Age Factors↗
PubMed1991

[Etiology of bronchial cancer: smoking, passive smoking, environment and occupation].

The inhaled tobacco smoke is the most important determinant in the etiology of lung cancer and there is a clear dose-effect relation between lung cancer risk and the duration of smoking, the number of cigarettes and the intensity of inhalation. The opinions about lung cancer risk from passive smoking are divided and the published data are still in discussion. Occupational substances include chromates, nickel, beryllium, alkylated compounds, vinylchloride, arsenic compounds and in particular asbestos. Fortunately air pollution has no or small part in the etiology of lung cancer.

Carcinogens, Environmental↗
PubMed1991

In vitro investigations on the antineoplastic effect of hexadecylphosphocholine.

The in vitro antineoplastic activity of hexadecylphosphocholine (HPC, CAS 58066-85-6) on methylnitrosourea (MNU)-induced mammary carcinoma in Sprague-Dawley rats and human mammary carcinoma was investigated with the modified Hamburger-Salmon-Colony-Assay (HSCA). The effect of HPC was also compared with ilmofosine (alkyllysophospholipid derivative) and N-(2-chloroethyl-N-nitroso-N'-2-hydroxyethylurea (HECNU). Moreover, the modified HSCA was performed with bone marrow cells and KB cells. In this investigation, no specific antineoplastic effect of the test compounds on MNU-induced mammary carcinoma and human mammary carcinoma was found in HSCA. Thus the antineoplastic activity of the compounds could not be compared on these cell types. In vitro, effects were only observed in bone marrow and KB cells at a very low concentration. The in vitro effect of HPC on mammary carcinoma cells, evaluated through HSCA, did not predict the effect of HPC in vivo. The reason has remained unknown but some hypotheses are discussed. Because of the contrary results of HPC in vitro and in vivo, it should be pointed out that drug development in this class of compounds mainly has to depend on in vivo experiments.

Animals↗
PubMed1991

Cytotoxic chemotherapy-induced second primary neoplasms: clinical aspects.

The incidence of second malignancies was assessed by retrospectively analyzing data from previous studies in well-defined and closely followed patient cohorts. After a median follow-up of more than 6 years following MOPP (mechlorethamine/vincristine/procarbazine/prednisone) chemotherapy with or without radiotherapy, 5% of patients with Hodgkin's disease developed second primaries, 60% of which were leukemias. Melphalan caused a 3% leukemia rate among 1129 patients with ovarian cancer who were followed for a median period of 4 years. No leukemia was observed among 1132 breast cancer patients treated with adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) after a median follow-up of 7.5 years. Long-term, comprehensive studies are needed to improve the current knowledge and the prognosis of patients with second primary neoplasms.

Antineoplastic Agents↗
PubMed1991

[The significance of hormone receptor content in primary tumors for cytostatic therapy of advanced breast carcinoma].

The influence of the hormone receptor content in the primary tumor on the survival of 83 non-selected patients with advanced breast cancer who underwent cytostatic chemotherapy was investigated. 89% of the patients received anthracycline-containing regimens. There were no significant differences between receptor-positive and receptor-negative patients with regard to the localization of metastases. No survival advantage from the start of chemotherapy was found in the overall group of patients with estrogen-receptor-(ER-)positive and/or progesterone-receptor-(PR-)positive tumors. However, separate analysis of the ER-status revealed a significant survival advantage for patients with positive ER compared to those with negative ER (median survival of 18 months from the start of chemotherapy in ER-positive patients versus 9 months in ER-negative patients). These data indicate that the ER-status in the primary tumor may have an impact on the survival of patients treated with cytotoxic chemotherapy for their advanced disease.

Adult↗
PubMed1990

Antineoplastic efficacy of melphalan and N-(2-chloroethyl)-N-nitrosocarbamoyl-omega-lysine, in combination with diazoxide or insulin in autochthonous mammary carcinoma of the Sprague-Dawley rat.

The anticancer activity of melphalan and N-(2-chloroethyl)-N-nitrosocarbamoyl-omega-lysine (CNC-omega-Lys), was compared in the autochthonous, methylnitrosourea-induced mammary carcinoma of the Sprague-Dawley rat. In addition, the influence on the therapeutic efficacy of the combination with diazoxide, causing a mild, reversible diabetes, and with insulin was investigated. The comparison of melphalan and CNC-omega-Lys clearly showed the superiority of melphalan. Both compounds displayed a significant tumour inhibition in their medium and the highest dosages in comparison to the untreated control. The combination with diazoxide resulted for almost all groups in an increased tumour inhibition. Only the lowest dose of CNC-omega-Lys + diazoxide did not reduce the tumour volume significantly versus the control group. The combination with insulin, however, resulted in a loss of tumour inhibition compared to the effect of the cytotoxic drug alone, although in these groups, too, a significant decrease of tumour volumes versus controls could be observed. Mortality was within tolerable limits (less than 20%) through the treatment period for all experimental groups. Median lifespans were increased in all therapy groups, but no additional benefit could be observed in the combination treatment groups.

Animals↗
PubMed1990

Anticancer-agent-linked phosphonates with antiosteolytic and antineoplastic properties: a promising perspective in the treatment of bone-related malignancies?

Bisphosphonates are compounds with a high affinity for bone and other calcified tissues. They inhibit tumor-induced bone destruction and the associated hypercalcemia by hindering the activity of the osteoclasts. Owing to a long biological half-life of bisphosphonates in the bone, a treatment using a prophylactic regimen seems possible. This paper summarizes preclinical studies with the bisphosphonate 3-amino-1-hydroxypropylidene-1,1-diphosphonic acid and two methyl derivatives; 3-N,N-dimethylamino-1-hydroxypropylidene-1,1-diphosphonic acid and 4-N,N-dimetyhlamino-1-hydroxybutylidene-1,1-diphosphonic acid with respect to their bone-protecting activity in therapy as well as in prophylaxis. To find substances that are useful for the treatment of primary tumor, as well as bone metastasis, we synthesized and tested cis-diammine[nitrilotris(methylphosphonato)(2-)-O1,N1]platin um(II) and cis-diammine[( bis-(phosphonatomethyl)amino]acetato(2-)-O1,N1)platinum(II), which contain both an osteotropic and an antineoplastic moiety. Experiments were carried out: (a) in the intratibial transplanted Walker carcinosarcoma 256B of the rat, which mimics osteolytic bone metastasis, and (b) in the transplantable osteosarcoma of the rat, which shows a histology and metastatic pattern similar to that found in man. These investigations indicate that it is possible to effect adjuvant therapy of bone metastases by combination of two compounds with different properties into one structure without losing the therapeutic characteristics of the parent compounds. They thus provide evidence that it may be possible to design compounds well suited for the therapeutic or prophylactic treatment of bone-related malignancies.

Animals↗
PubMed1990

An oestradiol-linked nitrosourea and site-directed chemotherapy in mammary carcinoma.

The half-life, peak concentration, peak accumulation and tissue availability of the DNA-crosslinking nitrosourea 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine (CNC-alanine) and its oestradiol-linked derivate (CNC-alanine-oestradiol-17-ester) were studied in liver, lung, spleen, uterus and mammary carcinomas in female Sprague-Dawley rats with chemically induced mammary carcinomas. Compared with CNC-alanine, the ester had a longer half-life, higher peak concentration, increased peak accumulation and enhanced tissue availability in all tissues. In oestradiol receptor positive mammary carcinomas, the oestradiol-linked drug showed a 2 times higher peak concentration, a 5 times longer half-life, a 10 times increased peak accumulation and a 20 times greater tissue availability compared with CNC-alanine. Oestradiol-linked nitrosoureas may offer new perspectives for site-directed chemotherapy of oestradiol receptor positive breast cancer.

Alanine↗