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Biomedical subjects

E Scherer

Publications and source records attributed to E Scherer.

At least 55 records · Page 3Linked to original sources
PubMed1986

Modification of DNA and metabolism of ethyl carbamate in vivo: formation of 7-(2-oxoethyl)guanine and its sensitive determination by reductive tritiation using 3H-sodium borohydride.

The modification of liver DNA of mice and rats by ethyl carbamate and its putative proximate metabolite, vinyl carbamate, has been investigated. Following treatment with [ethyl-1-14C]-ethyl carbamate, the main radioactive DNA adduct was identified as 7-(2-oxoethyl)guanine by cochromatography with the authentic marker in several separation systems. After reduction by sodium borohydride (NaBH4) to 7-(2-hydroxyethyl)guanine, the radioactive material again cochromatographed with the respective marker. Reduction of modified liver DNA by 3H-NaBH4, following administration of unlabelled ethyl carbamate or vinyl carbamate, allowed the quantitation of 7-(2-oxoethyl)guanine (as 7-(2-hydroxy-2-[3H]-ethyl)guanine). Vinyl carbamate led to about 100 times as much 7-(2-oxoethyl)guanine (on a molar basis) as did ethyl carbamate. Both the formation of 7-(2-oxoethyl)guanine by ethyl carbamate and vinyl carbamate, and the much higher activity of the latter compound, strongly support the existence of the metabolic activation pathway, ethyl carbamate----vinyl carbamate----epoxyethyl carbamate, as proposed by Dahl et al. (1978, 1980). The possible role of 7-(2-oxoethyl)guanine in the initiation of the carcinogenic process is discussed in view of the structural equilibrium with its hemiacetal conformation, O6,7-(1'-hydroxyethano)guanine. In the latter conformation, it is assumed to represent a promutagenic lesion. In addition, intrastrand cross-links between modified guanine and adjacent cytosine or adenine seem possible and may have promutagenic consequences. Replication of DNA containing such lesions may lead to the induction of mutations. This may be a critical event in the initiation, and eventually progression, of the carcinogenic process as determined by ethyl carbamate and other carcinogens, such as vinyl chloride, which lead to the same DNA modification.

Animals↗
PubMed1985

Immunohistochemical localization of O6-ethyldeoxyguanosine and deoxyguanosin-8-yl-(acetyl)aminofluorene in liver sections of rats treated with diethylnitrosamine, ethylnitrosourea or N-acetylaminofluorene.

Antibodies raised in rabbits against the bovine serum albumin conjugates of O6-ethylguanosine (O6-EtGuo) and N-(guanosin-8-yl)-N-acetyl-2-aminofluorene (Guo-8-AAF) have been used in a double peroxidase-antiperoxidase staining assay to visualize the localization of DNA-O6-ethyldeoxyguanosine (O6-EtdGuo) and some of the interaction products of N-acetyl-2-aminofluorene (AAF) with DNA guanine in liver sections of rats treated with diethylnitrosamine (DEN), ethylnitrosourea (ENU), or AAF respectively. O6-EtdGuo could be detected in nuclei of parenchymal cells after injection of DEN (12-50 mg/kg) or ENU (140 mg/kg). Clear time and dose dependencies were observed. The lowest dose of DEN which, at 5 h after injection, resulted in immunohistochemically detectable levels of O6-EtdGuo, was 12 mg/kg; 5 h after 6 mg/kg no consistent difference between treated and untreated rats could be observed. A striking heterogeneity in staining pattern was observed after DEN: centrilobular regions were stained much more than peripheral zones. At 7 days after a single DEN injection of 50 mg/kg small rims of significantly stained hepatocytes could still be observed around the central veins. No heterogeneity of staining pattern was observed 2 h after ENU. ENU, in contrast with DEN, also resulted in a significant staining of nonparenchymal cells. At 24 h after ENU no significant staining of hepatocytes could be detected, but positive staining was still present in bile duct cells, vascular endothelial cells and sinusoidal cells. The results indicate a detection level of approximately 5 mumol O6-EtdGuo/mol DNA-P, i.e., 5 X 10(4) O6-EtdGuo residues per diploid genome. Using the anti-Guo-8-AAF antiserum, positive results were obtained 6 days after a single AAF dose of 0.5-10 mg/kg, corresponding to a detection limit of less than or equal to 0.4 mumol dGuo-8-(A)AF/mol DNA-P. Staining was rather homogenously distributed over the liver lobules. Persistency of the AAF-DNA interaction products was investigated both after 10 and 2 mg/kg AAF. Increased nuclear staining could be observed up to 8 weeks after 10 mg/kg and 4 weeks after 2 mg/kg.

2-Acetylaminofluorene↗
PubMed1985

[Treatment possibilities of recurrences of lymphogranulomatosis].

The authors present seven typical cases chosen from a group of thirty patients with recurrent Hodgkin's disease. One out of these patients suffered from two recurrences, five patients from three recurrences each, and one patient from six recurrences. The observation period, beginning with the primary treatment, was between five and 16 years. None of the patients was exclusively irradiated or only treated by cytostatic drugs. Therefore after primary radiotherapy in the stages I to III A, later recurrences could often be successfully treated by an alternating application of cytostatic drugs and repeated radiotherapy. After primary chemotherapy of the advanced primary stages III B to IV B, too, a remission of the second and third recurrence could often be achieved by radiotherapy. Furthermore, the application of alternative schemes such as Holoxan-Vepesid has to be taken into account in the treatment of recurrences. The repeated application of C-MOPP after an interval of at least twelve months also produces good rates of response. The present results allow to make the conclusion that a successful treatment of the second and third and even of further recurrences is possible by a combined application of irradiation and cytostatic therapy.

Adolescent↗
PubMed1985

[Reduced-dose adjuvant CMF-chemotherapy combined with postoperative irradiation in breast cancer with lymphatic metastases. A prospective study of 45 patients].

From 1978 to 1982, 45 postoperative cases of breast cancer with lymphatic spread received radiation to the chestwall and axillary, supra- and infraclavicular lymph nodes up to 40 Gy. In addition, we gave 600 mg cyclophosphamide, 50 mg methotrexate and 750 mg 5-fluorouracil intravenously on day 1 of altogether nine 21-day cycles. The median follow-up is 37 months, and we calculate a 5-year over-all actuarial survival-rate which was 83% in the premenopausal and 77% in the postmenopausal patients. The disease-free 5-year survival-rate was 74% for the premenopausal and 61% for the postmenopausal women. There were twice as many patients with stage N2 in the postmenopausal group. No severe side-effects were observed. These promising preliminary results and the good tolerance of the above-mentioned combined therapy recommend it for future randomized studies.

Adult↗
PubMed1985

[Effect of antineoplastic agents and ionizing radiation on a human testicular cancer heterograft].

Chemotherapy has afforded a high percentage of definitive cures in advanced testicular cancer. Nevertheless some patients with large tumor burden still succumb to chemorefractory disease. Therefore preclinical and clinical evaluation of new drugs and agents not primarily used against this type of disease are still mandatory. For preclinical drug screening purposes heterotransplantation of specific human tumors yields a model with high validity for tumor markers and drug response. Heterotransplantation of a human embryonal testicular cancer was used for simultaneous testing of established agents such as cisplatin, melphalan, bleomycin, vinblastine, etoposide and adriamycin and some newer derivatives such as PHM or mafosfamide. Furthermore agents such as procarbazine, dacarbazine and methyl-CCNU that cross the blood-brain-barrier displayed some interesting activity. The results hint at a unique chemosensitivity pattern of the xenograft line, with some accordance between clinical response to vinblastine and bleomycin and good response of the xenografts to bleomycin but not to vinblastine. Radiotherapy was also effective against this tumor line, but there was not much difference in response when the schedule of fractionation was changed. It is concluded that a combined modality approach might salvage patients with residual, chemorefractory disease.

Animals↗
PubMed1985

Neutron and neutron boost irradiation of soft tissue sarcomas.

The results of neutron and neutron boost irradiation of 199 patients with soft tissue sarcomas treated between 1978 and 1983 are presented. The median follow-up period is 42 months. The recurrence free survival rates by last review are 93% for patients with T1 tumours (n = 14), 87% for T2 tumours (n = 84) and 73% for T3 tumours (n = 101). The actuarial survival rates at six years are 77% for T1, 63% for T2 and 34% for T3 tumours (p = 0.018). The actuarial survival rate for the group of patients irradiated after surgery without clinical evidence of residual tumour is 63.8% compared with 30.9% for the group of patients with measurable tumour volume at the beginning of radiotherapy (p = 0.002). The survival rates according to grading are 52% for patients with G1 tumours (n = 44), 54% for G2 tumours (n = 130) and 36% for G3 tumours (n = 25). The morbidity rate of 22% after full neutron irradiation was reduced to 15% by the introduction of a neutron boost. At the present time, the results of this modified treatment are not inferior to a full neutron course. The effectiveness of neutron or neutron boost irradiation in the postoperative treatment of soft tissue sarcomas will be evaluated in a forthcoming EORTC trial.

Fast Neutrons↗
PubMed1984

Neoplastic progression in experimental hepatocarcinogenesis.

The evolution of cancer through a series of progressive steps is discussed in the rat liver model on the basis of the multi-hit-multi-step hypothesis. The available evidence for this hypothesis is reviewed with special attention to its kinetic aspects. The neoplastic cell stages which can be distinguished during the protracted developmental process leading from the early precancerous foci to the malignant hepatocellular carcinoma are discussed in the light of the histological evidence for step-by-step progression manifested as focus-in-focus lesions. The inducibility of progression of the early precancerous foci to the transplantable neoplastic nodule stage by a new experimental protocol of the initiation-promotion-initiation type is indicative of the operation of a common molecular mechanism, i.e., somatic mutation, during the first and later steps of the carcinogenic process.

Animals↗
PubMed1984

[Successful treatment of choroid hemangioma with secondary changes caused by Sturge-Weber syndrome].

A 12 year old patient was treated for Sturge-Weber syndrome with choroidal haemangioma and total exsudative retinal detachment. The diagnosis was supported by echography and thin-layer computed tomography. Because of the exsudative retinal detachment photocoagulation could not be performed. Treatment by percutaneous radiotherapy with Caesium 137 was performed. The retina was reattached by application of 30 Gray. A flat pigmented scar developed in the area of the haemangioma at the posterior pole of the eye. No side effects appeared. The follow-up time is 26 months.

Adolescent↗
PubMed1984

Radiotherapy of soft tissue sarcomas with neutrons or a neutron boost.

A cooperative trial of neutron therapy for soft tissue sarcomas was started in 1978. 112 unselected and not previously irradiated patients (62% T3 tumours, 35% recurrent tumours) were treated up to June 1982 with neutrons alone. An analysis of these cases with a mean follow-up period of 22 months (range 12 to 45 months) is given in this report. Very preliminary results are presented for 60 patients treated with a neutron boost only. These showed a substantially lower complication rate. The major results of this phase II trial are: The survival rate of 3.5 years was strongly dependent on the stage of the tumour; for 8 patients with T1 tumours it was 100%, for 35 patients with T2 tumours, 77%, and for 69 patients with T3 tumours, 45%. The survival rate at 3.5 years was strongly dependent on surgery before the beginning of radiotherapy; for 54 patients after surgery without clinical evidence of residual tumour it was 73%, for 58 patients with inoperable primary or recurrent tumour, 47%. The survival rate of 31 patients with recurrence after neutron therapy was only 36%. The overall rate of serious complications was 28.6% after neutron therapy, but only 5% after neutron boost therapy (mean follow-up period: 12 months, range 5 to 48 months).

Follow-Up Studies↗
PubMed1984

[Current state and possibilities of radiotherapy in the inter- disciplinary treatment of malignancies of the stomach, pancreas and bile ducts. I. Stomach cancer].

Surgery is undoubtedly the therapy of choice in case of the advanced carcinoma of the stomach. In spite of more and more radical and extended operation techniques, the extremely unfavorable prognosis could not be improved. Based on experiences gained with palliative irradiations, the efficacy of radiotherapy can be considered to be proved. Its difficulties and problems are due to the topographic position of the stomach and to the radiosensitivity of the stomach and the adjacent organs. An additional application of radiotherapy seems sensible regarding the high rate of local recurrences and regional lymph node metastases following surgery (about 90%). The greatest effect of radiotherapy is to be expected in case of intraoperative application - alone or combined with postoperative percutaneous irradiation. However, the therapeutic effect of fast neutrons, hyperthermia, radiosensitizers has not been explored yet. The occurrence of remote metastases besides local recurrences in about 25% of all cases and the available results of some smaller studies suggest a therapeutic advantage to be obtained by an additional systemic cytologic therapy. The authors present the surgical, radiotherapeutic, and chemotherapeutic results achieved hitherto in the treatment of the advanced carcinoma of the stomach. Further possibilities for the future use of radiotherapy are proposed in order to encourage the establishment and application of interdisciplinary therapy conceptions.

Cisplatin↗
PubMed1984

[Present status and possibilities of radiotherapy in the interdisciplinary treatment of malignant tumors of the stomach, pancreas and bile ducts. III. Extrahepatic bile ducts and gallbladder].

The malignant tumors of the gall bladder and the extrahepatic bile ducts belong to those having the most unfavorable prognosis. Similarly to the carcinomas of the pancreas, most of these tumors are in a very advanced stage when they are diagnosed. The survival times have not been improved by radical and ultraradical operation techniques, the operation mortality, however, has increased. In the meantime, the efficacy of radiotherapy has been proved for these tumors, too. So an additional application of radiotherapy seems indicated regarding the fact that most of these patients present postoperative locoregional recurrences. As for the carcinomas of the stomach and the pancreas, the best effect of radiotherapy can be expected in case of an intraoperative irradiation; furthermore direct percutaneous intraductal irradiation techniques have been developed for suitable cases. A possible efficacy of additional chemotherapy cannot be assessed yet; a locally adjuvant effect, as in patients with carcinoma of the pancreas, could be imagined. The authors present the surgical, radiotherapeutic, and chemotherapeutic results achieved hitherto in the treatment of the carcinomas of the extrahepatic bile ducts and the gall bladder and propose further possibilities for the future use of radiotherapy. After the failure of surgery alone an improvement of the bad prognosis of these carcinomas by cooperative therapy conceptions is a vital necessity, the more as the role of obstructive jaundice as fatal factor has been eliminated by the non-surgical percutaneous transhepatic drainage of bile ducts.

Bile Duct Neoplasms↗
PubMed1984

Initiation-promotion-initiation. Induction of neoplastic foci within islands of precancerous liver cells in the rat.

The hypothesis that during the promotion phase of carcinogenesis a second rare event leads to a promoter-independent tumour cell was tested in an initiation-promotion-initiation type of experiment. Precancerous (island) cells induced in rat liver by 10 mg/kg N-nitrosodiethylamine given 24 h after partial hepatectomy were promoted by a protocol consisting of 2-acetylaminofluorene/partial hepatectomy. Administration of 25-100 mg/kg N-ethyl-N-nitrosourea served as second initiater. Microscopic foci of neoplastic cells were observed within the precancerous islands 66 days later; no such foci were noted in the appropriate controls. Deficiency of adenosine triphosphatase and glucose-6-phosphatase marker enzymes in the foci was more pronounced than in the surrounding island cells; glycogen storage was decreased and cytoplasmic basophilia slightly increased; gamma-glutamyltranspeptidase staining was negative or decreased with respect to the surrounding island cells, which exhibited a partially positive reaction. We conclude that a secondary change produced by N-ethyl-N-nitrosourea in precancerous island cells leads to focus-forming cells which grow, in the absence of promoter, into foci of neoplastic phenotype. Similar rare, initiation-like events might be involved in the process of tumour promotion in general.

2-Acetylaminofluorene↗