[In memoriam Anton Kerschensteiner, M.D].
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Biomedical subjects
Publications and source records attributed to D Gericke.
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The effect of a local pretreatment by radio-frequency hyperthermy upon the capability of germination and, hence, upon the oncolysis by intravenously given spores of oncolytic clostridia (M55) was tested with 2305 NMRI-mice carrying neck tumors. Using two different experimental tumors (Ehrlich adenocarcinoma and Harding-Passey-melanoma) it is possible to show the dependence of the intensification on the thermic dose. Additionally, there is a distinct dependence of the extent of oncolysis on the time interval between the hyperthermy treatment and the administration of clostridia. The intensification effect in both the tumors is mostly marked twelve hours after hyperthermy. The rapidly growing Ehrlich adenocarcinoma regenerates more quickly than the slowly growing Harding-Passey-melanoma. A period of 12 hours between hyperthermy and injection of clostridia represents a favourable interval for the timing of slowly as well as of rapidly growing tumors.
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In solid experimental tumors hypoxic cells preferably are inactivated by means of a short-termed radio-frequency treatment with eddy-current fields. Hence follows an increase of the necro-biotic areas. The presence of anoxic-necrobiotic areas is indispensable for the termination of certain anaerobic spores such as Clostridium butyricum s. oncolyticum (M 55). Local tumor hyperthermy is tested as a technique in altogether 861 mice bearing neck tumors, in order to enhance the germination of oncolytic Clostridia in tumors differing by their mode of formation and rate of growth. In all the three test systems used (Ehrlich solid carcinoma, Harding-Pasey-melanoma, fibrosarcoma induced by methylcholanthrene), the oncolysis being brought about by Clostridia can be intensified significantly by means of a short-termed warming of the tumor up to temperatures of 42 to 44 degress C using radio-frequency.
Mycoplasma must certainly be considered infectious agents in malignant tumors which actually show a certain affinity for tumor tissue. Under certain conditions their oncogenic potency must be conceded, and this is also true of questions of therapeutic efficacy. But all these problems have only been outlined so far and great efforts are required from many laboratories before a final assessment is possible.
Inhibition of DNA polymerase from oncorna viruses by a new class of macromolecular inhibitors is reported. The macromolecule, designated as mercaptopolycytidylic acid (MPC), is a chemically modified polycytidylic acid containing 5-SH cytidylic bases in the polymerase. Partially thiolated polycytidylic acids (MPC I-III, containing 1.7%, 3.5%, and 8.6% 5-mercaptocytidylate units, respectively) inhibited the DNA-polymerase of Friend leukemia virus (FVL) in the endogenic reaction as well as in the presence of poly rA-(dT)14 or poly (dA-dT) templates; the inhibitory activities were directly related to the percent of tholation. In a bacterial DNA polymerase (E coli-K12 with denatured calf thymus DNA as template) MPCI-III showed no activity. Biological experiments showed that MPC III inhibits the leukemogenic potential of cell-free spleen extracts from FVL-infected mice to about 60%, measured on the basis of spleen weight. The enzymatic and animal experiments have led us to carry out preliminary clinical trials in some cases of Children leukemia. These cases, resistent to the known therapeutic regimes (combination chemotherapy), responded well when treated with MPC along, or in combination with poly I. The experiments indicate that the development of modified polynucleotids with structural similarities to functional templates may be of potential use in the future chemotherapy of leukemia.
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Twenty-seven new derivatives of the 3-N,N-bis-(2-chlorethyl)-amino-4-methyl-benzoic-acid were synthesized and pharmacologically examined. The compounds showed to be highly active in the in vitro-vivo screening models (Crocker sarcoma 180, Sa-180; Friend virus leukemia, FVL) but less active in the in vivo screening models (leukemia L-1210; L-1210; Nemeth-Kellner lympho-sarcoma, NKL). The in vivo tumor growth inhibitions show that this class of compounds has possibilities for further improvement.
Spores of the apathogenic clostridium butyricum (M 55) germinate after intravenous application in mammalians in tumor tissue only. On the basis of these earlier findings a diagnostic and prognostic procedure, used so far, namely the agglutinationtest with vegatative forms of this clostridium was improved by creation of a hemagglutination reaction. With different methods some different hemagglutinins have been isolated. Their efficacy was tested against specific antibodies in rabbits and mice. The higher sensitivity of these procedures was demonstrated.
More than 200 nitro compounds, most of them nitroaniline derivatives substituted with one or more radicals having a basic reaction, were prepared and investigated as to their therapeutic activity against bacteria, fungi, protozoa, helminths, viruses and tumors. Several mono-nitrobenzenes with a radical having a basic reaction showed weak in-vitro activity against gram-positive bacteria and against Crocker's sarcoma 180; they also showed systemic activity against nematodes (Aspiculuris tetraptera) and viruses. The majority of therapeutically active compounds with pronounced in-vivo activity against Trichomonas fetus, Entamoeba histolytica, Schistosoma mansoni, cestodes, nematodes (Ancylostoma caninum), viruses (influenza, MHV, SAV and EMC) and various types of carcinoma (Ehrlich's carcinoma, leukemia 1210, Crocker's sarcoma 180) were dinitrobenzene derivatives with one radical having a basic reaction and electropositive groups or unreactive or reactive chlorine atom, and di-nitrobenzene with two equal or two different radicals having a basic reaction. Compound No. 70 revealed a marked in-vitro activity against fungi (Trichophyton; Microsporum, Candida albicans). Other nitro compounds such as bis-mono- and bis-dinitrobenzene derivatives likewise showed a systemic action against E. histolytica, viruses and, in particular, carcinoma (Crocker's sarcoma 180, Ridgway's osteosarcoma). Oxygen and sulfur analogue compounds as well as compounds produced by reduction also possessed a distinct activity against E. histolytica and viruses. On the basis of the present results particularly the dinitrobenzenes substituted with two radicals having a basic reaction include a number which have in common that a structure/activity relationship is recognizable in respect of E. histolytica, Schistosoma mansoni and different types of viruses. The activity against viruses in this class of compounds is probably due to an increased interferon production in the host animal. Whether the mechanism of action is the same against E. histolytica or Schistosoma mansoni has not been determined so far. A tumorigenic effect was observed mainly in those di-nitrobenzenes which are classed as alkylating compounds. Because of the small chemotherapeutic index the trials were not continued with the most effective compounds mentioned.
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