[Anticancer drug research in Hungary, 1950-2000]. / Daganat-kemoterápiás kutatások Magyarországon az 1950−2000 közötti években.

The present review about the history of anticancer drug research in Hungary intends to call attention to the importance of studies on their mode of action. Several lines of evidence suggest that clinically usable oncopharmacological properties could be revealed by this way. Among the numerous compounds certain alkylating sugar alcohols and 2'-deoxyuridine derivatives were submitted to detailed investigations concerning their mode of action. Myelobromol with selective action on the myeloid elements of bone marrow has been justified for its application in chronic myeloid leukemia therapy and also in bone marrow ablation before transplantation. Mitolactol is able to cross bloodbrain barrier, consequently could control certain brain tumors. 5-etil-2'-deoxyuridine by reducing dihydropyrimidine dehydrogenase activity is able to increase 5-fluorouracil concentration in the blood, resulting in improved antitumor effect. In contrast, 5-hexil-2'-deoxyuridine, as an inhibitor of glycoconjugate pathway by reducing heparan sulfate production, has the ability to prevent metastasis. Noteworthy, the remarkable effects of vinca alkaloids, antiestrogens, and GNRH analogues were also presented in this review.

[Action of cyclophosphane and degranol on the T- and B-lymphocyte populations in the lymph nodes when administered endolymphatically]. / Deistvie tsiklofosfana i degranola na populiatsii T- i B-limfotsitov v limfaticheskikh uzlakh pri éndolimfaticheskom vvedenii preparatov.

Experiments on rats demonstrated that endolymphatic administration of high doses of cyclophosphane and degranol produces prolonged but reversible decrease of relative content of T- and B-lymphocytes both in the regional and remote lymph nodes. In early periods after lymphatic infusion there was observed the predominant action of degranol on T-lymphocytes and that of cyclophosphane on B-lymphocytes. Differences in the character of changes in primary immune response magnitude after administration of the drugs are related probably to their diverse effects on different subpopulations of lymphocytes.

[Effect of cyclophosphane, chlorbutin and degranol on protein biosynthesis in the lymphocytes of donors and chronic lympholeukemia patients in vitro]. / Vliianie tsiklofosfana, khlorbutina i degranola na biosintez belka v limfotsitakh donorov i bol'nykh khronicheskim limfoleikozom in vitro.

The alkylating agents in different concentrations are studied for their effect on protein biosynthesis and the relative content of leu-tRNA. The rate of elongation and termination of polypeptide translation in lymphocytes of donors and of patients with chronic lymphoid leukemia in vitro is studied. The therapeutic doses of cyclophosphamide are shown to inhibit the amino acid incorporation into acid insoluble pool of predominantly leukemic lymphocytes, while chlorbutin and degranol caused the greater suppression of the amino acid incorporation into healthy cells. Chlorbutin, cyclophosphamide and degranol in doses above therapeutic caused approximately 95, 48 and 34% inhibition of the protein synthesis, respectively. The mechanism of action on the translation is different. Only chlorbutin acted directly on the translation rate and also increased leu-tRNA content. Degranol decreased the leu-tRNA content. Cyclophosphamide produces no effect on these processes in vitro.

[Correlation of the sister chromatid exchange level with chromosome aberrations induced by chemical mutagens in vivo]. / Korreliatsiia urovnia sestricheskikh khromatidnykh obmenov i khromosomnykh aberratsii, indutsirovannykh khimicheskimi mutagenami in vivo.

The data on the dose dependencies of the induction of sister chromatid exchanges (SCE) and chromosomal aberrations during exposure of mouse bone marrow cells in vivo to 5 alkylating substances are provided. The efficacy of SCE induction was found to be higher than that of chromosomal aberrations. It was established that SCE induced by chemical mutagens in vivo and in vitro are more sensitive and stable tests than chromosomal aberrations.

Effects of perineurally applied cytostatic, cytotoxic and chelating agents upon peripheral and central processes of primary nociceptive neurons.

After perineural application, the effects of mannomustine, cyclophosphamide, tetrameskylmannite, 6-mercaptopurine, azathioprine and d-penicillamine upon structure of peripheral nerves and the substantia gelatinosa Rolandi were studied by means of neurohistochemical techniques and compared to those of the microtubule inhibitors Vinblastine, Vincristine and colchicine. While the cytostatic and cytotoxic drugs induced only sporadic degeneration in the structure of the peripheral nerve and, accordingly, caused only a minor extent of transganglionic degenerative atrophy in the Rolando substance, the chelating agent d-penicillamine causes massive Wallerian degeneration after perineural application and, consequently, induces an extensive degenerative atrophy in the Rolando substance. The destructive effect of d-penicillamine upon conduction properties of the impaired nerve has been established also by means of electrophysiological recording. All the drugs studied differ fundamentally from microtubule inhibitors like the Vinca alcaloids that, by virtue of their blocking effect of axoplasmic transport, induce degenerative atrophy in the Rolando substance after perineural application without causing Wallerian degeneration in the peripheral nerve. Accordingly Vinca alcaloids are the most promising candidates as locally applied therapeutics in intractable pain.

[Effect of cytostatic drugs on the metabolism of incubated human blood platelets]. / Badania nad wplywem leków cytostatycznych na metabolizm inkubowanych krwinek plytkowych czlowieka

Degranol was chosen from the group of cytostatic drugs and Cytosar and Flucrouracil from the group of antimetabolites for investigations on the effects of cytostatics on the metabolism of thrombocytes. After isolation from blood collected on ACD fluid thromtocytes were suspended in own plasma containing EDTA and the cytostatic agent in a concentration of 6 x 10(-3)M and were subjected to incubation during 3 hours at 37 degrees C. After incubation the thrombocyte count, the levels of nucleotide compounds, and adenine nucleotides (ATP + ADP) released by thrombocytes under the action of thrombin, and the activity of dehydrogenase glucose-6-phosphate and lactic dehydrogenase were determined. The results of these determinations showed that only Degranol as a compounds belonging to the group of alkylating cytostatics caused lowering of ATP level (by about 30%) in the incubated cells. The drugs from the group of antimetabolites caused no significant changes in the studied parameters.

Mechanisms of spontaneous and induced heteroploidization and polyploidization.

Mechanisms of heteroploidization and polyploidization were studied in tissue cultures, using various methods and cell lines. In untreated populations cells with different chromosome number are formed by mitotic non-disjunction. Mononuclear polyploid cells are formed by repeated DNA synthesis (endoreduplication) and polynuclear giant cells by postmitotic fusion of the daughter cells. These phenomena occur more frequently in cell populations treated with cystostatic drugs. Most polyploid cells are not viable.

Experimental study of the combined effect of leukeran, degranol and predisolone.

The effect of the combined treatment with leukeran, degranol and prednisolone on the lymphoid tissue and marrow hamopoiesis in rats is studied. The simultaneous administration of these drugs is shown to cause a more effective inhibition of the lymphoid tissue and a less suppression of the marrow, as compared with their separate administration.