[Effect of a new benzodiazepine derivative on experimental malignant melanomas]. / Die Wirkung eines neuen Benzodiazepin-Derivates auf experimentelle maligne Melanome.

It was found, that (+)cis-3,4-dimethoxy-10,11-dimethyl-6,6aR,7,8,13, 13aS-hexahydro-[I]-benzopyrano-[4,3-b]-1,5-benzodiazepine (ZIMET 54/79) increased the life span (ILS) of C57BL/6/Jena mice suffering from transplanted B16 melanoma (ip.) by 57% (9 times ip. 250 mg/kg) and 90% (9 times ip. 500 mg/kg) respectively. In B6D2F1/Bln mice with transplanted B16 melanoma there was no ILS registered when a dose of 100-500 mg/kg was applied (ip. and p.o.). Using the Harding Passey melanoma (B6D2F1/Bln mice) only 59% tumour volume inhibition (500 mg/kg) without ILS was obtained. Finally ZIMET 54/79 tested on AMel 3 hamster melanoma (strain Z3) decreased the mean tumour volume by 72% (125 mg/kg).

[The synthesis and biologic activity of analogs of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone. 2. Substitution at the quinone ring by alkyl groups]. / Zur Synthese und biologischen Wirksamkeit von Analogen des 1,4-Benzochinon-guanylhydrazon-thiosemicarbazons. 2. Mitteilung: Substitution am Chinonring durch Alkylreste.

Because of the anticancer activity of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (1a) some analogues were synthesized, containing alkyl groups at the quinone moiety. If necessary, the structure of the obtained compounds was confirmed by 1H-NMR-spectroscopy. The anticancer and the antibacterial activities were investigated. The guanylhydrazone-thiosemicarbazones of tolu-,p-xylo-and thymo-quinone showed much lower activities not only against the murine leukemias L 1210 and P 388, but also against Bacillus subtilis ATCC 6633. No correlation could be found between the biological activity and the redox potential.

[Synthesis and biological activity of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone analogs. 1. Substitution at the S atom]. / Zur Synthese und biologischen Wirksamkeit von Analogen des 1,4-Benzochinon-guanylhydrazon-thiosemicarbazons. 1. Mitteilung: Substitution am S-Atom.

The synthesis of S-substituted derivatives of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone is described. The obtained 1,4-benzoquinone-guanylhydrazone-S-alkyl (resp. aralkyl)-isothiosemicarbazones, in comparison with the unsubstituted standard compound, showed a significantly decreased biological activity against the murine leukemias L 1210 and P 388 as well as against the growth of several kinds of bacteria. Therefore the S-substitution seems not to be useful for reaching a maximum activity.

[N-quaternary derivatives of tilorone]. / N-quartäre Derivate des Tilorons.

Tilorone (free base) reacts with alkyl halides forming quaternary ammonium salts. Bis- as well as mono quaternary compounds (2 resp. 3) were synthesized. The tilorone-bis-methoiodide (2a) was converted to several carbonyl derivatives (4 and 5). All produced compounds did not show any cytostatic activity against the murine leukemias L 1210 and P 388 in vivo. Especially the bis-quaternary derivatives 2 were highly toxic in the mouse.

[Biological activity of transition metal complexes. 5. Effect of dimethyl sulfoxide on the cytotoxic, antiviral and antitumoral properties of cis-dichlorodiammineplatinum (II): "cisplatin"]. / Uber biologische Wirkungen von Koordinationsverbindungen der Ubergangsmetalle. 5. Zum Einfluss von Dimethylsulfoxid auf die zytotoxischen, antiviralen und antitumoralen Eigenschaften von Cis-dichloro-diammin-platin (II): "Cis-Platin".

In water or dimethyl sulfoxide solutions cis-platinum is subject of time depending solvolytic reactions leading to compounds with different biological effectivity. Whereas the inactivation of vaccinia, vesicular stomatitis and adeno virus type 5 was not changed if dimethyl sulfoxide or dimethyl formamide instead of destilled water were used as solvents, long time stored solutions of cis-platinum in dimethyl sulfoxide were tolerated by cells cultivated in vitro in 8-25 times higher concentrations in comparison with a freshly solved preparation. Their antiviral effectivity was maintained. On the other hand experiments with mice showed that simultaneously with the decrease of toxicity of an aged cis-platinum solution in DMSO also its antileukemic activity disappeared. In a 5 weeks old cis-platinum solution in destilled water antitumor activity was preserved in spite of enhanced toxicity.

[Antineoplastic and curative antileukemic activity of 1,4-benzoquinone guanylhydrazone thiosemicarbazone and its hydrochloride on in vivo murine models]. / Tumorhemmende und kurative antileukämische Wirksamkeit von 1,4-Benzochinonguanylhydrazonthiosemicarbazon und dessen Hydrochlorid an murinen Testmodellen in vivo.

By means of four murine models, the authors demonstrated in vivo that 1,4-benzoquinone guanylhydrazone thiosemicarbazone (1), which is known to be antimicrobially active, and its hydrochloride (2) exert an antineoplastic effect. In leukaemia P 388 and leukaemia L 1210 both compounds had a curative action already after four oral administrations. The "cured" animals were resistant or cross-resistant to further transmissions of leukaemia. The resistance was transmissible by splenocytes.

[Differences in the Ca2+- and calmodulin-sensitivity of cyclic nucleotide phosphodiesterase [PDE] in microtubule preparations from brain and Ehrlich-ascites-tumor cells [EAT]]. / Unterschiede in der Ca2+- und Calmodulin-Empfindlichkeit der zyklischen Phosphodiesterase (PDE) in Mikrotubulipräparationen aus Hirn und Ehrlich-Aszites-Tumorzellen (EAT).

In MTP preparations from brain and EAT (isolation by the method of Doenges et al. 1977) assembled in vitro by two cycles of polymerization and depolymerization, differences appeared in the activation of the cAMP-phosphodiesterase by Ca2+ and Calmodulin. cAMP-PDE-activity in the MTP from brain is not influenced by Ca2+ or Calmodulin. However the PDE-activity in the EAT-MTP is decreased by Ca2+ (!) and is increased by Calmodulin. cGMP-PDE-activity is present in brain-MTP, and in contrast to this it is absent in MTP from EAT.

[Antineoplastic activity of lambdamycin in different murine test models compared with cyclophosphamide, 6-mercaptopurine and 5-fluorouracil (author's transl)]. / Antineoplastische Wirksamkeit von Lambdamycin an verschiedenen murinen Testmodellen im Vergleich zur Wirkung von Cyclophosphamid, 6-Mercaptopurin and 5-Fluoruracil.

Lambdamycin, a chromoglycoside antibiotic like chartreusin was found to be very active against leukemias L 1210 and P 388 and moderate effective against melanoma B 16 and Lewis lung carcinoma of mice. It was nearly without any effect when tested on Walker 256 carcinoma of rats. The effectiveness of lambdamycin was compared with that of cyclophosphamide, 5-fluorouracil and 6-mercaptopurine.

Griseorubins, a new family of antibiotics with antimicrobial and antitumor activity. II. Biological properties and antitumor activity of the antibiotic complex griseorubin.

The antibiotic complex griseorubin has antimicrobial activity against Gram-positive as well as -negative bacteria, mycobacteria, mycoplasma and protozoa in vitro but it is not active against yeast and fungi. Tests with transplantable rodent tumors indicate that griseorubin is inhibitory to the growth of lymphatic leukemia L1210 in mice and Zajdela ascites hepatoma in rats. The acute LD50 of griseorubin in mice is 50 mg/kg of body weight when given intraperitoneally. Attempts to potentiate the antitumor activity by complexing with DNA proved to be unsuccessful.

Beta-[1-Phenyl-5-bis(beta-chloroethyl)-amino-benzimidazolyl-(2)]-DL-alanine (ZIMET 3164): an immunosuppressant without marked anti-cancer effect.

ZIMET 3164 inhibited the growth of sarcoma 180 P, sarcoma 180 G, and Walker 256 carcinosarcoma, but was unable to prolong the survival time of mice bearing Ehrlich ascites carcinoma or the leukaemias L 1210 and LAJ I to a worthwhile extent. The primary and secondarantly suppressed in mice. The drug exerted maximum effect when given on days--2 to +2 relative to antigenic stimulus. Administration exclusively prior to immunization induced only moderate immunosuppression while injection afterwards failed to affect the primary response at all, suggesting that the drug interfers with the afferent limb of immune response. In general, ZIMET 3164 proved to be half as effective as cyclophosphamide, but more effective than chlorambucil.

[Cancerostatically active 6,6a,7,8,13,13a-hexahydro-1-benzopyrano[4,3-b]-1,5-benzodiazepine diastereoisomers (author's transl)]. / Cancerostatisch wirksame 6,6a,7,8,13,13a-Hexahydro-1-benzopyrano[4,3-b]-1,5-benzodiazepin-Diastereoisomere.

The action of many psychotropic drugs on the adenylate cyclase system and its role in the regulation of tumour cell division justify the expectance that potentially psychotropic 1-benzopyrano[4,3-b]-1,5-benzodiazepine derivatives (3a,b and 6a,b) will also exert a cancerostatic effect. The synthesis of 6,6a,7,8,13,13a-hexahydro-1-benzopyrano[4,3-b]-1,5-benzodiazepines (4a and b) and their separation into the antileukaemic (L 1210) cis-forms and the inefficacious trans-forms are described. The cis-form 5a, unlike the trans-form 6a, stimulated the adenylate cyclase system.

[Carbonyl derivatives of tilorone. Part 2: On the cancerostatic activity of carbonyl derivatives of tilorone (author's transl)]. / Carbonylderivate des Tilorons. 2. Mitteilung: Zur cancerostatischen Wirksamkeit von Carbonylderivaten des Tilorons.

A series of carbonyl derivatives of tilorone was synthetized by reaction with appropriate amino compounds, mainly hydrazines and hydrazides. The condensation products obtained were tested for cancerostatic activity against the murine leucaemia L 1210 and the Walker carcinosarcoma of the rat. Only three of the substances under investigation (1a, 5, 13) proved active against the Walker carcinosarcoma, one of which (5) being comparable to tilorone. No activity against L 1210 was observed, even tilorone exerted no effect. The reduction in activity against the Walker carcinosarcoma which resulted from the carbonyl substitution might be caused by a decrease in the ability to intercalate into DNA.

[Antineoplastic effects of violamycins depending on the number of sugar-components in the molecule (author's transl)]. / Zur antineoplastischen Wirkung der Violamycine in Abhängigkeit von den im Molekül enthaltenen Zuckern.

Violamycin B, an antibiotic-complex, inhibited the growth of Sarcoma 180 in a well defined manner. The products Violamycin A, BII, and BI obtained by gelfiltration, were tested against the lymphoid Leukemia L1210. The results showed an increase of the toxicity and, simultaneously, a decrease of the antineoplastic effect, depending on the number of the sugar-components.

[Inhibition of concanavalin A and phytohemagglutinine P mediated agglutination of L 1210 cells by different azomethines and possible relations to their cytostatic activity (author's transl)]. / Hemmung der durch Concanavalin A und Phytohämagglutinin P vermittelten Agglutination von L 1210-Zellen mit verschiedenen Azomethinen und mögliche Beziehungen zu deren zytostatischer Wirksamkeit.

Compounds of a special azomethine type have been tested on their activity against concanavalin A and phytohemagglutinine P mediated agglutination of leukemia L 1210 cells. With exception of two compounds possessing a bis-(beta-hydroxyethyl) amino group at the phenyl moiety in para-position to the azomethine group all substances considerable inhibited agglutination of L 1210 cells. In vitro active concentrations are also obtained in animal experiments at least for a short time at the site of injection (i.p.) The importance of cellular reactions for effectivity in vivo is discussed.

Effect of potential cytostatic and immune modulating chemicals on the plasma membrane of red blood cells (RBC) as revealed by osmotic hemolysis, cell electrophoresis and scanning electron microscopy (SEM).

The influence on red blood cells (RBC) of two cancerostatic-(ZIMET 3106 and ZIMET 3393) and two immunomodulating agents (ZIMET 3164 and ZIMET 86/76) administered subcutaneously, or intraperitoneally in case of the radiolabelled N-mustard compounds, to mice, was studied by means of measurements of the radiolabelled compounds in blood, by cell electrophoresis, filipin-induced hemolysis of pretreated RBC and by scanning electronmicroscopy. The portion of doses applied which binds to RBC-surface decreases in the sequence of ZIMET 3106, ZIMET 3164, ZIMET 3393 and ZIMET 86/76. However, the highest reduction of the electrophoretic mobility and protection from filipin-induced hemolysis of pretreated RBC was found with ZIMET 3164. In both tests ZIMET 86/76 proved to be ineffective. These findings are in good agreement with the modifications demonstrated in pretreated RBC after filipin-induced hemolysis by means of SEM. The results presented point to a N-mustard specific interaction between the cholesterol of the membrane and/or other membrane constituents. However, these fundamental differences found in binding affinity, surface-charges and membrane interactions caused by the chemically similar compounds cannot be attributed merely to the N-mustard group.