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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.

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.

Eight of fifteen Fluorenone-Azomethines without alkylating function have been found effective against the leukemia L 1210. Little modifications concerning the structure of the compounds caused loss of effectiveness. It seems remarkably that one corresponding derivative with a nitrogen mustard group (4) was ineffective. Correlations between chemical structure and biological effect have not yet been found.

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.

Lambdamycin-producing strains were detected by means of the BIP test method. The isolation technique and the physicochemical and biological properties of lambdamycin, an antibiotic produced by Streptomyces glaucoachromogenes, are described. Lambdamycin is a yellow-green pigment of the chromoglycoside type. Digitalose and fucose are the sugar components. The physicochemical properties of lambdamycin resemble those of chartreusin. However, the known biological activity is different. The antibiotic can be isolated from culture filtrates and from the mycelium by extraction with lower aliphatic alcohols. It can be purified by gel filtration methods. Lambdamycin displays antimicrobial activity, particularly against grampositive bacteria. Strains which produce enzymes inactivating different commercial antibiotics are also inhibited. Moreover, lambdamycin shows antiviral activity, as well as cancerostatic and ergotropic action in vitro and in vivo. The acute LD50 of lambdamycin in mice after 21 days was greater than 125 mg/kg when administered intraperitoneally.

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.

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.

The cytoxicity of 10 pyridazine-3,6-dione and 11 pyridazine-6-one derivatives was studied on L-1210 cells using the proliferation inhibition (PI) test and particle counter (PC) test. Eight compounds with ED50 value below 1 microgram/ml in the PI system and with minimal effective concentration (MEC) below 0.2 mg/ml in the PC system, were qualified for further in vivo investigation. A good solubility-activity relationship depending on bromine substituents at C-4 and C-5 in the pyridazine-3, 6-dione group was observed. The activity of soluble, pyridazine-3,6-diones depended proportionally on the number of bromine substituents at C-4 and C-5 -contrary to solubility inversely proportional to the number of bromine atoms. The moderately soluble and moderately active compounds appear to have the highest efficiency. Activity of pyridazine-6-ones seems also to be related to the number of chlorine atoms substituted at those positions. The preliminary information about the cellular mechanism and quantitative differences in the action of model analogues in correlation to structure-solubility was obtained. A new cytotoxic particle counter index (CPCI) was helpful for differentiation of activity of pyridazine analogues.

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.

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.

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.

A Streptomyces strain which is similar to S. diastatochromogenes (Krainsky) Waksman et Henrici 1948 sensu Hütter (1967) was found to produce a new antibiotic designated trypanomycin. The red-pigment antibiotic, which has novel trypanocidal activity in vitro and in vivo, was isolated from a C-, N-, and iron-containing culture of the strain IMET JA 10081/9 by extraction with organic solvents, transfer into the aqueous phase, reextraction with organic solvents at pH 6.8, precipitation by hydrocarbons, and purification by chromatographic methods. Trypanomycin has indicator properties. The main constituents of the antibiotic mixture are readily soluble in water and are very stable in distilled water at room temperature (28 C) for 24 hr. The composition of the base of trypanomycin A(2) (melting point, 175 to 183 C) corresponds to the empirical formula C(41-42)H(52-56)NO(21-22). The absorption spectra in the ultraviolet and visible regions are very similar to those of the 4,5,8-trioxyanthrachinones. Trypanomycin has strong antiprotozoal activity, e.g., against trypanosomes. The natural substance additionally inhibits the growth of gram-positive bacteria, stable as well as unstable L-forms of gram-negative bacteria, mycoplasmas, yeast protoplasts, and tumor cells in vitro. The LD(50) of trypanomycin in mice was 60 mg/kg when administered intravenously and 31 mg/kg on intraperitoneal administration. If the antibiotic was added to cultures of animal or human cells in vitro, mitotic inhibition and chromosomal aberrations resulted. Trypanomycin differs in its biological activities and chromatographic behavior from other anthracyclines, e.g., cinerubine A and B, daunomycin, adriamycin, nogalamycin, rutilantin, pyrromycin, cyclamycin, and ryemycin.