Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5'-pyrophosphate) in Sprague-Dawley rats.

The dietary supplement Citicoline free-base (choline cytidine 5'-pyrophosphate) was toxicologically evaluated in Sprague-Dawley rats using oral gavage. In an acute 14-day study, 2000 mg/kg was well tolerated. In a 90-day study, 100, 350, and 1000 mg/kg/day doses resulted in no mortality.

Acute and subchronic toxicity studies of cryogenically-frozen, cryomilled, Pelodiscus sinensis (Japanese soft-shelled turtle--suppon) powder administered to the rat.

Sprague-Dawley rats received "cryogenically-frozen suppon" (CFS), a cryomilled product derived for the Japanese soft-shelled turtle (Pelodiscus sinensis), widely consumed for its nutritious value and medicinal properties, especially for the maintenance of normal blood pressure and insulin levels, and in women for the treatment of menopausal symptoms. In this acute study, a single limit dose of 2.0 g/kg was given po.

Toxicity of methylsulfonylmethane in rats.

Methylsulfonylmethane (MSM) is a popular dietary supplement used in a variety of conditions including pain, inflammation, allergies, arthritis, parasitic infections and the maintenance of normal keratin levels in hair, skin and nails. Despite its popularity, there is little published toxicology data on MSM. The objective of this study was to evaluate the acute and subchronic toxicity of MSM in rats at a dose five to seven times the maximum recommended dose in humans.

Comparison of tumor growth inhibitory and toxic effects of a new fluorouracil--nitrosourea derivative (B-3839).

The toxic effect and anti-tumor activity of B-3839, a new molecular combination of pyrimidine antimetabolite 5-fluorouracil (5-FU) with the alkylating agent N-Chloroethyl-N-nitrosourea (BCNU), was compared to that of BCNU and 5-FU given alone and in physical combination. The tumor inhibitory effect of B-3839 was similar to that of BCNU given alone or combined with a low dose of 5-FU in the i.m.

The role of comparative pharmacokinetics in the planning of human dose escalation: the experience with diacetyldianhydrogalactitol.

The pharmacokinetics of diacetyldianhydrogalactitol (DADAG) was compared in mice, rats, and humans. The ratios of human therapeutic dose (ThD) to the LD10 were 8 and 5 in mice and rats, respectively. The ratios of the corresponding AUCs of DADAG were 20 and 17, whereas those of dianhydrogalactitol (DAG), the main, active metabolite of DADAG, were 8 in both species.

Development and some characteristics of a P388 leukemia strain resistant to 1, 2:5, 6-dianhydrogalactitol.

Repeated intraperitoneal treatment of standard P388 mouse leukemia with dianhydrogalactitol (DAG) resulted in the development of a P388/DAG experimental mouse tumor which was resistant to the drug. Resistance was stable without DAG treatment throughout 80 passages. P388/DAG shows cross-resistance to alkylating agents such as nitrogen-mustard, cyclophosphamide and diacetyl-DAG but not to selected antimetabolites and tubulin binders and exhibits reduced sensitivity to nitrosoureas.

Relation between dose, plasma concentration and toxicity in a phase I trial using high dose intermittent administration of an alkylating agent, diacetyldianhydrogalactitol (DADAG).

Diacetyldianhydrogalactitol (DADAG), a new alkylating sugar alcohol derivative, was administered as single, 30-min infusions in doses ranging from 390 to 1200 mg/m2. The dose-limiting toxicity was myelosuppression. The median times to WBC nadir and regeneration were 16 and 21 days, and to platelet nadir and recovery 20 and 27, respectively.

Effect of herbicide 2,4,5-trichlorophenoxyethanol (TCPE) containing dioxin on mutation and induction of sister chromatid exchanges.

Previous studies have indicated that both herbicide 2,4,5-trichlorophenoxyethanol (TCPE) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhance liver tumor incidence in male Swiss mice in a dose-dependent manner. In this report the mutagenicity of TCPE (containing 0.1 p.

Cytochemical characterization of Yoshida sarcoma cells resistant to dibromodulcitol.

Two Yoshida ascites sarcoma cell populations, one of them originally sensitive and another rendered resistant to the alkylating agent dibromodulcitol (DBD), were compared for doubling time, labeling index, survival time, morphological features, cellular DNA content and modal DNA value. Cross-resistance studies were carried out on bilaterally growing solid tumours derived from the sensitive and resistant Yoshida cell populations. Glycogen-containing granules appeared in the cytoplasm of the DBD-resistant sarcoma cells; these were not present in the sensitive tumour.

Effects of some sugar alcohol derivatives on mutation and induction of sister chromatid exchanges.

The mutagenicity of various alkylating sugar alcohol derivatives in the Salmonella-microsome assay was studied, and the effects of these compounds on the colony-forming ability and the frequency of sister chromatid exchange (SCE) in Chinese hamster cells were determined. Cytostatic drugs under clinical trial [Elobromol (DBD), Myelobromol (DBM), Lycurim (LY), Zitostop (ZI)], others in preclinical analysis [dianhydrogalactitol (DAG), 3,4-diacetyldianhydrogalactitol (DiacDAG), 3,4-disuccinyldianhydrogalactitol (DisuDAG)], and compounds without any known antitumor effect in transplantable tumors [1-bromo-3,6-anhydrodulcitol (BAD), 1,2-epoxi-3,6-anhydrodulcitol (EAD)] were examined. All the tested compounds except DisuDAG were directly mutagenic in Salmonella strains TA 1535 and TA 100.

Toxicity, antitumour and haematological effects of 1,2-anhydro-6-bromogalactitol and d-mannitol: a comparison with the related dibromo- and dianhydro-derivatives.

1,2-Anhydro-6-bromo-6-deoxygalactitol (BrEpG) and its D-mannitol analogue (BrEpM) intermediary metabolites in the conversion of dibromodulcitol (DBD) and dibromomannitol (DBM) into dianhydrogalactitol (DAG) and dianhydromannitol (DAM) have been prepared. The three types of derivative of each hexitol have been compared in their toxicities towards mice, tumour inhibitory activities against the Walker carcinosarcoma and haematological effects in rats. The bromoepoxides showed intermediate potency in all tests.

Effect of phenobarbital on the toxicity and antitumor activity of dibromodulcitol and dianhydrogalactitol.

5-Ethyl-5-phenylhexahydropyrimidin-2,4,6-trione (phenobarbital) pretreatment significantly decreased the acute toxicity of 1,6-dibromo-1,6-dideoxygalactitol (dibromodulcitol) in H/Riop-Swiss mice and Wistar rats. Toxicity of dianhydrogalactitol, however, was not influenced to a considerable measure. Phenobarbital did not alter in itself the growth rate of the tumours examined.

Mutagenicity of dibromodulcitol (DBD), an alkylating anticancer drug) and its mono- and bifunctional conversion products studied by the Salmonella/microsome assay.

Dibromodulcitol (DBD) and one of its most important bifunctional transformation products, dianhydrogalactitol (DAG) with similar cytostatic effect, were tested by the Salmonella/microsome assay on strains TA 1535, TA 1538, TA 98 and TA 100 using the plate incorporation technique. Both drugs were direct mutagens in strains TA 1535 and TA 100 and non-mutagenic in other strains. Their mutagenic effect was not influenced by S-9 mix from rat liver.

The mode of action of Vinca alkaloids.

P388 leukemia-bearing mice were given a single i.p. injection of [14C]-vincristine and the levels of radioactivity in the tumors and host tissues were determined as a function of time.

Complex evaluation of the effect of some cytostatic hexitol derivatives.

The antitumor effect of three structurally closely related alkylating hexitol derivatives (DBD, DAG, DiacDAG) was evaluated using a complex multi-parameter evaluation system. It comprised toxicology, action on ascites and solid tumors, as well as on subpopulations isolated by isopyknic centrifugation, cross-resistance and their action on chromatin components (DNA, histone, nonhistone proteins). The results indicate that in spite of their same mode of action, considerable differences could be observed in tumor specificity, inhibition of tumor growth and in their interaction with chromatin components.

[Value of experimental results in clinical tumor chemotherapy (author's transl)].

IN a critical analysis of experimental tumor chemotherapy different screening methods, tumor models, applications methods, polychemotherapeutic methods, preclinical toxicology and pharmacokinetic experiments are described and their importance for clinical tumor chemotherapy is demonstrated. Experimental tumor chemotherapy, guided by clinical requirements, is an indispensable and direct tool for clinical tumor chemotherapy.

Heterogeneity of tumor cell populations.

Ascites tumor cell populations proved to be heterogeneous with respect to density. Subpopulations separated by isopycnic centrifugation differed from each other in several respects including cell cycle time, chromosome number and distribution and chemotherapeutic sensitivity. The results indicate that density separation is a useful technique to study the behavior of subpopulations within tumor and offers new possibilities in comparative experimental chemotherapy.

Role of pesticides in hepatocarcinogenesis.

Pesticides are biologically active substances that are significant environmental contaminants. Only a few of the many pesticides have been subjected to short- or long-term carcinogenicity tests. To date, 16 of them have been identified as hepatocarcinogenic agents in animals, usually mice.

Research related to the herbicide buvinol, especially for possible carcinogenicity.

The Budapest Chemical Works (Hungary) has conducted a study on a new herbicide called 'Buvinol', containing 2,4,5-trichlorophenoxyethanol (TCPE). In long-term carcinogenicity testing, the oral administration of the maximum tolerated dose of TCPE (70 mg/kg), containing 0.1 ppm 2,3,7,8-tetrachlorodibenzo-para-dioxin, increased the incidence of liver tumours in male mice, while smaller doses (1/10 and 1/100) did not.

Carcinogenic bioassay of the herbicide, 2,4,5-trichlorophenoxyethanol (TCPE) with different 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) content in Swiss mice.

The carcinogenic effect of a herbicide trichlorophenoxyethanol (TCPE) was investigated. The substance always contains 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) as a trace contaminant. Outbred Swiss-H/Riop mice were treated for 1 year with different doses of the various admixtures of the two compounds and those of dioxin alone to determine whether their carcinogenic effects are dose-dependent.

Study of the antitumoral activity of S-carbamoyl-L-cysteine derivatives in animal experiments.

The antitumoral activity of three amino acid derivatives, S-carbamoyl-L-cysteine, S-ethyl-carbamoyl-L-cysteine, and S-chloroethyl-carbamoyl-L-cysteine, was studied. The ethyl and chloroethyl derivatives had a pronounced curative effect on certain animal tumors. It is interesting in the case of S-carbamoyl-L-cysteine that N-ethylization of the substance resulted in increased chemotherapeutic effectivity with no simultaneous change of the toxicity.