The pharmacological disposition of 1,3-dimethyl-1-nitrosourea (dimetinur) in intact rats and animals with Walker carcinosarcoma, glioma 2211, colon adenocarcinoma was studied by the colorimetric assay using an oral drug dose of 100 mg/kg. Computer analysis of data was based on a single-compartment model using the area under the concentration-time curve (S) and the intact drug half-life (t1/2) as main pharmacokinetic parameters. The highest level of the drug (S) was observed in tumour and brain tissues on an equality with drug distribution between blood, spleen, kidney and lungs. The half-life of the dimetinur removal from blood exceeds the known values for certain active NAM type. The antitumour activity of the drug against the studied tumours correlates positively with pharmacokinetic parameters for the tumours (S and 1/tmax).

Formation of dispersed phases from complexes of (closed circular DNA (c.c. DNA)--antibiotics (drugs) in PEG-containing solutions has been studied. It is shown that under definite concentrations of bound antibiotics relatively intense bands in the CD spectra of dispersed phases in the absorption region of DNA and antibiotics chromophores appear. The properties of liquid crystalline phases formed from the complexes of linear DNA with antibiotics were compared to those of dispersed phases formed from c. c. DNA. Such comparison demonstrates existence of some differences in the optical properties of the phases formed from linear and c.c. DNA molecules. For example a change of the bands sign in the CD spectra of dispersed phases formed from the complexes (c.c. DNA--antibiotics), which is the case with all the substances studied, does not exist in the case of liquid crystalline phases formed from the complexes of (linear DNA--antibiotics). It was shown that a change of the bands sign in the CD spectra correlates with a change of the sign of superhelical twist of closed circular DNA molecules.

Antitumour drugs prospidine and spirobromine were shown to suppress the activity of the mouse liver lysosome enzymes in vivo and in experiments in vitro. The revealed effect was underlied by a decrease of lysosomal membrane permeability for the corresponding substrates and enzymes rather than a reduction of the catalytic activity of acid hydrolases.

In experiments on CBA/Lac J mice it was found that the course administration of adriamycin (0.95 mg/kg), vinblastine (0.24 mg/kg) and cyclophosphan (27 mg/kg) in 1/10 LD50.10 causes persistent disturbances of the functional activity of the lymphoid tissue manifesting by inhibition of the proliferative response of the spleen lymphocytes to T- and B-cell mitogens one month and to a lesser extent three months after cytostatic action. The lymphotropic effect of adriamycin is due to the predominant damage of the functional activity of T-lymphocytes. Vinblastin suppresses T- and B-cell link of the immunity system and the inhibitory effect of cyclophosphan is directed mainly to B-cell population.

The paper discusses the results of combination chemotherapy of 652 patients using platinum derivatives. The treatment proved effective in patients with metastatic tumors (79.7%), ovarian cancer (71.2%) and breast carcinoma (71.2%). Longer survival was obtained in cases of complete regression of ovarian tumor and in effectively treated patients with breast cancer. Response was registered in 30.8% of cases of osteogenic sarcoma. Application of cisplatin in chemoradiation treatment for inoperable bladder cancer resulted in regression of tumor in 57.4%. Literature data on some newly developed platinum derivatives undergoing phase-I and -II clinical trials outside the USSR are discussed.

Comparing the toxicities of potential anticancer agents for tumorous and normal cells derived from human intestinal epithelium may be a preferred approach for in vitro testing of compounds directed against colon carcinoma. 5-Hydroxymethyldeoxyuridine, a thymidine analog, was preferentially cytotoxic for two lines of human colon adenocarcinoma cells compared to a cell line derived from normal human fetal intestine. Unlike deoxyuridine and deoxycytydine, thymidine protected HT-29 human adenocarcinoma against 5-hydroxymethyldeoxyuridine toxicity, suggesting that thymidilate synthetase is the probable target enzyme of this thymidine analog. 5-Hydroxymethyldeoxyuridine may hold promise as an agent with specific activity against human adenocarcinoma cells.

A comparative study was carried out with two alkylating agents IMB-MM and IMB-97 which are di-(2-halogenoethyl) hydrazides of amino acid derivatives. They have been found to exert a high activity towards wide spectrum of experimental tumours. Both agents caused inhibition of incorporation of 3H-thymidine into DNA of melanoma B16, marrow, intestinal mucosa, spleen and liver cells of mice with tumours. A maximal inhibition of DNA synthesis in all tissues was observed 24 h after the single doses of drugs. However 96 h later this effect was removed excluding the tumour cells. The cytofluorimetric study have shown that IMB-MM, like sarcolysine, caused an accumulation of tumour cells in G2/M phase of cell cycle, while IMB-97 increased accumulation of S-phase cells. The difference in phase sensitivity of tumour cells towards IMB-MM and IMB-97 is due to the differences in aminoacid carriers of di-(2-halogenethyl) hydrazide groups.

DNA liquid crystals forming in water-salt solutions containing polyethylene glycol were used as a system for testing consequences of reactions of antitumor compounds belonging to two different groups with molecules of nucleic acids. It was found that with due account of the level of DNA molecule filling with daunorubicin it was possible to form two cholester phases characterized by the textures of "finger prints" and CD spectra with intensive bands of unlike signs, as well as the nematic phase characterized by the texture of the "black twisted fiber" system and the absence of the CD spectrum intensive band. Modification of the DNA molecules resulting from the reaction with cysdichlorodiamine platinum (II) led to formation of a new liquid crystalline phase with properties differing from those of the liquid crystalline phases of the cholester or nematic type.

It was shown that changes in the redox potential can be due to the influence of compounds which alter the intracellular pH (acetate or propionate, protonophore carbonyl-cyanide-m-chlorophenyl hydrazone, permeate cation TPP+). A correlation was found between the redox potential changes and the number of SH-groups in the medium and on cell surface. It was shown also that the previously reported redox potential shifts during the transition of E. coli and B. subtilis cultures to the stationary phase under glucose or ammonium exhaustion are due to the increase in the number of SH-groups in the medium and on cell surface. A hypothesis is put forward, according to which the changes in intracellular pH play a trigger role, whereas those in the thiol: disulfide ratio inside and outside the cells are thought to amplify regulatory signals.

The mutagenicity of thaliblastine (Bulgarian potential antitumor drug) was investigated in vitro in lymphocytes from healthy donors, and in vivo in lymphocytes of oncological patients after thaliblastine administration. No increase in the rate of chromosome aberrations was noted with increasing thaliblastine concentrations in vitro and in the course of therapy in vivo. Some polyploid metaphases were found in the lymphocytes of the patients treated with thaliblastine, as a result of the statmokinetic effect of the drug. Thaliblastine exerts extraordinarily slight mutagenic effect, as compared with other cytostatics.

The action of the anthracycline antibiotics rubomycin and its nitroxyl analogue ehoxyl(ruboxyl) at the concentration 100 mg/l was studied in the experiments, have been carried out with the isolated bundles of frog atrium using simultaneous registration of the ionic currents (or the active potentials) and the contraction. It has been shown, that rubomycin caused an action of potential shortening, membrane depolarization, increasing of the background outward current IKI, slowing of the muscle relaxation and the growth of the ionic contraction, associated with the Na/Ca exchange. Nitroxyl derivative of the rubomycin ruboxyl, exhibited small toxicity, did not change the ionic currents and the parameters of the mechanical activity. It is assumed, that cardiotoxicity of anthracyclines is in the great degree due to their ability to block the elimination of the Ca++ from the cell via the Na/Ca exchange, that results in the disturbance of the Ca-homeostasis of the cardiomyocyte and its calcium overload.

The morphological and functional states of hemopoiesis at late periods (up to 6 months) after using daunorubicin, carminomycin and doxorubicin, antitumor antibiotics of the anthracycline group in doses of 1/10 LD50 for 10 days were studied on 764 noninbred rats and 240 BALB/c mice. On various compensatory-functional models of hemopoiesis strain there was shown persisting inhibition of hematopoietic tissue functional activity and limited reserve reactions of granulocyto- and erythropoiesis 3 and to a lesser extent 6 months after the cytostatic action.

The study of the effect of a new antitumor drug cortifen on humoral immunity in experiments on CBA mice showed that it is a potent and long acting immunodepressant. The degree of immunity depression was found to be drug dose-dependent. The hormonal components of cortifen failed to exert the immunodepressive action. The alkylating component, chlorphenacyl, on the contrary, had the immunostimulating effect.

The method of the estimation of interaction between two harmful effects based on the statistical survival rate data is discussed. In terms of the competitive risk model, an independent effect was defined as a product of survival functions corresponding to an isolated effect of each injurious factor. The proposed method is based on the comparison between the animals' lifetimes in the case of the isolated effects and the actual survival rates after the combined radiation effect. The comparison of the two alternatives was made by the regression model of Cox adapted for the purposes of this study.

Formation of 13-dihydro derivatives of rubomycin (daunorubicin), carminomycin, doxorubicin and some of their semisynthetic derivatives under the effect of pure aldo-keto reductase from the rat liver was studied. Attachment of an oxy group to C-14 markedly retarded formation of the 13-dihydro derivatives while attachment of the bulky radicals to the same position prevented their formation. Binding of the anthracycline antibiotics to human serum albumin had no impact on the fermentative reaction rate. Rubomycin, carminomycin and doxorubicin significantly differed in their lipophilic properties and capacity for binding to serum albumin.

The anthracycline antibiotics rubomycin (daunorubicin) and carminomycin at concentrations which stimulate mitochondrial respiration in the absence of ADP induce the swelling of rat liver mitochondria. Under these conditions, the lipid peroxidation (LPO) inhibitor ionol slows down both the respiration and swelling of mitochondria. This suggests that stimulation of respiration and swelling under effects of the antibiotics largely depend on LPO. In the presence of the respiration inhibitor antimycin no effect of ionol is observed. Adriamycin (doxorubicin) stimulates mitochondrial respiration in a lesser degree than rubomycin and carminomycin and fails to induce mitochondrial swelling.