Possible determination of individual chemosensitivity of tumors to 5-fluorouracil was investigated using new original data and suggestions that lymphocytes of the tumor carrier have an ability to assimilate chemical drugs. Such an ability is likely due to the fact that 5-fluorouracil as an antimetabolite converted its action by inclusion of lymphocytes to the nucleic acid metabolism. The relation between the phenomenon and the chemotherapy efficacy is possibly realized through two mechanisms. One of them is the direct cytotoxic action of chemical drugs on lymphocyte tumor-associated clones resulting in impairment of the tumor growth control. The other is possible participation of lymphocytes in transport of chemical drugs to the tumor tissue. The in vitro model for estimation of tumor carrier chemosensitivity by the level of the nucleic acid metabolism reflects the impact of the immune system on realization of the antitumor effect of chemical drugs.

A new method for intravital assessment of the functional activity of anticancer drug efflux transporters in intact solid tumor specimens was developed. The method is based on the well-known approach to the transporter functional evaluation by intracellular accumulation of antitumor drugs and particularly the anthracycline antibiotic doxorubicin (Dox). The main new point of the method providing investigation of intact solid tumor specimens which markedly simplified the procedure is the fact that the intratissue and intracellular accumulation of Dox is determined not by the level of the drug in the tissue but by its fluorescence decrease in the incubation medium. To assess just the intracellular content of Dox and to estimate the transporter functional activity, investigation of the influence of membrane transporter inhibitors such as verapamil (P-gp inhibitor) and sodium azide (inhibitor of all the energy-dependent ABC transporters) on the drug fluorescence decrease in the incubation medium is stipulated. The validity of such an approach was experimentally proved with the specimens of the Ehrlich solid tumor transplants in mice (a sensitive variant of the tumor and the tumor with induced drug resistance). Biopsy specimens of human breast tumors were investigated with the new method and functional activity of various efflux transporters was revealed: (1) only P-gp, (2) both P-gp and other ABC transporters, (3) only transporters different from P-gp, (4) no functional activity of efflux transporters. The main trends of the further investigation of efflux transporter functional activity in human solid tumors possible for the first time with the use of the new method are defined.

It was shown in vitro that high concentrations of lovastatin, a competitive inhibitor of hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibited human malignant cells MOLT-4. The activity of lovastatin in doses of 50-250 microM was dose-dependent. Addition of mevalonate in a concentration of 3 mM to the growth medium completely prevented the cytotoxic effect of 100 microM of lovastatin. At the same time, exogenous mevalonate did not decrease the cytotoxicity of the anthracycline antibiotic carminomycin. Moreover, in a high concentration (7 mM) mevalonate slowly but significantly inhibited the growth of the malignant target cells and the effect was added to the cytotoxic effect of carminomycin low concentrations (0.08 to 0.175 microgram/ml). The results and the literature data suggested that combination of mevalonate, HMG-CoA reductase inhibitors and anthracyclines could be useful in tumor chemotherapy. The suggestion needs further investigation.

A single intravenous infusion of 4.5 mg/kg of the new antineoplastic drug platidium induces structural-metabolic changes in the liver of rats (necrosis of hepatocytes, decrease of the glycogen and RNA content and accumulation of lipids in the cytoplasm of the hepatic cells, and increased activity of aspartate- and alaninaminotransferase in blood serum). An additional toxic factor (CCl4) applied one month after platidium infusion revealed incompleteness of reparative processes in the liver. The hepatoprotector essentiale weakens the injurious effect of the cytostatic on the hepatocytes and stimulates regeneration of the liver.

Experiments on male CBA/CA Lac mice [correction of rats] showed that a maximum tolerance dose of platidiam suppresses the primary humoral immune response stimulated by the thymus-dependent antigen in the late period (30 days), and has practically no immunosuppressive effect at the early stages (4 days) after injection of the cytostatic drug; it raises the phagocytizing activity of the peritoneal macrophages and increases the number of monocytes in the peripheral blood.

The hemostimulating activity of the drug glycyrram and the recombinant granulocytic-macrophagic colony-stimulating factor (CSF) was compared on models of myelosuppression induced by injection of an alkylating agent cyclophospane (CF) or the antimetabolite 5-fluorouracil (5-FU). It was found that glycerram stimulated hematopoiesis more effectively after 5-FU injection but to a lesser extent (in relation to CSF) in CF injection.

The effect of calcium gluconate on the toxicity and specific activity of the anthracycline antibiotic doxorubicin was studied on mice with transplanted hemoblastosis La or plasmocytoma MOPS-406. In both cases after the animal exposure to nontoxic therapeutic doses of doxorubicin no influence of calcium gluconate on the antibiotic antitumor activity was observed. When doxorubicin was used in toxic (and even lethal) doses the antitoxic effect of calcium gluconate and an increase of the antibiotic therapeutic activity were stated. The combination of calcium gluconate and doxorubicin made it possible to significantly increase the maximum therapeutic effect of doxorubicin (higher levels of the animal survival and some cures) and to widen the ranges of the drug therapeutic doses at the account of decreasing the toxicity of the antibiotic and increasing its dose. The results suggested that the antitoxic modifier calcium gluconate could be used for increasing anticancer efficacy of doxorubicin which is given now at the total dose limit of 550 mg/m2 even in cases with preserved tumor sensitivity to the drug.

The investigation was concerned with clinical application of cardioxane (dexrazoxan, ICRF-187) which is intended to counteract the cardiotoxic effect of anthracycline drugs. It was tested in 24 courses of combination chemotherapy (CAP) in 48 cases of extended ovarian tumor. The "threshold" total dose of doxorubin (500 mg/m2) which caused persistent cardiomyopathy in such patients as well as cases of relapse was practically never reached due to the absence of therapeutic effect. The total dose of doxorubicin of 120 mg/m2 raised the likelihood of acute cardiac intoxication. With prophylactic administration of cardioxane, clinical signs of acute cardiointoxication were slight; irreversible intoxication was recorded in 0.8%. The drug improved tolerance; it neither increased the overall toxicity of combination chemotherapy nor affected the results.

Experiments were performed on Wistar rats to evaluate comparatively the morphological and functional state of the ovaries in the early and late-term periods after a single injection of a platinum-containing cytostatic drug platidiam and an antibiotic of the anthracycline series farmorubicin. It was found that the antineoplastic agents caused a similar toxic effect on the animal's sexual glands. The number of generative elements in the ovaries decreased in this case and the duration of the estrous cycle, the indices of embryonal death, and the pregnancy index increased.

A method of the synthesis of lipophilic glycoconjugates (vectors) on the basis of polyethyleneglycol-containing detergent was proposed. It has been shown by flow cytofluorometry that fluorescent labeled liposomes equipped with beta-galactosyl conjugate are bound human leukosis HL-60 cells more effectively than liposomes embedded with the beta-glucosyl conjugate or vector-free liposomes. A new lipid derivative of antitumor drug rubomycin (daunorubicin), N-(rac-1,2-dioleoylglycero-3-oxalyl)rubomycin (RubDG) has been synthesized. Liposomes loaded with RubDG and equipped with galactosyl vector showed higher cytotoxic activity in vitro against HL-60 cells than analogous unvectored liposomes or liposomes bearing glucosyl conjugate.

To assess benefit for children with malignant blood disease (MBD) of the hepatoprotector heptral.

Dynamics of changes of the reduced glutathione contents, activity of glutathione transferase, glutathione reductase and gamma-glutamyl transpeptidase in rat organs at a single injection of embiquine in a dose of 1/2 LD50 has been studied. It was shown that injection of the alkylating antitumor preparation lead to the decrease of the reduced glutathione contents in the early period of intoxication together with compensatory increase of tripeptide concentrations 3 hours later in the liver tissue and 24 hours later in the kidney tissue. Embiquine caused the steady increase of the glutathione transferase activity in all the organs studied. Significant increase of liver, kidney and spleen gamma-glutamyl transpeptidase by the end of the investigation period was noted at the injection of the alkylating agent.

Bone marrow hemopoiesis, a state of the committed precursor cell pool and the nature of their interaction with hemopoiesis-inducing microenvironment (HIM) elements, the level of humoral stimulants of secretion, was studied following a single injection of 5-fluorouracil (5-FU), cyclophosphamide (CF) or adriamycin (A) to mice in maximum tolerance doses. Cytostatic-related changes in hemopoietic recovery were shown to depend primarily on the proliferation-differentiation relationships in the hemopoietic cells, which is in its turn determined by the status of HIM cells after cytostatic exposure. The enhanced functional activity of HIM elements in response to hemopoietic tissue damage induced by A or CF promotes rapid hemopoietic recovery which becomes much more accelerated while using recombinant colony-stimulating factor (CSF) and, to a lesser degree, glycyrrham, a plant drug. At the same time 5-FU that caused prolonged bone marrow hypoplasia impaired the function of microenvironment cells. The use of this model demonstrated a lower efficiency of CSF than glycyrrham that normalized the structure of HIM.