The dimethylnitrosourea action after oral and parenteral administration was comparatively evaluated on the basis of criteria for the antitumour and cytogenetic activity, as well as for the immune (T-cell) reactivity of tumour-bearing and intact animals. A considerable antitumour effect and the induction of the overload chromosomal aberrations in tumour cells with the complete preservation of bone marrow cells were observed during the oral drug application. Dimethyl nitrosourea-induced T-cell depression in murine spleen was transitory and reversible. Thus the oral administration of the drug was shown to be optimal for realization of its therapeutical activity with the least toxic side effect on the host normal hemopoietic and immunocompetent cells.

The method of fibrin plates and electrophoresis in PAAG was used to study the activity and forms of plasminogen activators (PA) in extracts of normal tissues (muscle, lungs) as well as of the malignant tumours and the lungs of mice during metastatic spreading and under certain drugs (trielin and cyclophosphane). It was stated that determination of the specific activity level of plasminogen activator in a target organ (lungs) may be used as one of the indices during evaluation of the antimetastatic effect.

The paper describes the antitumor activity of a newly-developed hormonocytostatic drug testiphenon--a complex ether of 5 alpha-dihydrotestosterone and chlorphenacyl (17 beta-[n-di/2-chloroethyl/aminophenylacetate]-5 alpha-androstan-17 beta-ol-3-on). Its antitumor properties were studied in 15 models of transplantable solid tumors and systemic neoplasms of mice and rats such as sarcoma 298, sarcoma 37, sarcoma-180, Lewis lung epidermoid carcinoma, carcinoma of the forestomach-5, large bowel adenocarcinoma, Harding-Passey's melanoma, cervical cancer-5, mammary adenocarcinoma Ca-755, hemoblastosis La, plasmacytoma MOPC-406, Rauscher's erythroblastosis, Walker's carcinosarcoma 256, sarcoma 45, alveolar carcinoma of the mammary gland and DMBA-induced mammary tumors of mice. The spectrum of antitumor activity of testiphenon proved wider than those of its components or other estrogeno-cytostatic drugs--phenestrol and estracyt. The drug is specifically intended for selective action upon target tissues for androgens and tumors developing from the said tissues.

The Ames test on indicator bacteria S. typhimurium TA 1950 and TA 100 and the differential spectrophotometry have shown that cytochrome P-450-dependent monooxygenases of mammalian liver participate in the metabolism of antitumour drugs (cyclophosphamide, thiophosphamide) and of nitrosomorpholine (promutagen). Data concerning prospidin indicate that microsomal liver enzymes either induce no metabolic transformations of this preparation or the formed metabolites possess the mutagenic activity similar to that of the parent compound.

Improvement and development of new methods for primary screening of antitumour drugs in vitro are based on the data on the points open to injury in the tumour cell metabolism and on the evidence of the known carcinostatic drug mechanism. Further development of the primary screening methods should proceed, probably, in two main directions. Further improvement of the methods for cloning tumour cells in the semifluid nutrient media is of great interest. On the whole the creation of new test systems is a significant trend of the scientific screening.

57 patients with disseminated tumors of various sites received 10 daily doses of 600 mg/m2 leakadin intravenously. The immunostimulating effect was observed (OKT4/OKT8 normalization). The data on leakadin pharmacokinetics are discussed.

Cooperative clinical trials of a newly-developed antibiotic--bleomycetin (a purified fraction of bleomycin A5) conducted in 172 patients at 7 oncological centers revealed a spectrum of antitumor activities similar to that displayed by Japanese-made bleomycin. When administered by intravenous or intramuscular injection in single or total doses amounting to only 50-70% of those of bleomycin (bleocin), bleomycetin proved effective in the treatment of extended squamous cell carcinoma of the head and neck, skin, cervix uteri, embryonal cancer of the testicle and, particularly, recurrent Hodgkin's disease and non-Hodgkin's lymphoma. Single administration of 15-50 mg bleomycetin (total dose--50-150 mg) to serous cavities was followed by the cure of specific pleurisy and ascites in 47%. Unlike bleomycin, bleomycetin treatment was free of pulmonary toxicity, and skin hyperpigmentation, hyperkeratosis, vomiting and alopecia were significantly less frequent.

The effect of various doses of antitumor antibiotic aclarubicin on the peripheral blood system and medullary hemopoiesis was studied on Wistar rats. It was shown that intraperitoneal administration of the drug in doses of 0.08, 0.33 and 1.2 mg/kg daily for 6 months did not induce any significant changes in the blood count of the animals. The dose of 1.2 mg/kg which is almost 2.5 times higher than the maximum course dose of aclarubicin for patients induced a decrease in the hemoglobin count recorded within the whole observation period. A single administration of aclarubicin in LD50 equal to 17.4 mg/kg resulted in marked suppression of hemopoiesis. The drug had the most prolonged suppressive effect on the bone marrow myeloid body. Depression of erythropoiesis was short-term.

Using nucleoprotein celite chromatography, it has been shown that DNA of human cultured fibroblasts was strongly bound to the proteins of the nuclear matrix. N-methyl-N-nitrosourea and prospidin-active antitumor agents with marked mutagenic action--were shown to attenuate the interactions, which appeared to be partially sensitive in cultured fibroblasts from patients with Down's syndrome.

The effectiveness of re-infusions of auto-blood after isolated irradiation used for the correction of hemocytopenia developing during cancer chemotherapy was studied in 77 patients. 200 ml of the patient's blood was taken into a flask with a preservative and irradiated at an absorbed dose of 220 Gy on the RUM-17 x-ray apparatus. After irradiation the blood was reinfused to a patient. Posttransfusion reactions in the patients were absent. The efficacy and technical simplicity of the method of re-infusions of auto-blood after isolated irradiation make it applicable in clinical practice for the correction of hemopoietic disorders in cancer patients.

It has been shown that the antitumour drug Cu-2 (copper complex compound) inhibited the activity of liver monooxygenases in male CBA mice. The in vivo experiments have revealed a considerably increased duration of sleep in mice treated with hexenal after the administration of different Cu-2 doses. In vitro, after the incubation of intact mouse liver microsomal fractions with different concentrations of Cu-2 the level of cytochrome Y-450 was decreased and a non-active form of hemoprotein--cytochrome P-420--appeared. At the same time, after the incubation of Cu-2 with liver microsomal fractions stabilized by 20% glycerol type I spectral changes (Ks 330 microM) were registered. This shows the possible metabolism of Cu-2 by cytochrome P-450. The role of the revealed interaction of Cu-2 with liver microsomes is being discussed for the chemotherapy of cancer.

Tissue pharmacokinetics of aclarubicin and its active metabolites was studied with high performance liquid chromatography. The drug was administered to rats intravenously in single doses of 5 and 10 mg/kg and orally in a single dose of 10 mg/kg. With both the administration routes the highest concentrations of the drug and its metabolites were attained in the lymph nodes. Then followed the spleen and lungs. The lowest content of the drug was detected in the heart. The total values of the areas under the concentration/time curves for aclarubicin and its metabolites in the tissues of the heart, lungs, lymph nodes and spleen after oral administration were respectively 2, 3, 4 and 7 times lower than those after the drug intravenous administration in the same dose. The concentrations of the active metabolites MA144N1 and MA144T1 exceeded those of aclarubicin and were detected in the tissues within a longer period as compared to the unchanged drug. With repeated administration preferential accumulation of the metabolites in the tissues and their increased contribution to the aclarubicin antitumor effect could be suspected.

Blood pharmacokinetics of the antitumor antibiotic aclarubicin and its metabolites was studied in rats with high performance liquid chromatography. The drug was administered intravenously in single doses of 5 and 10 mg/kg and orally in a single dose of 10 mg/kg. Aclarubicin pharmacokinetics was shown to be nonlinear. However, within every dose level it obeyed a two-compartment model. The nonlinearity could be due to saturation of aclarubicin binding to blood plasma proteins. The blood concentrations of metabolites MA144 N1 and MA144 T1 were close and after 12-18 hours exceeded those of unchanged aclarubicin. The half-lives of aclarubicin and its metabolites ranged from 16 to 21 hours. The MA144 T1 content was not significant. Following oral administration aclarubicin was rapidly absorbed and its bioavailability amounted to 35 per cent. Total bioavailability of aclarubicin, MA144 N1 and MA144 T1 was equal to 89 per cent. This enabled to consider the oral route of aclarubicin administration promising in tumor therapy.

Data are reviewed concerning the results of study of multidrug-resistant (MDR) tumor cells. MDR often develops in the course of chemotherapy or in vitro selection of tumor cells by vincristine, adriamycin, actinomycin D, colchicine, etc. MDR cells are resistant to all these drugs though their targets and mechanisms of toxic action are quite different. Resistance is due to the decreased accumulation by MDR cells of these compounds. The genetic basis for MDR is amplification of a large genomic region that contains a number of genes coding for products and functions that are under extensive study. Specific karyotype and amplified DNA alterations occur during the development of MDR imitating the processes of appearance and variability of multigene families. The obtained data demonstrate the ways of overcoming of tumor multidrug resistance in clinic.