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No adverse side-effects were reported in an investigation of the antitumor effect of turbulent magnetic field (TMF) carried out as a component of preoperative chemoradiotherapy for breast cancer at the Center's Clinic. The study group included 114 patients with locally advanced tumors(T3, N1-N3, M0). According to the clinical, roentgenological and histological evidence on the end-results, the procedure was highly effective. Also, it was followed by shorter and less extensive postoperative lymphorrhea.

The permeabilization of tumor cells in vitro under the action of pulsed electric fields with a duration of 6 mks in the range of amplitudes 1-7 kV/cm was studied. In the mode of excitation in the ambience of localized plasma discharge in a chamber of special design, an enhanced damage to cells in suspension was observed. It is assumed that the enhancement is due to the synchronous action of the electric field and acoustic shock wave pulses. In the mode without the plasma breakdown of ambience, when the pulse duration of electric field of intensity of 1-2 kV/cm was increased to 60 mks, the efficiency of permeabilization increases nearly by one order. The experimental results are compared with the known theoretical models of cell membrane electroporation.

The aim is to study the pattern of a cell population (ploidy) and to evaluate the latter's significance in the prognosis of different carcinomas. A total of 467 patients with primary carcinomas of the breast (n = 177), lung (n = 88), head and neck (n = 140), and colon and rectum (n = 62) were examined. All the patients underwent surgery alone or in combination with radiotherapy (X-ray)/chemotherapy. A follow-up lasted 6 to 120 months. DNA was measured in the operative tumor tissue specimens by using an ICP-22 flow cytometer. Diploid and aneuploid cancers occurred in 20.4-53.6 and 43.6-79.6% of cases, respectively. The frequency of recurrences was mainly associated with aneuploidy and it was more than thrice higher than that with diploidy (21.0-43.2 versus 4.5-14.4%). Five-year survival was twice worse in patients with aneuploid tumors than in those with diploid ones. The survival rates after one operation, preoperative, and postoperative radiation therapy was greater in patients with diploid tumors than in patients with aneuploid ones. Thus, DNA-ploidy of the study neoplasms is of high informative value in predicting the course of a tumorous process and in choosing treatment policy on an individual basis.

The study has been concerned with DNA ploidy and its significance for prognosis of different neoplasms. The investigation included 314 patients: primary cancer of the lung (96), head and neck (146) and large bowel (72). Patients received surgery alone or surgery plus either radiotherapy or chemotherapy; they were followed up for 6-20 months. DNA levels were assayed in resected material using an ICP-22 flow cytometer. Diploid and aneuploid cancers were detected in 20.4-53.6 and 43.6-79.6%, respectively. The recurrence rates in cases of aneuploid cancers were more than 3 times those of diploidy (21.0-43.2 and 4.5-14.5%, respectively). Overall 5-year survival in diploid patients was twice that in aneuploid ones. Similarly, survival after surgery alone, preoperative chemotherapy and postoperative radiotherapy among diploid patients was longer than in aneuploid ones. Hence, DNA ploidy examination of tumors is of great informative value in prognosing tumor process and working out individually-tailored approach to treatment.

Cytotoxic screening of 2,000 chemical compounds against human tumor cell lines has identified certain antimetabolities, platinum complexes, actinomycin D derivatives and somatostatin analogs as possible antitumor agents. Differential sensitivity of such lines derived from five cancers (lung, colon, ovary, breast and leukemia) to certain antitumor agents has been established. This panel of cell lines is currently employed as a model for in vitro drug screening to identify biological response profile at earlier stages.

A cell differentiating agent N-methylformamide (MF) was studied for its antitumor activity against a murine ascitic hepatoma 22A. After a 48 hour NMF administration (i/p) the tumor cell number was monitored; the distribution of these cells in the cell cycle was registered by flow cytometry, ultrastructural changes were studied by electron microscope. The polar solvent MF inhibited tumor growth, reduced mitotic activity, and nuclear/cytoplasmic ratio, led to structural complication of endoplasmic reticulum and mitochondria. The analysis of these events is suggestive that in consequence of MF effect on tumor cells, proportion of G0/G1 and M cells was decreased, while the proportion of S and G2 cells was increased.

DNA flow cytometry (FCM) was used for the clinical prognosis in patients undergone surgical removal of a tumor. The relationship between the structure of the tumor cell population (ploidy) and the frequency, time of a relapse onset (recurrence, metastasis), and the survival length were analyzed. All the patients had presurgical treatment (chemo- and/or radiotherapy). The patients were followed up for 5 to 9 years after surgery. The groups under study included 177 cases of breast cancer, 81 cases of larynx cancer, and 62 cases of colon cancer. Among the patients, the onset of a relapse was earlier and occurred more frequently in cases of aneuploid tumors among the patients regardless of the tumor type. In patients with aneuploid tumors, the most unfavorable prognosis was inherent in the hyperdiploid and multiclonal ones. The probability of 5-year survival for patients with aneuploid tumors appeared to be 20-30% lower than that in cases of diploid ones.

The effects of RNAase from Bacteroides intermedius and pancreatic RNAase on the dynamics of cellular cycle phases were studied in the cells of ascitic lympholeukemia NK/Ly in vivo and in vitro, in the cells of the human ovary carcinoma CaOv and in the cells of ascitic leukemia P388 in vivo. It was shown that both the RNAases induced cell accumulation (blocking) in the G2/M phase of a cellular cycle with simultaneous certain depletion of the proportion of DNA-synthesizing cells (S-phase). In in vitro experiments, there was a higher efficiency of pancreatic RNAase. In animal experiments, RNAase from B. intermedius was more efficient. The likely target of the in vitro and in vivo effects of the enzymes on the cellular cycle dynamics and biological activity are discussed.

The influence of new synthesized fluoro-silicium-organic complexes on the virus-induced Rauscher leukosis and cell-transferred MX-11 mouse sarcoma was studied. We also studied the cytotoxic effects of these complexes in vitro in the human CaOv cells. Two complexes from seven studied were cytotoxic for CaOv cells. Five complexes from seven studied diminished the mortality of animals with MX-11 tumors on the 27-th day of observation, but the total life duration of the animals in the experimental group was the same as in controls. One complex from seven studied increased the life duration of mice with MX-11 tumors. No effects were noted in relation to mice virus-induced Rauscher leukosis.

1-beta-D-Ribofuranosyl-4-methylthiopyrazolo(3,4-d)pyrimidine (I) has been converted into its 5'-monophosphate (III) by reacting with POCl3 in trialkyl phosphates or by phosphorylating 2',3'-O-ethoxymethylidene derivative of riboside (I) using 2-cyanoethyl phosphate in the presence of DCC and subsequent removal of blocking groups. Condensation of nucleotide (III) imidazolide with pyrophosphoric acid afforded corresponding 5'-triphosphate. Pools of natural NTPs and riboside (I) phosphates were monitored by HPLC after administering riboside (I), phosphate (III), or 4-methylthiopyrazolo(3,4-d)pyrimidine (II) into mice with leukemia L1210 or after incubating CaOv culture cells with these compounds. Treatment with riboside (I) or nucleotide (III) possessing antileukemic and cytotoxic activites led to much higher level of monophosphate (III), than treatment with biologically inactive base (II). ATP and GTP levels in CaOv cells incubated with (I) or (III) decreased by 60-70%, whereas (II) did not affect NTP pool. Bioactivation of nucleoside (I) into monophosphate (III) proceeds via direct phosphorylation by adenosine kinase. No tranformation of (II) into (I) or (III) occurs under these conditions.

The influence of methionine-gamma-lyase from Pseudomonas putida on DNA synthesis by CaOv and L-8 cell lines has been studied. The agent has been demonstrated to inhibit the incorporation of 3H-thymidine into L-8 cell line and to have no effect on CaOv cells.

L-lysine-alpha-oxidase from Trichoderma sp. fungi inhibits the synthesis of DNA, RNA and protein in cultivated cells of the Burkitt lymphoma (strain P3HRj) in vitro, which results in the blocking of the cells' transfer from phase S to phase G2/M of the mitotic cycle.

Problems on the anticancer drugs' screening in vitro are reviewed on the basis of generalized data from literature. The probability to screen in vitro the active substances is not less than the chance to screen the drugs active against the human tumours in experiments on animals. The use of special test-systems permits screening specific substances including those inducing the tumour cell differentiation.

The effect of different inorganic and organic selenium compounds on the nucleic acid synthesis in culture of human carcinoma ovary cells was studied. The rate of synthesis was determined by the incorporation of 3H-thymidine in the DNA and 3H-uridine in the RNA. Selenium compounds in the concentration to 1 mg/ml inhibited the nucleic acid synthesis in human tumour cells. The level of nucleic acid inhibition depends on the concentration of examined compounds. The tetravalent selenium compounds possessed the most pronounced cytotoxic effect.

The effect of homological and heterological (mice, pigs) interferon on cell cycle kinetics of human lymphoma cell in cultures (lines Molt-4, P3HRj, Namalva, Raji) was studied by the cytofluorimetric method. Different cell populations demonstrated unequal sensitivity to the antiproliferative interferon action. In sensitive cell populations (lines Molt-4, P3HRJ) nonspecific changes were revealed in the cell cycle kinetics. The action of the homological and heterological interferon on the investigated tumour cells was nearly the same.

L-lysine-alpha-oxidase, a new fungal enzyme catalyzing oxidative deamination of L-lysine, exerts an inhibitory effect on DNA, RNA and protein synthesis in human cells of carcinoma ovarius (CaOv) in vitro.

L-lysine-alpha-oxidase, a new fungal enzyme catalyzing oxidative L-lysine deamination, was shown to have an inhibitory effect on the in vitro synthesis of DNA, RNA and proteins in human carcinoma ovarian (CaOv) cells.

Specific L-asparaginase activity and non-specific cytotoxicity of asparaginase-glutaminase preparation from Pseudomonas fluorescens were studied. Two cell lines, i.e. the asparaginase-dependent (Berkitt lymphoma cells) and the asparaginase-independent (the ovary cancer cells) were used as the test-system. Incorporation of 3H-timidine into DNA was used as the criterion of the drug effect on the cells. Krasnitin was used as the reference preparation. The preparation of asparaginase-glutaminase was inferior to krasnitine by its specific antitumour asparaginase activity and superior to it by the general cytotoxicity in the cells of CaOv. With the help of the above test-system it is possible to study the specific asparaginase activity of the drugs containing L-asparaginase. For studying the specific glutaminase properties it is necessary to develop another cell test-system.

The action of homological and heterological (pig) leukocytic interferon on cell cycle kinetics of cultivated human tumour cells (lines HeLa, CaOv) and diploid strain was studied by flow cytofluorimetry. The cells of HeLa line and dFch strain demonstrated low sensitivity to interferon administration. The cells of interferon-sensitive line CaOv reacted by the change in cell cycle kinetics (arrest in G2/M). The action of heterological interferon on sensitive cells was similar to that of homological one.

Non-specific cytotoxicity and specific antitumor activity of 5 preparations of L-asparaginase from E. coli were studied. Two cell line, i.e. the asparagine-dependent (Berkitt lymphoma cells) and asparagin-independent (human ovary cancer cells) were used as the test-system. Incorporation of 3H-thimidine into DNA was the criterion of the preparation effect on the cells. Preparation I with the specific activity of 60-90 IU per 1 mg of protein obtained at the first stages of purification had high non-specific cytotoxicity. Preparation II obtained after further purification of preparation I, as well as preparation II without any stabilizer with the specific activity of 200 IU/mg were not inferior to the "Bayer" preparation by their biological properties. Addition of L-asparaginase to the preparation as a stabilizer of excessive glycine (preparation IV) increased its non-specific cytotoxicity and interfered with the study of its properties in the cell systems. Mannitol (preparation V) had no effect on the biological activity of L-asparaginase preparation.

L-Asparaginase sensitivity and asparagin-deficiency of 5 tumor cell populations, i.e. mouse lymphoma L-1210, LI0-1, LTL, Berkitt lymphoma and human ovary cancer, line CaOv were studied. Radiometric estimation of 3H-thimidine incorporation into the cells of DNA served a criterion of cytotoxicity. "Krasnitin" (FDR) was used as L-asparaginase. The cells of leukemia L-1210, lymphosarcoma LIO-1 and line CaOv were asparagine-independent and non-sensitive to L-asparaginase. The cells of mouse lympholeukemia LTL and the cultures of Berkitt human lymphoma proved to be asparagin-dependent and highly sensitive to L-asparaginase. In concentration of 50 IU/ml the drug inhibited incorporation of 3H-thimidine in the cells of LTL and Berkitt lymphoma by 97-98 and 75-80 per cent respectively. Inhibition of 3H-thimidine incorporation in the cells of LTL and Berkitt lymphoma was more pronounced after incubation with the drug for 8 and 24 hours respectively. Two out of the 5 tumor cell populations were chosen as a result of the study. One of these 2 populations, i.e. the cells of Berkitt lymphoma was asparagin-dependent and highly sensitive to L-asparaginase, the other, i.e. the cells of line CaOv was asparagin-independent and resistant to the specific antitumor effect of the enzyme. The use of a system of these two cell lines provided estimation of the ratio of the specific cytostatic (antitumor activity) and non-specific cytostatic properties in the preparations with L-asparaginase activity.

The in vitro experiments on CaOv cells demonstrated that ribamidyl (ribavirine) (Rb) enhances the intracellular pool of pyrimidine precursors of DNA. This was the basis for studies of its modifying effect on the antitumour activity of antimetabolites. In experiments with intact hybrid mice F1 (CBA+C57B1) the five times administration of ribavirine increase sharply the toxicity of 5-FU. The data should be taken into consideration when combining Rb with antimetabolites in clinical practice.