[Polysuccinimide exhibited antitumor activity in the experiment].

Antitumor activity of the novel for oncology compound, such as polysuccinimide, against some of experimental tumor models (Lewis lung carcinoma, Acatol adenocarcinoma, Ca-755 adenocarcinoma) has been established. This drug induced 60-80% tumor growth inhibition of these murine solid tumor strains. Polysuccinimide is also effective (60%) against development of metastatic process in lung (Lewis lung carcinoma). Polysuccinimide causes no changes in pH level in tumor tissue (P-388 leukemia, Acatol adenocarcinoma). This agent may be recommended for further profound preclinical study.

[Anti-nitrosative system as a factor of malignant tumor resistance to cytotoxic effect of nitrogen monooxide].

The inhibitory action of binuclear dinitrosyl iron complexes with glutathione on the growth of implanted solid tumor in BDF1 mice bearing Lewis lung carcinoma cells was found. The effect was induced by intraperitoneal injection of the binuclear dinitrosyl iron complexes to mice at a dose of 200 µM/kg daily on days 1-5 and 7-11. At the binuclear dinitrosyl iron complexes: free glutathione ratios of 1:1; and 1:10 in solutions, the inhibitory effect of the DNICs reached the level of 70% and 85%, respectively. When B-DNICs were not further infused, intensive tumor growth, a more rapid rate of tumor growth than control, was observed. The selective accumulation of DNICs as well as iron nitrosyl complexes of heme-containing proteins in tumors were detected by EPR method. The latter were found also in the tumors in control animals. Tumor growth delay in course of B-DNIC administration to the mice is supposed to be due to the elaboration of anti-nitrosative defense in tumor tissue in response to the action of NO released from B-DNIC.

[Anti-Tumour Activity of Dinitrosyl Iron Complex with Glutathione and S-Nitrosoglutathione Preparations: Comparative Studies].

The anti-tumor activity of the binuclear form of dinitrosyl iron complexes with glutathione against Lewis lung carcinoma, found earlier upon intraperitoneal administration of the complexes, was also observed when this preparation was injected subcutaneously. A 100 µM/kg subcutaneous dose of the complex being used daily (as calculated per one iron atom in binuclear dinitrosyl iron complexes) for 10 or 15 days, inhibited the tumor growth by 43%. The effect was observed during the first two weeks after tumor transplantation. After that, the tumors began to grow at the rate equal to or even higher than that one for control animals. The mean survival time for treated mice exceeded the control values by 30%. Binuclear dinitrosyl iron complexes administered intraperitoneally was also effective against Ca-755 adenocarcinoma. However, in this case the mean survival time for treated animals increased only by 7%. The anti-tumor activity of S-nitrosoglutathione against Lewis lung carcinoma growth inhibition by 70% and Ca-755 adenocarcinoma growth inhibition by 90% was also shown. However, unlike binuclear dinitrosyl iron complexes the anti-tumor effect of S-nitrosoglutathione decreased when a daily dose of the compound increased (from 200 to 400 µM/kg) The initial anti-tumor effect of binuclear dinitrosyl iron complexes and S-nitrosoglutathione is suggested to be due to NO released from both compounds. A subsequent suppression of the effect is determined by the development of anti-nitrosative and anti-oxidant defense systems in tumors.

[Polyacrylates of noble metals as potential antitumor drugs].

The antitumor activity of polyacrylates of the noble metals containing argentum (argacryl), aurum (auracryl) and platinum (platacryl) has been studied using experimental murine solid tumor models (Lewis lung carcinoma and Acatol adenocarcinoma). It has been found that polyacrylates of the noble metals are capable of inhibiting tumor development by 50-90% compared to control. Auracryl that inhibites the growth of Lewis lung carcinoma and Acatol adenocarcinoma by 80 and 90%, respectively, compared to control is the most efficient among the tested compounds and can be recommended for the further profound preclinical studies.

[Anti-tumour activity of dinitrosyl iron complexes with glutathione].

The anti-tumour dose-dependent effect of binuclear dinitrosyl iron complexes with glutathione as NO donors on solid tumour in the mouse Lewis lung carcinome was detected. The complexes being injected at the doses of 21, 42, 105 mg/kg daily during 10 days blocked completely the development of the tumour for the first week after tumour cell implantation into animals. After that, the part of tumour cells which remained in intact alive state began to grow at the rate equal to that for control animals. The effect was proposed to be caused via the formation of the anti-nitrosative defense system in the cells as a response to NO attack to cells. It was also hypothesized that this system can be inactivated by higher doses of dinitrosyl iron complexes. The data were obtained which were in line with the hypothesis.

Inhibition of tumor growth with ultralow doses of doxorubicin under experimental conditions.

Antitumor activity of ultralow doses of cytostatic doxorubicin was studied on BDF1 mice with Lewis lung carcinoma. The preparation was injected intraperitoneally in single doses of 10(-5), 10(-10), 10(-15), and 10(-20) M on the next day after tumor inoculation. The effect of ultralow doses was compared with that of a standard therapeutic dose of doxorubicin (8 mg/kg, 1.4 x 10(-3) M). Doxorubicin in ultralow doses produced an antitumor effect comparable with that induced by the preparation in standard doses. On day 12 after administration of doxorubicin in ultralow and standard doses, tumor size in mice did not exceed 20% of the control level.

[The sensitivity of experimental tumor systems to ultra low doses of doxorubicin]. / Chuvstvitel'nost' éksperimental'nykh opukholevykh modelei k sverkhmalym dozam doksorubitsina.

Biological effect of doxorubycin in standard (10(-3) mol/l) and ultra low doses (10(-5)-10(-20) mol/l) against some "signal" animal tumor systems--Lewis lung carcinoma, 755 adenocarcinoma, B-16 melanoma, Ehrlich carcinoma and L1210 leukemia was studied. The all models were very sensitive to the action of the drug in standard dose. Solid tumors' growth inhibition by 80-95% as well as increasing in life span of mice with L1210 leukemia by 86% in comparison with control and surviving of animals with Ehrlich carcinoma had been revealed. It had been shown that the drug in the area of ultra low doses occurred the following effects: inhibition of Lewis lung carcinoma growth by 80-95% compared to control after administration of the all tested ultra low doses; increasing of the life span of the animals with Ehrlich carcinoma and L1210 leukemia by 86-123% and 6-23%, correspondingly, upon the action of all tested ultra low doses; inhibition of B-16 melanoma growth by 50 and 70% after administration of the drug in doses 10(-20) mol/l and 10(-5) mol/l, correspondingly as well as deceleration of 755 carcinoma growth by 40% compared to control after action of the drug in the dose 10(-20) mol/l; stimulation of the B-16 melanoma growth by 20% relative to control after 10(-10) mol/l dose injection and enhancement of tumors sizes by 20-60% above control levels as a result of treatment of mice with 755 carcinoma by the drug in such ultra low doses as 10(-5) and 10(-15) mol/l. So, it was found that all tested tumor systems revealed certain sensitivity to the some ultra low doses of the drug. At the same time it was shown that doxorubycin in ultra low doses displayed alternative character of its biological effect, directivity of which varied according with the dose level and tumor strain.

[Antitumor effect of joint action of low intensity electromagnetic fields and ultra low doses of doxorubicin]. / Protivoopukholevaia éffektivnost' sovmestnogo vozdeistviia nizkointensivnogo élektromagnitnogo polia i sverkhmalykh doz doksorubitsina.

Combined action of a low intensive physical factor and a chemotherapeutic agent in ultralow doses against Lewis lung carcinoma was studied. Antitumor activity of low intensiwe electromagnetic field was expressed as inhibition of tumor growth at 60% compare to control. Ultra low doses of doxorubicin as well as its standard dose resulted in inhibition of tumor growth by 60-70% in comparison with control. Joint action of both factors leaded to increasing in the antitumor effect that reached such level of tumor growth inhibition as 85% relative to control.

[Taxotere and methylnitrosourea: experimental appraisal of combination chemotherapy]. / Taksoter i nitrozo metilmochevina: élsperimental'naia otsenka éffektivnosti sovmestnogo primeneniia.

The effectiveness of taxotere and methylnitrosourea (MNU) combined application against murine P388 leukemia has been studied. Antitumor drugs were administered separately or in combination in doses of 50, 60 or 70 mg/kg per day, i/p, beginning from day 1 after tumor transplantation. Combined administration was shown to potentiate antitumor effect, which also largely depended on schedule. Survival increase varied within 50-130% of control values. Optimal effect was observed with the following schedules: taxotere + MNU, 24-hour interval between injections, and MNU-taxotere, 4-day interval between injections. Synergism was in evidence since the therapeutic effect of combination treatment was significantly higher than that of either drug administered alone.

[Sensitivity of human melanoma xenografts to nitrosoalkylurea antineoplastic agents]. / Chuvstvitel'nost' ksenograftov melanomy cheloveka k protivoopukholevym preparatam klassa nitrozoalkilmochevin.

We studied the sensitivity of human melanoma (Bro strain) xenografts to drugs of the nitrosoalkylurea (NAU) class: nitrosomethylurea (NMM), karmustin (BCNU), nimustin (ACNU), nitrulin, and ADEKO. High antitumor activity of NAM was shown when the drugs were applied not only at the early, but also at the late stages of tumor progression (tumor mass 400 and 1200 mg, respectively). The therapeutic effect of the drugs was estimated with the use of criteria characterizing the kinetics of tumor regression, increased life span, and survival of treated animals. After early administration of the drugs (Day 4 after tumor transplantation), 67% and 50% of animals survive under the influence of nitrulin and ACNU, respectively, while the rate of tumor regression increased in the sequence nitrulin < karmustin < NMM < ACNU. After late administration (11 days after tumor transplantation), NMM was most effective at increasing survival (35% of survived animals by 35 days of observation), while the rate of tumor regression increased in the sequence ADEKO < NMM < karmustin < nitrulin < ACNU.

[Kinetics of development of human melanoma xenografts in immunosuppressed animals]. / Kinetika razvitiia ksenograftov melanom cheloveka na immunosupressirovannykh zhivotnykh.

An experimental model of development of the human tumor xenografts (melanomas HCMB and Bro) in immunosuppressed phenotypically normal animals (CBA/Ca mice) was developed. Optimal conditions were established for immunodeficiency induction in the animals. Kinetics of development of the xenografts in the immunosuppressed animals was studied. The level of 0(6)-alkyl-guanine-DNA-alkyltransferase, an enzyme responsible for repair of DNA damage in the tumor cells induced by chemotherapeutic agents (nitroalkylurea), was determined.

[The cytogenetic effect of ultralow doses of nitrosomethylurea]. / Tsitogeneticheskii éffekt sverkhmalykh doz nitrozometilmocheviny.

Cytogenetic effects of ultra low doses of nitrosomethylurea in the range 10(-12)-10(-17) mol/(kg x day) on the chromosome structure were studied in the Ehrlich tumor and leucosis L-12110 cells. It was shown that nitrosomethylurea at an ultra low dose of 10(-17) mol/(kg x day) induces chromosome aberrations in the cells of the both studied tumors after a single and multiple injections to random bred and linear animals. The recorded effect suggests that with the decrease of therapeutic dose by 13 orders of magnitude the cytogenetic activity of the drug decreases by no more than one order of magnitude.

[An antimutagenicity study of bioginseng]. / Izuchenie antimutagennosti biozhen'shenia.

We studied antimutagenic properties of bioginseng, a biotechnological product obtained from the callus culture of the ginseng root cells by alcohol extraction (bioginseng-1) and lyophilization (bioginseng-2). We have estimated the frequency of sister-chromatid exchange and chromosome aberrations in the culture of Chinese hamster cells, of chromosome aberrations in cells of the Ehrlich-ICF ascite strain, and of micronuclei in the mouse bone marrow cells. The bioginseng exerted an antimutagenic effect with respect to nitrosomethylurea and cyclophosphamide. The sister-chromatid change in the culture of Chinese hamster cells decreased under the influence of bioginseng due, apparently, to enhanced DNA repair. The most distinct protective effect was observed when ginseng was introduced 2 h prior to the cell treatment with mutagens.

[Adaptation to chemical mutagens]. / K voprosu ob adaptatsii k khimicheskim mutagenam.

Pre-adaptation of normal and tumor cells to the action of methylnitrosourea was studied. To attain these ends, a single low dose (10 mg/kg) was administered to animals two hours prior to the administration of main therapeutic dose (100 mg/kg) and the number of chromosomal rearrangements was determined. A significant decrease in translocation incidence was observed in metaphases of Ehrlich-ICP ascitic strain. Similar results were obtained on cells of murine bone marrow. The mechanisms of pre-adaptation to the action is discussed.

[The dose-dependent cytogenetic and growth-inhibiting effects of a new antitumor preparation from the nitrosourea group]. / Dozozavisimyi tsitogeneticheskii i rostingibiruiushchii éffekt novogo protivoopukholevogo preparata gruppy nitrozomochevin.

Kinetics of growth-inhibiting and cytogenetic effect of a new carbon-substituted nitrosourea derivative (ADEKO) has been studied in a wide dose range. A linear dose-effect dependence was observed. The level of damaged cells in a population is connected with a number of chromosomal aberrations per cells with a semilogarithmic dependence. The drug has a pronounced clastogenic effect that reveals itself in total damaging of chromosomal structure of tumor cells. It also causes cell polyploidization with the increase in does and duration of action. Chromosomal aberrations induced by the drug are observed in the tumor long after the action of the drug and their level correlates positively with antitumor activity of ADEKO. ADEKO damages preferentially tumor cells as compared to bone marrow.

[Comparative evaluation of the antitumor, cytogenetic and immunodepressive effects of dimetinur when used perorally and parenterally]. / Sravnitel'naia otsenka protivoopukholevogo, tsitogeneticheskogo i immunodepressivnogo éffektov dimetinura pri peroral'nom i parenteral'nom primenenii.

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.

[Dynamics of the chromosomal damages to Ehrlich ascitic cancer and bone marrow cells of mice by the antitumor preparation dimetinur]. / Dinamika povrezhdenii khromosom kletok astsitnogo raka Erlikha i kostnogo mozga myshei protivoopukholevym preparatom dimetinur.

The dimetinur effect upon chromosomes of the Ehrlich ascite carcinoma and bone marrow cell populations was analyzed by the cytogenetic method for 10 days after i.p. and i. v. drug administration in doses from 50 to 150 mg/kg. Kinetic regularities of changes in a fraction of cells with chromosome breakages and in the number of broken chromosomes per cell as well as "dose-effect" relations are determined. A linear correlation is established between the level of residual chromosome damages in a population of tumour cells and the coefficient of activity chi* characterizing the antitumour effect of dimetinur. Selectivity of the dimetinur mutagenic action expressed as a more deep and prolonged damage of the genetic system of tumour cells as compared to bone marrow cells of tumour-bearing animals is shown under conditions of a pronounced therapeutic activity.

[Cytogenetic characteristics of the leukemia L1210 strain in the development of drug resistance]. / Tsitogeneticheskaia kharakteristika shtamma leikoza L1210 pri razvitii lekarstvennoi ustoichivosti.

The dose and schedule dependent resistance occurred at the 17th (L1210/D1) and 27th (L1210/D2) generations during leukemia L1210 transplantation by the cells treated with suboptimal diazane doses. With growth of the resistance to diazane the selection of modal cell class with 39 chromosomes took place while in the parent leukemia line the modal cell class consists of the cells with 40 chromosomes. No reliable differences were observed in G-banded karyotypes between the resistant subline L1210/D1 and the parent line L1210. When the resistant sublines were transplanted without supporting the diazane doses no restoration of the leukemic cells sensitivity to the drug was observed (the time of observation for L1210/D1 was 92 transplantation generations and for L1210/D2-48 generations). The changed number chromosome characteristics remained the same in this case.

Effect of N-nitrosomethylurea on substrains of Fisher lymphadenosis L-5178 resistant to antitumoral antibiotics.

A cytogenetic analysis of variants of Fisher mouse lymphadenosis L-5178 resistant to the antitumoral antibiotics bruneomycin and rubomycin C showed that the cytogenetic characteristics of the changes in the tumor cell population correlate with the chemotherapeutic indices of the development of drug resistance. Cytogenetic and kinetic analyses showed that variants of Fisher lymphadenosis L-5178 resistant to bruneomycin and rubomycin C retain sensitivity to N-nitrosomethylurea (NMU). The activity of NMU in an experiment on resistant substrains of lymphadenosis can serve as a basis for the clinical use of NMU in the treatment of lymphomas resistant to antibiotics.