[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.

[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.

[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.

[A trial of the efficacy of using the synthetic antioxidant dibunol in the chemotherapy of experimental tumors]. / Opyt éffektivnosti primeneniia sinteticheskogo antioksidanta dibunola pri khimioterapii éksperimental'nykh opukholei.

We studied the therapeutic efficiency of the synthetic antioxidant Dibunol alone and in combination with cytostatic drugs on animals with experimental tumors after simultaneous and successive administration. Introduction of Dibunol to animals (tumor carriers) soon after the transplantation of tumor cells had adverse consequences, stimulated tumor growth and reduced the life span of animals. Dibunol exerted a therapeutic effect only in cases of developed tumors. Simultaneous introduction of cytostatic drugs (cyclophosphamide, dimethylnitrosourea, ADEKO) and Dibunol to tumor carriers was efficient and increased the mean life span of animals. The antitumor effect of the cyclophosphamide-Dibunol combination did not, in practice, depend on the interval between introductions of these drugs. However, the mean life span and survival of animals were somewhat higher the intervals between introductions or simultaneous application of the drugs were short.

[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.

[The sensitivity of tumor cells to low doses of antitumor preparations]. / Chuvstvitel'nost' opukholevykh kletok k nizkim dozam protivoopukholevykh preparatov.

The anticancer activity of water solutions of nitrosomethylurea, adriblastin and cisplatin at low and extra low concentrations (to 10(-15) M) was studied in the mice with experimentally induced tumor. Single and multiple administration of these drugs at extra low doses changed the life duration. Nitrosomethylurea (10(-15) M) increased the life duration by 20-86%. Nitrosomethylurea at extra low concentrations modifies the organism and tumor sensitivity to subsequent action of a high dose of this drug.

[A high-resolution 31P-NMR study of the disorders in the energy metabolic system of Ehrlich ascites cancer cells exposed to antitumor preparations]. / Issledovanie metodom 31P-IaMR vysokogo razresheniia narusheii v sisteme énergeticheskogo metabolizma kletok astsitnogo raka Erlikha pri vozdeistvii protivoopukholevykh preparatov.

The disturbance in energetic metabolism of Ehrlich ascite carcinoma cells during antitumor drug treatment was examined using high-resolution 31P-NMR. The value of antitumor drug effect was shown to be characterized by the kinetics of ATP and KF level alteration in tumor cells. The results correlated with the indexes of therapeutical activity of studied drugs.

[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.

[14Co-dimetinur distribution in mice in relation to the stage of the development of tumor process]. / Raspredelenie 14Co-dimetinura v organizme myshei v zavisimosti ot stadii razvitiia opukholevogo protsessa.

Pharmacokinetics of the antitumour agent 14CO-dimetinur (100 mg/kg) after oral administration to the intact mice and those with solid leukemia P 388 is characterized by its rapid delivery to organs and tumours with the achievement of maximum radioactivity 5 hours later and the further gradually decline during 4 days. The increased accumulation of the 14CO-products in kidneys and their retarded output from the brain and lungs against a background of the relatively equal distribution of radioactivity between other tested organs have been established. The same level of carbamoylated products in large tumours (the 16th day after leukemia transplantation) as well as in small tumours (the 9th day after inoculation) is in agreement with the conservation of the initial marked inhibitory effect of the drug against advanced tumours.

[The pharmacokinetics of the antitumor preparation of dimetinur]. / Farmakokinetika protivoopukholevogo preparata dimetinur.

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).

[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.

[Effectiveness of nitrosomethylurea derivatives in the combined chemotherapy of experimental tumors]. / Effektivnost' proizvodnykh nitrozometilmocheviny v kombinirovannoi khimioterapii éksperimental'nykh opukholei.

An antitumour activity of combined application of two nitrosomethylurea derivatives--dimethylnitrosourea and ADEKO with cytostatics of various groups was studied in transplanted tumours of La and L 1210 leukemias and Lewis lung carcinoma. A combined treatment by ADEKO with cyclophosphamide, methotrexate and dibunol resulted in therapeutic synergism evaluated by the tumour growth inhibition activity (kappa *) and by life span (delta tau) increase of tumour-bearing animals. An additive antitumour effect was established in case of a combined application of ADEKO with ftorafur, vincristine, prednisolone and dimethylnitrosourea with methotrexate.

[Induced resistance of experimental tumors to nitrosomethylurea]. / Indutsirovannaia rezistentnost' éksperimental'nykh opukholei k nitrozometilmochevine.

A nitrosomethylurea (NMU)--resistant strain of transplantable solid mammary gland tumor, which arose spontaneously in a F1CBA X S57Bl mouse, was developed, following successive transplantations of tumors from animals which received single intraperitoneal injections of 60-80 mg/kg of NMU. The basic tumor showed a high sensitivity to NMU (4th generation). Resistance to NMU was obtained after the 8th transplantation of tumor from NMU-treated animals: When the treatment of animals with NMU-resistant tumors was continued, tumor growth was stimulated and the time of survival became shorter. Tumors with induced resistance to NMU retained sensitivity to cyclophosphamide and sarcolysin and were refractory to dimethylnitrosourea treatment.