Comparative Study of Antitumor Efficiency of Intraperitoneal and Intravenous Cytostatics in Experimental Rats with Disseminated Ovarian Cancer.

Antitumor efficiencies of cytostatics dioxadet, cisplatin, mitomycin C, melphalan, and paclitaxel after a single intraperitoneal or intravenous injection in doses of 1.5, 4, 1.5, 2, and 5 mg/kg, respectively, were studied on the model of transplanted ovarian tumor in 124 rats. The antitumor effects were evaluated by the increase in median survival. Dioxadet, cisplatin, and melphalan injected intraperitoneally significantly prolonged the lifespan median - by 79, 88, and 114%, respectively, and were in fact ineffective, when injected intravenously. Intraperitoneal mitomycin C prolonged lifespan median by just 35%, intravenous - by 152%. Paclitaxel injected intraperitoneally and intravenously prolonged the lifespan median by 45 and 81%, respectively.

[Plasma low-molecular-weight DNA in patients with chronic obstructive pulmonary disease]. / Nizkomolekulyarnaya DNK plazmy krovi u bol'nykh khronicheskoi obstruktivnoi bolezn'yu legkikh.

AIM: To determine plasma extracellular low-molecular-weight DNA (elmwDNA) as an indicator of apoptosis in patients with chronic obstructive pulmonary disease (COPD) in remission versus healthy donors, patients with chronic non-obstructive bronchitis (CNOB), and their first-degree relatives (FDRs). SUBJECTS AND METHODS: The investigation recruited 110 participants, including 17 healthy donors, 31 patients with COPD, and 20 patients with CNOB in remission, 19 healthy FDRs of patients with COPD, and 23 healthy FDRs of those with SNOB. The plasma levels of elmwDNA were determined in the study participants. Nucleic acids were isolated by phenol/chloroform extraction, precipitated with ethanol, and treated with RNase; elmwDNA was analyzed by electrophoresis. RESULTS: In patients with COPD, the mean level of elmwDNA was 7.8±2.0 ng/ml, which was 3.9 and 3.0 times statistically significantly lower than that in healthy donors and patients with SNOB, respectively; while the level of elmwDNA in the latter did not differ statistically significantly from that in healthy donors. In both the blood relatives of patients with COPD and FDRs of those with SNOB, the mean level of elmwDNA was not significantly different from that in healthy donors. The content of elmwDNA tended to increase in COPD patients aged 60-80 years as compared to those aged 45-59 years; that in both age groups was, however, significantly lower than in healthy donors of the same age. CONCLUSION: The level of elmwDNA in plasma and, accordingly, apoptosis in the lung are reduced in patients with COPD in remission, whereas that is unchanged in those with SNOB. In patients with COPD, blood elmwDNA release is unrelated to heredity and varies little with age. The determination of elmwDNA is recommended for use in patients with COPD to assess apoptosis.

[Low-frequency noise as a hazard increasing occurrence of chromosomal aberrations and promoting cell death.]

The authors studied influence of low frequency noise on cells genome and cell death processes. Vistar male rats were exposed to low frequency noise with maximal range up to 250 Hz with noise pressure of 120.dB or 150 dB once (during 17 minutes) or repeatedly (17 minutes 5 days per week over 13 weeks), after that frequency of chromosomal aberrations in bone marrow cells and serum low-molecular DNA were assessed. In comparison with reference values, single exposure to low frequency noise with noise pressure of 120 or 150 dB reliably increased frequency of%chromosomal aberrations more than 10-fold and caused dicentrics in aberrations spectrum, significally increased serum-low-molecular DNA over 7-fold, with low-molecular DNA level remaining high during 7 days after exposure to low frequency noise. Repeated exposure to low frequency noise with noise pressure 120 and 150 dB resulted in reliable increase of low-molecular DNA level 36-fold and 22-fold respectively vs. reference values. Thus, low frequency noise harms genome, with more frequency of chromosomal aberrations, and increases apoptosis that manifests in higher level of extracellular low-molecular DNA. Some part of the work was performed with governmental financial support of leading universities of Russian Federation (grant 074U01).

Generation of high-intensity spectral supercontinuum of more than two octaves in a water jet.

In this paper, we demonstrate experimentally for the first time (to our knowledge) the generation of spectral supercontinuum (SC) of more than two octaves with high intensity in a water jet. The spectrum of the generated SC extends from 350 to 1400 nm, with intensities up to 1011 W/cm2, and its generation efficiency is more than 50%. For the pump intensity 3.0×1012 W/cm2 in the spectral range from 400 to 800 nm, the spectrum is nearly flat (less than 40% deviation), which is useful for many applications.

Radioprotective and Apoptotic Properties of a Combination of α-Tocopherol Acetate and Ascorbic Acid.

We studied radioprotective and apoptotic properties of a combination of α-tocopherol acetate and ascorbic acid. α-Tocopherol acetate (10 mg/kg body weight) or ascorbic acid (20 mg/kg) or combination of these agents in the same doses was orally administered to male rats at various terms before and after single whole-body exposure to γ-irradiation in the doses of 2 and 8 Gy. Irradiation increased the frequency of chromosome aberrations in bone marrow cells and plasma level of low-molecular-weight DNA. Vitamin combination administered before or after irradiation significantly reduced the frequency of chromosome aberrations by 2-2.5 times. Administration of this combination 10 min before irradiation 1.5-fold increased the content of low-molecular-weight DNA in blood plasma in comparison with the control animals exposed to radiation. The combination of α-tocopherol acetate and ascorbic acid produced radioprotective effects and enhanced apoptosis in irradiated cells.

Toxicogenomic Effects in Rat Blood Leukocytes and Chemoprophylaxis of Radiation-Induced Carcinogenesis.

Toxicogenomic parameters were studied in the blood of female rats after exposure to ionizing γ-radiation in a dose of 4 Gy and chemoprophylaxis with α-difluoromethylornithine, eleutherococcus or leuzea extracts, which were used in animals with morphological manifestations of tumor growth under conditions of radiation-induced carcinogenesis. Life-time evaluation of toxicogenomic effects was carried out by express method for measurements of blood nucleotid DNA - fluorescent indication. The level of hyperaneu/polyploidy increased in the blood leukocytes of control rats 30 days after radiation exposure. A significant decrease of genotoxicity as a result of drug treatment in comparison with the number and multiplicity of tumors in irradiated animals was found only in the endocrine and reproductive organs of rats treated by eleutherococcus extract.

[Relationship between benign prostatic hyperplasia and prostate cancer: new opportunities for prostate cancer chemoprevention].

In a review article the relationship between benign prostatic hyperplasia (BPH) and prostate cancer (PC) has been conducted. Epidemiological data on increasing the risk of PC in patients with BPH are presented. There are discussed common for BPH and PC constitutional, food, and life style etiologic factors and also common for the both diseases pathogenetic factors such as androgens, inflammation, metabolic syndrome. Pharmaceutical drugs and natural agents that have unidirectional therapeutic and preventive effect on BPH and PC are presented. Results of experimental studies of the authors to prove the link between BPH and PC are presented. It is concluded that BPH is a risk factor for PC and, ideally, drugs for the treatment of BPH should have a chemo preventive effect on PC.

[Hyperthermic intraperitoneal chemotherapy combined with cytoreductive procedure in patients with peritoneal pseudomyxoma].

AIM: To study the results of intraperitoneal chemoperfusion combined with cytoreductive procedure in patients with peritoneal pseudomyxoma. MATERIAL AND METHODS: For the period 2006--2015 seven patients with peritoneal pseudomyxoma underwent aggressive treatment using hyperthermic intraperitoneal chemoperfusion combined with cytoreductive procedure at the Department of General Oncology of N.N. Petrov Research Institute of Oncology. RESULTS: Two patients had postoperative complications. One of them died after 12 days postoperatively. Features of postoperative complications were predominantly determined by volume of cytoreduction. Advanced tumoral process caused death in 2 patients additionally. Other patients are still alive during 4--28 months after surgery. CONCLUSION: Hyperthermic intraperitoneal chemoperfusion combined with cytoreductive procedure is advisable for peritoneal pseudomyxoma to improve survival. Optimal cytoreduction should be developed in researches with large number of patients to decrease incidence of complications.

[Release of Extracellular DNA after Administration of Radioprotective Combination of α-Tocopherol and Ascorbic Acid].

Radioprotective and apoptotic activities of α-tocopherol acetate (vitamin E) and ascorbic acid (vitamin C) have been studied in 180 Wistar male rats. Rats were administered a single oral dose with vitamin E, vitamin C or their combination at prophylactic doses before or after the single whole body exposure to irradiation at the doses of 2 or 8 Gy. The radioprotective effect was evaluated by the frequency of chromosomal aberrations at metaphase plates of the bone marrow cells, apoptotic--by the level of circulating low-molecular-weight DNA (ImwDNA) in the blood plasma of irradiated rats. Administration of the combination of vitamins E and C before and after the irradiation at the dose of 2 Gy reduced the number of the cells with chromosomal aberrations thus providing the radioprotective effect, but separately administration of these vitamins did not show the significant radioprotective activity. Administration of the combination of vitamins E and C before irradiation with 8 Gy increased the lmwDNA in blood thus providing the apoptotic effect. So, synergy of radioprotective activities has been revealed in vitamins E and C action at prophylactic doses. Radioprotective effect of the combination of vitamins E and C can be associated with the apoptotic activity and can be explained by elimination of the least viable irradiated cells from the cell population.

[Nucleosome fracton of extracellular dna as the index of apoptosis].

Review is devoted to the analysis of changes of the extracellular DNA (excDNA) in pathological conditions involving the process of apoptosis, and the possibility of using of excDNA in the diagnosis and evaluation of course of various diseases. Apoptosis is the main mechanism of the appearance of the DNA in the circulation. ExcDNA found in the norm, its function is considered to be the part of the immune response. The excDNA content increases substantially during the induction of apoptosis. Dynamics of increase of excDNA content in stroke allows to diagnose the form of stroke and massiveness of destruction of brain tissue. Reduced content of excDNA is associated with the inhibition of apoptosis, it was shown that under such conditions there is a change of composition of excDNA. Investigation of excDNA character changes in the progression and treatment of cancer substantiates the possibility of early assessment the effectiveness of treatment. It is experimentally shown the immunosuppressive action of excDNA of tumor and its transforming effect on the cells. Ionizing radiation is an examples that demonstrated the association of induction of apoptosis and the release of excDNA. It is characterize some of the genome sequences of excDNA. Created on the basis of excDNA study tests of minimally invasive diagnostics are potentially useful in oncology and other areas of medicine. The study of tandem repeats, which are absent in the assembled genome, but there is a part of excDNA, will create tests for the diagnosis of cancer in the early stages.

Simulation of Chemoperfusion Treatment for Abdominal Carcinomatosis.

Experimental perfusion system and technology for normothermic and hyperthermic intraperitoneal chemoperfusion are developed for the treatment of abdominal carcinomatosis in rats with transplanted ovarian cancer. MTD of cisplatin in normothermic intraperitoneal chemoperfusion and hyperthermic perfusion are 40 and 20 mg/kg, i.e. by 10- and 5-fold higher than the dose of this cytostatic for routine intraperitoneal injection. Normothermic intraperitoneal chemoperfusion with cisplatin increases median survival time by 200% (p=0.039) in comparison with intraperitoneal injection.

[Intraperitoneal chemotherapy--a method of improving treatment effectiveness in ovarian cancer].

The study or antitumor effects of dioxadet, cisplatin, melphalan, paclitaxel, mitomycin C, cyclophosphamide and gemcitabine at intraperitoneal (i.p.) and intravenous (i.v.) administration as monochemotherapy and polychemotherapy in a rat model of ascitic ovarian cancer was carried out in 244 female Wistar rats. Ovarian cancer was transplanted i.p. at a number of 1 x 10(7) tumor cells. The drugs were administered once in 48 hours after ovarian cancer transplantation i.p. or i.v. for monotherapy--in maximum tolerated doses, for i.p. polychemotherapy--in half doses from maximum tolerated doses. Antitumor effects of the treatment were estimated in increase in median survival time (MST) compared to control rats who were administered saline i.p. At i.p. administration dioxadet, cisplatin and melphalan increased MST by 79%, 88% and 144%, respectively, while at i.v. administration these drugs didn't affect MST. Mitomycin C and paclitaxel had stronger antitumor action at i.v. administration increasing MST by 152% and 81%, respectively, while at i.p. administration these drugs increased MST by 35 and 45%, respectively. Combinations dioxadet + cisplatin, dioxadet + cyclophosphamide and dioxadet + paclitaxel at i.p. administration increased MST by 305%, 277% and 133%, respectively, and had additive antitumor action compared to mono-effects of these drugs. Gemcitabine and combination dioxadet + gemcitabine at i.p. administration didn't significantly affect survival of rats with ovarian cancer. Intraperitoneal monochemotherapy and polychemotherapy could be more effective in the treatment of peritoneal carcinomatosis from ovarian cancer compared to systemic administration of the drugs.

[Intraoperative intraperitoneal chemoperfusion treatment with cisplatin and dioxadet on a model of peritoneal carcinomatosis in ovarian cancer: safety and efficacy evaluation].

A comparative study of safety and efficacy of normothermic and hyperthermic intraperitoneal chemoperfusion (IPEC and HIPEC) with cisplatin and dioxadet was carried out in 143 female Wistar rats. Ovarian cancer was inoculated intraperitoneally (i.p.). In 48 hours after ovarian cancer inoculation the drugs were administered i.p. or IPEC and HIPEC with the drugs were performed using maximum tolerated doses (MTD). Content of cisplatin was determined in the perfusate and blood plasma during HIPEC with the drug. The leukocyte count was measured using veterinary hematologic analyzer in peripheral blood of rats at different time points after HIPEC with dioxadet. Efficacy of the treatment was estimated in increase in median survival time (MST). During HIPEC cisplatin was accumulated in the abdominal cavity in a considerable amount with minimal systemic absorption. HIPEC with dioxadet didn't significantly affect the leukocyte count in peripheral blood while i.p. administration of dioxadet suppressed leukopoiesis. MST of rats after IPEC with cisplatin was 37.5 days which was significantly higher compared to MST after i.p. administration of cisplatin (19.5 days, p = 0.037). HIPEC with dioxadet was the most effective regimen of treatment with MST of rats reaching 49 days which was significantly higher compared to MST after HIPEC with cisplatin (25.5 days, p = 0.002).

[Therapeutic activity of gemcitabine in intracranial tumors].

Gemcitabine is known to exert a therapeutic effect on brain tumors despite the limited permeability of the blood-brain barrier (BBB). In our experimental research single intraperitoneal (i.p.) injection of gemcitabine 25 mg/kg provided increase in median survival of mice with intracranially transplanted Ehrlich carcinoma by 41-89% (p < 0.001). In this experimental model i.p. administration of gemcitabine (permeability of the BBB of less than 10%), carmustine (good permeability of the BBB), cyclophosphamide (poor permeability of the BBB) and cisplatin (doesn't penetrate through the BBB) increased median survival of mice by 88% (p < 0.001), 59% (p = 0.001), 35% (p = 0.005) and 18% (p = 0.302) respectively. Considering strong correlation between antitumor activity of the drugs (carmustine, cyclophosphamide and cisplatin) and their permeability of the BBB, efficacy of gemcitabine in intracranial tumors could be due to its wide range of therapeutic doses.

[CHEMOPERFUSION TECHNOLOGIES IN TREATMENT FOR MALIGNANT TUMORS].

The data of literature on possibility of the use of perfusion technologies in combined treatment for malignant tumors of different sites are presented. Possible complications during hyperthermic chemoperfusion are discussed and the effectiveness of this method is analyzed.

[Sequencing of low-molecular-weight DNA in blood plasma of irradiated rats].

Extracellular low-molecular-weight DNA in blood of irradiated rats was sequenced for the first time. The screening of sequences in the DDBJ database displayed homology of various parts of the rodent genome. Sequences of low-molecular-weight DNA in rat's plasma are enriched with G/C pairs and long interspersed elements relative to rat genome. DNA sequences in blood of rats irradiated at the doses of 8 and 100 Gy have marked distinctions. Data of sequencing of extracellular DNA from normal humans and with pathology were analyzed. DNA sequences of irradiated rats differ from the human ones by a wealth of long interspersed elements. This new knowledge lays the foundation for development of minimally invasive technologies of diagnosing the probability of pathology and controlling the adaptive resources of people in extreme environments.

[Experimental technology of chemoperfusion treatment for abdominal carcinomatosis in ovarian cancer].

An experimental technology of normothermic intraperitoneal chemoperfusion and hyperthermic intraperitoneal chemoperfusion with cisplatin and dioxadet has been elaborated to treat abdominal carcinomatosis in ovarian cancer. Antitumor effects of the treatment were evaluated for the duration of animal life. Normothermic intraperitoneal chemoperfusion and hyperthermic intraperitoneal chemoperfusion with cisplatin and dioxadet in comparison with the standard intraperitoneal administration significantly increased the median life expectancy by 75-92%. Hyperthermic intraperitoneal chemoperfusion with dioxadet demonstrated potentiation of antitumor effect of hyperthermia and dioxadet. Experimental technology is recommended for testing new drugs and methods of chemoperfusion for malignant tumors affecting the peritoneum.

[Antitumor effect of dioxadet in intraperitoneal chemoperfusion treatment for advanced ovarian cancer in experimental setting].

The study of antitumor efficacy of dioxadet in chemoperfusion treatment of ascitic ovarian cancer was carried out in 125 Wistar female rats. Ovarian cancer was inoculated intraperitoneally at a number 1x10(7) tumor cells per rat. Intraperitoneal administration of dioxadet as well as chemoperfusion was performed once in 48 hours after the ovarian cancer inoculation. Dioxadet was used at maximal tolerated doses which were 1.5 mg/kg for intraperitoneal administration, 30 mg/kg for normothermic intraperitoneal chemoperfusion (IPEC), and 15 mg/kg for hyperthermic intraperitoneal chemoperfusion (HIPEC). Antitumor effects of dioxadet were estimated in increase of median survival. In the control group, where animals didn't receive any treatment, the median survival was 9 days. Increase of the median survival after intraperitoneal administration of dioxadet, IPEC and HIPEC with dioxadet was 211% (p=0,001), 244% (p=0,001) and 444% (p=0,001), respectively, compared to the control group. Hence, intraperitoneal chemoperfusion with dioxadet (normo- or hyperthermic) is more effective compared to standard intraperitoneal administration of the drug. At HIPEC with dioxadet potentiating antitumor action of hyperthermia and dioxadet on the ovarian cancer growth was achieved.

[Opportunities of intraoperative hyperthermic perfusion application in treatment of peritoneal carcinomatosis].

Normothermic intraperitoneal perfusion (IPEP) and hyperthermic intraperitoneal perfusion (HIPEP) were performed in 44 Wistar female rats with transplanted ascites tumor of the ovary. Opportunities of intraoperative hyperthermic perfusion application in treatment of peritoneal carcinomatosis. Antineoplastic affects were evaluated according to increase of animals' survival. IPEP and HIPEP increase median survival time by 78% (p=0.307) and 150% (p=0.005) respectively in comparison with conventional intraperitoneal introduction of physiological solution. Thus HIPEP has statistically more significant antineoplastic affect in vase of peritoneal carcinomatosis.

[Comparative effects of difluoromethylornithine and tincture of Siberian ginseng root on radiation carcinogenesis and life span in rats].

Influence of alpha-difluoromethylornithine (DFMO) and tincture of Siberian ginseng root (TSGR) on radiation carcinogenesis and life span in rats has been studied. The results of the study demonstrate that DFMO as well as TSGR significantly improved survival and decreased incidence and multiplicity of malignant and benign tumors in rats subjected to ionizing radiation. Beneficial effect on the rat survival rate and anticarcinogenic action of DFMO were more expressed compared with TSGR.