Adsorptive therapy as a modificator for tumor-host interaction.

The potential of one of the adsorption methods, enterosorption (ES), using the new generation of carbon adsorbents to correct the negative manifestations of tumor-host interaction in the framework of paraneoplastic syndrome (PNS) as well as systemic toxicity of chemo- and radiation therapy, is discussed. The ES influence on the development of PNS was demonstrated in C57/BL6 mice with transplanted Lewis lung carcinoma. Two-week administration of carbon enterosorbents resulted in a significant suppression of metastasis and correction of tumor-related anemia, activation of granulocytic line in the bone marrow with nearly 3-fold enhancement of its mitotic activity. ES exerted a positive influence on the structural-morphologic indexes and regenerative potential of kidneys and liver, mitigated manifestations of oxidative stress, decreased the level of endogenous intoxication, increased resistance of erythrocyte membranes and decreased ligand loading of blood plasma transport proteins. The effect of ES on anticancer activity and toxic reactions of cisplatin (CP) was evaluated in Guerin carcinoma-bearing rats. ES reduced significantly creatinine and other kidney biochemical indexes elevated in the blood plasma of rats after CP treatment. ES attenuated dystrophic changes in the histological structure of internal organs (kidney, liver, spleen), caused by tumor growth and significantly aggravated under the influence of CP. Such changes were specially traced in the kidneys and well reflect the nephroprotective potential of ES. In rats irradiated with X-ray in sublethal dose, highly activated granulated carbonic enterosorbents facilitated the restoration of white blood cells and lymphocyte count. The results obtained confirm the insights of academician R.E. Kavetsky predicting the future of adsorptive detoxification with activated carbons in the treatment of cancer patients.

Highly activated carbon enterosorbent mediates the suppression of paraneoplastic syndrome associated with Lewis lung carcinoma in mice.

AIM: To investigate the effect of enterosorption on the development of paraneoplastic syndrome in mice with Lewis lung carcinoma (LLC). MATERIALS AND METHODS: The study was performed on male С57/ВL6 mice with transplanted LLC. As an enterosorbent, highly activated powder fraction of HSGD was administered per os daily at a dose of 0.625 g/kg for two weeks starting from the 7th day after tumor cell transplantation. Analysis of hemo- and myelograms, morphological alterations in vital organs, the activities of catalase and superoxide dismutase, biochemical analysis of blood and quantitative analysis of hydroperoxides, malonic dialdehyde, аdvanced oxidation protein products was carried out by standard methods after completing the course of enterosorption. Ligand loading of blood plasma proteins was estimated by the method of differential scanning microcalorimetry. RESULTS: Administration of enterosorbent resulted in inhibition of LLC growth and in nearly 2-fold decrease of lung metastases number (p < 0.05). Activation of granulocytic line in the bone marrow with nearly 3-fold enhancement of mitotic activity took place after enterosorbent administration. Red cell lineage indices and bone marrow cellularity remained unaltered. After enterosorption session, the studied biochemical indices of peripheral blood evidenced on decreasing the endogenous intoxication and oxidative stress levels, improving the functional state of kidneys, increasing the resistance of erythrocyte membranes and lowering the ligand loading of blood plasma transport proteins. Morphological structure of kidneys and liver confirmed significant positive effect of enterosorption. The data of morphologic examination of gastric fundus, small intestine, and large bowel slides after 2-week administration of enterosorbent showed its high safety and proper evacuation from intestine. CONCLUSION: The two-week long enterosorption session in mice with LLC caused the suppression of tumor growth and metastasis, normalization of bone marrow hemopoiesis. Enterosorption exerted a positive influence on the structural-morphologic indexes and regenerative potential of kidneys and liver, mitigated manifestations of oxidative stress, decreased the level of endogenous intoxication, promoted deliganding of albumin molecule and deloading of erythrocyte membranes.

The influence of enterosorption on some haematological and biochemical indices of the normal rats after single injection of melphalan.

AIM: One of the most prominent side effects of intensive cancer chemotherapy is bone marrow suppression which is an independent negative prognostic factor for the time to tumor progression. The aim of the study was to evaluate the myeloprotective possibilities of carbon enterosorbents in the case of usage of alkilating drug melphalan (L-PAM). MATERIALS AND METHODS: L-PAM was injected intravenously to healthy inbred rats to cause the myelosuppression. 3 days before and 7 days after this, suspension of two types of carbon granulated enterosorbents were administered per os one time per day. On 8(th) day after L-PAM injection, the rats were weighted and blood and liver tissue were taken under Ketamine general anesthesia for biochemical examination. Peripheral blood smears were made also. RESULTS: Melphalan at a dose of 3 mg/kg causes expressed myelotoxic reaction: leucopenia, decreasing of erythrocytes, hemoglobin and platelets counts. Even on 8(th) day after single injection of this cytostatic we can detect expressed signs of oxidative stress like increasing of hydroperoxides, TBA-reactive substances, and decreasing of activity and level of main endogenic antioxidants - superoxide dismutase (SOD), catalase and reduced glutathione. L-PAM causes also the violation of kidney function such as increase of urea and creatinine level; and rising of endogenic intoxication with elevation of middle mass molecules level. In a dose of 3 mg/kg melphalan has no negative influence on liver function on 8(th) day of experiment. Enterosorption with carbon enterosorbents C1 (bulk density γ = 0.28 g/cm(3), granules diameter 0.15-0.25 mm, BET pore surface 1719 m(2)/g, therapeutic dosage 1400 mg/kg) and C2 (bulk density γ = 0.18 g/cm(3), granules diameter 0.15-0.25 mm, BET pore surface 2162 m(2)/g, therapeutic dosage 900 mg/kg) diminishes and mitigates negative side effects caused by single intravenous injection of melphalan. Carbon enterosorbent C2 have rather more expressed positive effect than C1 for practically all indices. The most important curative effect due to C2 administration is prominent myeloprotection of bone marrow of experimental animals. CONCLUSION: Carbon enterosorbent C2 is promising and perspective sorbent for prophylaxis and treatment of side effects of cytostatic chemotherapy including myelotoxicity, mucositis, kidney injuries, gonadotoxicity, etc.

Optimization of physico-chemical properties of carbon enterosorbents and evaluation of their sorption activity for use in the treatment of paraneoplastic syndrome and other endogenous intoxications in cancer patients.

AIM: Development of carbon enterosorbents with optimal physical-chemical properties and high adsorptive capacity for their usage in the treatment of paraneoplastic syndrome and other endogenous intoxication in cancer patients. METHODS: physical-chemical and biochemical methods of investigation. RESULTS: In the work it has been shown that performance of additional steam activation on pilot plant developed in R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, allows produce highly active granulated and fibrous carbon enterosorbents which possess well developed porous surface providing potent sorption potential toward compounds of hydrophilic and hydrophobic nature. Being placed in gastro-intestinal tract lumen these sorbents may cause certain effect on functional activity of detoxifying body systems and regeneration potential of many organs and tissues. CONCLUSION: The usage of carbon enterosorbents with optimal physical-chemical properties and high adsorptive capacity could be very perspective for correction of biochemical, immunologic, morphologic and hematological manifestations of paraneoplastic syndrome.

[P66shc action on resistance of colon carcinoma RKO cells to oxidative stress].

P66shc protein is an alternative transcript product of SHC1 gene. While two other isoforms (p52shc and p46shc) have adaptor function in RAS signaling pathway, p66shc regulates reactive oxygen species (ROS) level. P66shc genome knockout significantly extends lifespan in mice. Though p66shc was determined to translocate into mitochondria and led to increase in intracellular ROS, the mechanism by which the protein take part in signaling pathways that regulates resistance to cellular stresses remains poorly studied. P66shc has an important role in carcinogenesis and its increased expression correlates with poor prognosis in colon cancer. In this work we have applied RNA interference using lentiviral constructions that express short hairpin RNA (shRNA) against N-terminal CH2 domain of p66shc isoform. Using this approach p66 but not p52 and p46 SHC1 isoform expression was selectively suppressed in colon carcinoma RKO cells. RKO cells with p66shc knockdown have shown to be more resistant to oxidative stress induced by hydrogen peroxide or serum starvation. Fragmentation of mitochondria that depends on mitochondrial ROS accumulation during oxidative stress was significantly decreased in this cells. The data obtained are in agreement with hypothesis that p66shc participates in ROS accumulation in mitochondria and by this means promotes induction of apoptosis.