Theoretical ground for adsorptive therapy of anthracyclines cardiotoxicity

Anthracyclines play an important role in treatment of variety types of cancer due to their high effectiveness and broad spectrum of activity. However, a major limitation of their use is the dose-limiting cardiotoxicity. The inability to predict and prevent anthracycline cardiotoxicity is in part due to the fact that the molecular and cellular mechanisms remain controversial and incompletely understood. This review focuses on the biochemical basis of the anthracyclines toxic cardiac effects and pharmacological measures to their treatment and preventing. We describe the theoretical substantiation of the enterosorption abilities for diminishing of cardiac damage

Enterosorption as a method to decrease the systemic toxicity of cisplatin

A perspective adsorptive method to minimize systemic toxic effects of chemotherapy is enterosorption (ES). However, the capabilities of this method are far from being completely studied. The question remains opened — should ES be initiated in the first hours on completing cytostatic infusion without the risk of their anticancer activity to be decreased. Aim: to analyze ES influence on anticancer activity and toxic reactions of cisplatin (CP) upon the use of carbon enterosorbent in 1 h after intravenous administration of cytostatic. Methods: CP at the dose of 1 mg/kg body weigh (BW) was administered to Guerin carcinoma-bearing rats each second day for two weeks. Enterosorbents on the basis of highly activated carbon fibers were administered by per os daily 1 h after CP injection. 3 days after the last CP administration the rats were weighted and blood under ether narcosis has been taken for biochemical examination. Tumors and innate organs were isolated, weighted, and fixed in 4% buffered formalin for morphologic examination. Results: In rats administered with CP at the background of ES, BW loss was in 1.6 times lower than in animals after CP session. Relative kidney weight in CP-treated rats was 33.9% higher than in normal ones (p ≤ 0.05). No significant differences were detected between relative kidney weights in the CP + ES-treated and intact animals. Introduction of ES allowed prevent an 30% increase of creatinin content observed in blood plasma after CP treatment (р ≤ 0.05). Urea content was 1.7 times lower in blood plasma of CP + ES-treated rats than after CP treatment. CP caused significant toxic injuries in kidneys, liver, and spleen tissues. Morphologic structure of organs in rats treated with CP at the background of ES was affected at much lower degree. In tumors, large areas of newly formed connective tissue and blood vessels have been fixed after the CP+ES action instead of large necrotic area observed after CP treatment. ES caused insignificant suppression of Guerin carcinoma growth and had additional impact to inhibitory action of CP. Conclusion: Active carbon enterosorbents which are administrated just 1 h after CP administration possesses detoxicating potential sufficient for significant elimination of toxic effect of the cytostatic at the background of complete preservation of its antitumor activity

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

Carbon adsorbents in oncology: achievements and perspectives

The results of own investigations and literature data are summarized to determine the place of the main methods of adsorption therapy in complex treatment of the patients with malignant tumors. New possibilities for the usage of new generation of carbon adsorbents and modern adsorptive technologies in cancer treatment are discussed

Prevention of myelosuppression by combined treatment with enterosorbent and granulocyte colony-stimulating factor

Hematotoxicity and its complication are the prominent limiting factors for rational treatment of malignancies. Granulocyte colony-stimulating factor (G-CSF) is used to increase granulocyte production. It has been shown previously that enterosorption causes prominent myeloprotective activity also. Still, no trial was performed to combine both of them. Aim: To study the influence of combination of enterosorption and pharmaceutical analogue of naturally occurring G-CSF (filgrastim) on bone marrow protection and the growth of grafted tumor in a case of injection of melphalan (Mel). Materials and Methods: Mel injections were used for promotion of bone marrow suppression in rats. Carbon granulated enterosorbent C2 (IEPOR) was used for providing of enteral sorption detoxifying therapy. Filgrastim was used to increase white blood cells (WBC) count. Results: The simultaneous usage of enterosorption and filgrastim had maximum effectiveness for restoring of all types of blood cells. WBC count was higher by 138.3% compared with the Mel group. The increase of platelets count by 98.5% was also observed. In the group (Mel + C2 + filgrastim) the absolute neutrophils count was twofold higher, in comparison with rats of Mel group. Conclusion: Simultaneous admi­nistration of G-CSF-analogue and carbonic enterosorbent C2 is a perspective approach for bone marrow protection, when the cytostatic drug melphalan is used. Such combination demonstrates prominent positive impact on restoring of all types of blood cells and had no influence on the antitumor efficacy. Key Words: myelotoxicity, melphalan, enterosorption, granulocyte colony-stimulating factor

The study of possibility to elevate antitumor activity and decrease of systemic toxic effects of cisplatin by its binding with deliganded albumin

Aim: To evaluate antitumor and toxic action of cisplatin (CP) in non-bound form and in a complex with deliganded albumin. Methods: To study complex-formation between CP and albumin, differential scanning and isothermic flow microcalorimetry were used. For quantitive evaluation of albumin-bound CP, the method of ultrafiltration was applied. Concentration of platinum in the samples was determined by atomic-absorption spectral analysis. Antitumor and toxic effect of CP and CP-albumin complex was studied in vivo using Guerin carcinoma (GC) model. Results: It has been shown that the second drug-binding site, located in the III domain of albumin molecule is one of the main points of binding of CP. Purification of officinal human serum albumin (HSA) on highly active carbon hemosorbents of HSGD mark allows to obtain deliganded albumin (dHSA) with elevated complex-forming ability toward CP. Administration of CP-dHSA complex provides higher rate of GC growth inhibition, than that of CP, and the content of creatinine in blood plasma of GC-bearing rats increases by 15% versus 40% in the case of CP administration. Conclusion: The data obtained allow recommend application of CP-dHSA to complex for enhancement of antitumor action and decrease of toxic effects of cisplatin.Цель: оценить противоопухолевое и токсическое действие цисплатина (ЦП) в свободной форме и в комплексе с делигандизированным альбумином. Методы: дифференциальную сканирующую и изотермичную проточную микрокалориметрию использовали для исследования комплексообразования ЦП с альбумином. Для количественной оценки связанного с альбумином цитостатика использовали метод ультрафильтрации. Концентрацию платины в образцах определяли методом атомно-абсорбционного спектрального анализа. Противоопухолевый и токсический эффекты ЦП и ЦП в комплексе с делигандизированным альбумином изучали на крысах с карциномой Герена. Результаты: показано, что одним из основных мест связывания ЦП является второй лекарственный сайт, расположенный в III домене молекулы альбумина. Очистка фармакопейного сывороточного альбумина (ЧСА) на высокоактивных углеродных гемосорбентах марки ГСГД позволяет получить делигандизированный альбумин (дЧСА) с повышенной комплексообразующей способностью в отношении ЦП. ЦП в связанной с дЧСА форме обеспечивает повышение ингибирующего влияния цитостатика на рост карциномы Герена, при этом содержание креатинина в плазме крови повышается на 15% по сравнению с 40% при использовании несвязанного ЦП. Выводы: результаты проведенных исследований дают основания рекомендовать использование ЦП в комплексе с альбумином для усиления его противоопухолевого действия и снижения токсических эффектов

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. 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. Key Words: activated carbon, enterosorbents, porous surface, adsorptive capacity

Enterosorption combined with granulocyte colony stimulating factor decreases melphalan gonadal toxicity

Today due to improvements in cancer treatment there is an increasing number of long-term cancer survivors, many of whom suffer from infertility caused by malignancy itself and chemo- or radiotherapy. Also, anticancer therapy may cause myelosuppression. Presently granulocyte colony stimulating factor (G-CSF) is used for prevention and treatment of myelosuppression. Another treatment option used to decrease intoxication and ameliorate side effects of cancer therapy is sorption technology. The aim of our investigation was to study the efficiency of combined use of enterosorption and G-CSF to decrease gonadal toxicity of chemotherapy. Materials and Methods: Melphalan (L-PAM) injected i.v. at a single dose of 4 mg/kg to white inbred rats was used as gonadotoxic and myelosuppressing agent. Carbon enterosorbent C2 was administered by intragastric route as a suspension in saline at a dose of 5 ml per 1 kg of rats’ body weight (or 900 mg/kg of the dry mass of enterosorbent) daily for 3 days before and for 7 days after L-PAM injection. G-CSF was injected once a day for 4 days starting from the next day after L-PAM administration at a dose of 50 µg/kg. Histological preparations of testicular tissues were examined by light microscopy. Results: Our findings have shown that melphalan caused marked damage of testicular tissues and seminiferous, especially spermatogenic epithelium. The most expressed protection of the histological structure of testes was observed when enterosorbent and G-CSF were used in combination. Conclusion: Gonadal toxicity of chemotherapy could be efficiently decreased by the combined use of enterosorption and G-CSF

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 8th 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 8th 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 8th day of experiment. Enterosorption with carbon enterosorbents C1 (bulk density γ = 0.28 g/cm³, granules diameter 0.15–0.25 mm, BET pore surface 1719 m²/g, therapeutic dosage 1400 mg/kg) and C2 (bulk density γ = 0.18 g/cm³, granules diameter 0.15–0.25 mm, BET pore surface 2162 m²/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. Key Words: L-PAM, myelosuppression, oxidative stress, carbon enterosorbents

Effect of enterosorption on paraneoplastic syndrome manifestations in mice with highly angiogenic variant of lewis lung carcinoma

Aim: To study the correcting effects of microgranulated HSGD enterosorbent on hematological, morphological and biochemical indices of paraneoplastic syndrome in mice with highly angiogenic variant of Lewis lung carcinoma LLC/R9. Methods: The study was performed on male С57/ВL6 mice with transplanted LLC/R9. Enterosorbent HSGD was administered daily at a dose of 0.625 g/kg for 2 weeks starting from 7th day after tumor cell transplantation. When enterosorption was completed, an analysis of peripheral blood, biochemical indices and morphological structure of tumor, lung, liver, spleen and thymus was carried out by standard methods. Results: It has been shown that administration of enterosorbent did not affect LLC/R9 growth but resulted in nearly two fold decrease of the volume of lung metastases (p < 0.05). Erythrocyte number and hemoglobin level were higher by 30.0% (p < 0.05) and 23.3% (p < 0.05), respectively, in mice treated with enterosorbents as compared to untreated animals. In addition sorbent treatment completely normalized the thrombocyte index resulting in elevation of platelet number by 54.5% (p < 0.01) up to their level in intact mice. The morphological examination of liver and biochemical analysis of peripheral blood evidenced on significant positive correcting effect of enterosorption on histological structure of this organ and its functional acti­vity. Normalization of total proteins and serum albumin level as well as significant decrease of total lipid concentration by 29% (p < 0.01) in blood of treated mice were observed. Conclusion: Positive influence of microgranulated carbon sorbent on some hematological, morphological and biochemical indices of tumor associated symptoms in LLC/R9-bearing mice denotes that enterosorption-based therapy can be considered as a prospective treatment for correction of some paraneoplastic syndrome signs in cancer patients. Key Words: paraneoplastic syndrome, Lewis lung carcinoma LLC/R9, enterosorption