Представлены результаты изучения противоопухолевой активности отечественного аналога соматостатина цифетрилина на экспериментальных опухолях животных. Выявлен максимальный противоопухолевый эффект цифетрилина в дозе 10 мг/кг на перевиваемой модели рака шейки матки РШМ5 непосредственно после окончания применения препарата (торможение роста опухоли, ТРО = 86 %). Показано, что цифетрилин в дозе 120 мг/кг способствовал увеличению продолжительность жизни (УПЖ) животных с аденокарциномой Са755 на 59 % (ТРО = 86 %). Препарат подавлял рост аденокарциномы толстой кишки АКАТОЛ в течение 9 дней: ТРО = 79 % и 62 % в 1-й и 9-й день наблюдения, соответственно, а меланомы В16 — в течение 17 дней, ТРО = 77 – 62 %. Установлено, что режим ежедневного перорального введения препарата в течение 5 дней является наиболее эффективным: на РШМ5 эффект цифетрилина оставался статистически достоверным (ТРО = 54 %) до 22-го дня наблюдения, а на Са755, АКАТОЛе и меланоме В16 — на протяжении 14 дней (ТРО 82, 58 и 59 %, соответственно). Показаны высокая противоопухолевая эффективность цифетрилина в отношении развившейся опухоли РШМ5 (ТРО = 79 – 76 %), а также антиметастатическая эффективность препарата (61 % торможения роста метастазов) в комбинации с хирургическим удалением опухоли.

Introduction. Governments around the world seek to reduce rapidly rising health care costs. Using the same high quality and often cheaper than the original brands, generics greatly reduces costs while providing an adequate quality of care. Therefore the development of generic medicines is an important task. The purpose of the study - the reproduction of the pharmaceutical dosage form for creation of national drug-generic epirubicin. Materials and methods. The study used a substance epirubicin (Ph. Eur current edition, Teva Pharmaceutical Industries Ltd., Israel); “Farmorubicin”, production “Pfizer Italia Srl” for “Pfizer Inc.”, Italy / US and excipients conforming to with relevant regulatory documents. Mice transplanted tumor: lymphocytic leukemia P388. Methods: technological, pharmaco-analytical, biological and pharmacological. Results. Pharmaceutical analysis of reproduced generic-drug “Epirubicin-RONC®” showed that itfully meets the requirements of manufacturer’s monograph. The results of “acute” toxicity study in rats and observations of the experimental animals within 30 days after a single administration suggest that both drugs have similar toxicological properties and are almost identical. Generic “Epirubicin RONC®” and “Farmorubicin” in lyophilized dosage form for injection 10.0 mg/vial, administered once, shows equal antitumor effect at two administration routes in mice with transplantable tumor: lymphocytic leukemia P-388. Conclusion. N.N. Blokhin Russian Cancer Research Center Ministry of Health of Russia has been reproduced generic - “Epirubi-cin-RONC®”, which is fully conform to the imported drug.

Objective: Evaluation of antitumor activity of a novel alkylnitrosoureas derivative Ormustine (an alkylnitrosocarbamoyl L-ornithine) in mouse lymphoid leukemia models. Materials and methods Antitumor activity of Ormustine has been evaluated in B6D2F1 mice with ascites form of leukemia (L1210, L1210/arenosa, L1210/citrullin and P388) and the solid (P388) form. In this study we used preparations from the alkylnitrosourea group: Ormustine, Aranoza and Lizomustine. Treatment of animals was started 24 hours after inoculation of leukemia intraperitoneally, and 48 hours after inoculation subcutaneous P388. Drugs in a wide range of doses were administrated once intravenously. The follow up period of the animals continued until their death. Criteria of antitumor effect were increasing life expectancy and cure. Evaluation criteria of antitumor effect was the increase in life of experimental mice compared to control ones. Results. Antitumor activity of a novel alkylnitrosoureas derivative, Ormustine has been studied in vivo on the growth of transplanted lymphoid leukemia, such as L1210 (ascites version) and P388 (ascites and solid tumor). Effective dose of single intravenous injection Ormustine against lymphoid leukemia L1210 and P388 was 125 mg/kg. The drug effectively inhibited growth of experimental leukemia. The significant part of the mice with limfoleukemia has been cured. We have also established the single intravenous therapeutic dose of Ormustine on L1210 and Р388 leukemia - 125mg/kg of body weight. Conclusion. The data obtained characterizes Ormustin as a promissing anticancer drug.

At present, the hormone somatostatin analogues is increasing interest in connection with their activity against hormone-dependent tumors, which leads to the need to develop domestic drugs belonging to this group. In the laboratory of chemical synthesis Institute of experimental diagnostics and chemotherapy of FSBI «N.N. Blokhin RCRC» synthesized new domestic pentapeptide somatostatin analogue of hypothalamic hormone (AGGS). In preliminary studies of this substance demonstrated sufficiently high antitumor activity AGGS on transplanted solid tumors of mice. Due to the insolubility of the substance in the water as an alternative liposomal formulation proposed, allowing to increase the bioavailability of the drag due to the possibility of intravenous administration, increased therapeutic efficacy and reduce side effects, by improving the selectivity of action against tumor cells. During experiments on the development of the liposomal formulation AGGS pre-established model containing as essential components of the liposomal bilayer and egg lecithin PEG-2000-DSPE in a molar ratio 72/1 and as a ciyo- protectant - sucrose. In developing the technological parameters of the process of obtaining dosage form (LF) found that for an acceptable size derived phosphohpid vesicles needs about 7 cycles extrusion. The lack of stability of liposomal dispersion selected composition during storage has led to this problem by means of freeze-drying, which kept the physico-chemical parameters LF at the initial level. The efficacy of the model LF on transplantable tumors of mice - breast adenocarcinoma Ca-755, which was more than 60 % of ITG at a dose of 5 mg / kg and more than 80 % ITG with 20 mg / kg. The findings of biological experiments indicate the prospects for further research and improvement liposomal LF to produce high-performance domestic anticancer drag from the group of somatostatin analogues.

The study investigated antitumor activity of 10 new compounds in the series of N-glycosides of indolo[2,3-a] carbazoles. The results identified strong antitumor activity of compounds LCS-1208, LCS -1054, LCS -999 and LCS-1006 against lymphocytic leukemia P-388 (ILS=85 - 119%). Glycosides LCS-1208, LCS-999 and LCS-1006 exhibited high antitumor activity immediately after treatment for Lewis epidermoid lung carcinoma LLC (TGI =90%). In addition, the antitumor effect after LCS-999 and LCS-1006 treatment kept on for 10 days, and LCS-1208 - for 15 days. Glycoside LCS-1208 had a therapeutic efficiency on melanoma B-16 for 7 days (TGI=91 - 58%). Thus, the study of relation «structure-activity» in a series of derivatives of N-glycosides of indolo[2,3-a]carbazoles allowed to select highly effective compound LCS-1208 for preclinical studies.

The research is devoted to development and study of photosensitizers on a base of injectable nanoparticular formulations of phthalocyanine derivatives absorbing at long wavelength (near-infrared) range of 710–740 nm: Thiosens [liposomal form of aluminum hydroxide 1,8,15,22-tetrakis(phenylsulfanyl)phthalocyanine] and Octasens [polymeric micellar form of zinc 1,4,8,11,15,18,22,25-octachloro-2,3,9,10,16,17,23,24-octakis-(decylsulfanyl)phthalocyanine based on domestic poloxamer Emuxol-268]. Experiments have shown that the photosensitizers under study show high selectivity of accumulation and prolonged retaining at high concentration in tumor, relatively fast clearance from normal tissue and high therapeutic efficiency of photodynamic treatment on model tumors.

The study investigated antitumor activity of 10 new compounds in the series of N-glycosides of indolo[2,3-a] carbazoles. The results identified strong antitumor activity of compounds LCS-1208, LCS -1054, LCS -999 and LCS-1006 against lymphocytic leukemia P-388 (ILS=85 119%). Glycosides LCS-1208, LCS-999 and LCS-1006 exhibited high antitumor activity immediately after treatment for Lewis epidermoid lung carcinoma LLC (TGI =90%). In addition, the antitumor effect after LCS-999 and LCS-1006 treatment kept on for 10 days, and LCS-1208 for 15 days. Glycoside LCS-1208 had a therapeutic efficiency on melanoma B-16 for 7 days (TGI=91 58%). Thus, the study of relation «structure-activity» in a series of derivatives of N-glycosides of indolo[2,3-a]carbazoles allowed to select highly effective compound LCS-1208 for preclinical studies.

This article presents the results of preclinical study of antitumor activity of indolo[2,3-a]carbazoles N-glycosides derivative (LCS-1208) in pharmaceutical dosage form for intravenous administration - lyophilisate for injection. LCS-1208 high antitumor efficiency has been shown by different regimens of administration on tumors of diverse histogenesis: LCS-1208 exhibited increase of life span (ILS) 76% on lympoblastosis P-388 and ILS 76 % and 33 % recovery of Fisher lympadenosis L5178Y by 25 mg/kg daily intravenous administration during 5 days. Whereas LCS-1208 demonstrated high antitumor efficiency on solid tumors by 150 mg/kg single intravenous dosing: on LLC - tumor growth inhibition (TGI) 95% - 81% during 9 days and on RShM-5 (TGI 74% - 56% during 9 days). LCS-1208 appeared statistically significant TGI 51 % and 47 % on 3rd and 7th days after 150 mg/kg single intravenous dosing on established tumor. Comparative study of LCS-1208 substance and dosage form by intraperitoneal injection has shown that decrease of therapeutic dose to 110 mg/kg, which doesn’t induce death of animals, resulted only in dosage form antitumor effect (TGI 74-75 % during 8 days after the end of treatment).

The implementation of liposome delivery systems ensures the intravenous introduction of hydrophobic photosensitizers used in the treatment of tumors by the photodynamic therapy method with their preservation in a therapeutically effective nonaggregated form and high accumulation selectivity in the tumor. Phthalocyanines are one of the fastest growing classes of antineoplastic photosensitizers, most of which are hydrophobic compounds. In this study the authors have developed the unique composition and technology of preparing the lyophilized liposomal formulation of infrared photosensitizer: aluminum hydroxide tetra-3-phenylthiophtalocyanine (Thiosens). At the stage of biological experiments on model mouse tumors, the preservation of high accumulation selectivity in the tumor (selectivity index is higher than 4) and antineoplastic effectiveness (inhibition of tumor growth is from 70 to 94%) were found during the transition from the previously studied model dosage form to the created lyophilized liposomal one. To estimate chemical and pharmaceutical criteria and the photodynamic efficiency of the photosensitizer on a number of transplanted mice tumor models in vivo, we have conducted a preclinical study which has demonstrated the stability of antitumor activity and quality consistency of the developed dosage form for one and a half years.

The efficiency of photodynamic therapy with photosensitizer Tiosens (Russia) was evaluated in mono- and combined therapy of rats with malignant gliomas (glioblastoma 101/8, oligodendroglioma 14-4-9, and C6 glioma). The efficiency of photodynamic monotherapy was not high: the animals died from brain edema developing in tumor tissue and in the adjacent normal cerebral tissue. Pathomorphological studies of tumor tissue detected necrosis and apoptosis, destruction of vessels with hemorrhages, and vascular thrombosis. Combined therapy for malignant gliomas including Tiosens photodynamic therapy and subsequent temodal or lysomustine chemotherapy, was the most effective. In glioblastoma 101/8, combined therapy with lysomustine or temodal led to prolongation of the lifespan by 127 %; 62.5 and 50 % rats were cured, respectively; in oligodendroglioma 14-4-9, animal lifespan was prolonged by 80 and 60 %, with 43 and 45 % rats cured, respectively. Glioma C6 was least sensitive to therapy.

Cytestrole acetate (CA), in the structure of which the steroidal antiestrogen component is associated with bis-β-cloroethylamino group, exhibits a strong cytotoxic activity against hormone-dependent cancer cell lines (CaOV, HeLa, MCF-7). In doxorubicin-resistant MCF-7 cells, CA potentiates the cytotoxic effect of etoposide and doxorubicin, and the IC50 for CA in these cells is 40 times lower than that for tamoxifen (TAM). In transplantable mice breast adenocarcinoma Ca-755, the therapeutic CA dose is 25 mg/kg when administered subcutaneously in oil solution for 5 days. On the DMBA-induced mammary tumors in rats, CA injected subcutaneously led to partial regressions 4 weeks after treatment in 75% of test rats, whereas TAM produced this effect in 43% of rats. Among various drug forms of CA, the most active were oil solution of CA in gelatin capsules for oral use and liposomal emulsion for intravenous administration, since these forms exhibited the highest values of Ca-755 tumor growth inhibition index (TGI = 97 – 98%).

Cytestrole acetate (CA), in the structure of which the steroidal antiestrogen component is associated with bis-β-cloroethylamino group, exhibits a strong cytotoxic activity against hormone-dependent cancer cell lines (CaOV, HeLa, MCF-7). In doxorubicin-resistant MCF-7 cells, CA potentiates the cytotoxic effect of etoposide and doxorubicin, and the IC50 for CA in these cells is 40 times lower than that for tamoxifen (TAM). In transplantable mice breast adenocarcinoma Ca-755, the therapeutic CA dose is 25 mg/kg when administered subcutaneously in oil solution for 5 days. On the DMBA-induced mammary tumors in rats, CA injected subcutaneously led to partial regressions 4 weeks after treatment in 75% of test rats, whereas TAM produced this effect in 43% of rats. Among various drug forms of CA, the most active were oil solution of CA in gelatin capsules for oral use and liposomal emulsion for intravenous administration, since these forms exhibited the highest values of Ca-755 tumor growth inhibition index (TGI = 97 - 98%).

Authors have developed the composition, technology of preparation. dosage form and sucrose-protected lyophilization protocol for formulation for systemic administration of near-infrared range photosensitizer thiosens based on PEG-liposomal formulation of aluminum hydroxide tetra-3-phenylthiophthalocyanine derivative. Optimization of preparations allowed to formulate the quality control and standardization criteria for the drug "thiosens liposomal lyophilisate for injection 1.5 mg" and establish a pharmacopoeia monograph for the drug candidate. Preclinical studies of chosen pharmachemical criteria and photodynamic efficiency of photosensitizer on a number of transplanted mice tumor models in vivo demonstrated stability of antitumor activity and quality consistency of the photosensitizer over about 15 year what allow to recommend the shelf life at least of 1 year.

Dye family of naphthalocyanines and their relatives are potent photosensitizers for photodynamic therapy of tumors. One of the best photosensitizers in this series is tiosens – the original domestic product, created by FGUP GNC “NIOPIK”. It is hydrophobic aluminum hydroxide tetra-3-phenylthiophthalocyanine absorbing in a infrared spectral range (absorption maximum at 717 nm). With the purpose of targeted delivery tiosens in a tumor and overcoming of insufficient solubility of liposomal form is developed. Experiments revealed the preservation of physical and chemical properties and high photodynamic activity of the liposomal photosensitizer for the duration of storage. References Krasnopol'skij Ju.M., Stepanov A.E., Shvec V.I. / Biofarm. zh. 2009. №3. P.18-29. Mishra B., Patel B.B., Tiwari S. / Nanomed. Nanotechnol., Biol., Med. 2010. V. 6. P. 9–24. Meerovich I.G., Oborotova N.A. / Ros. bioterapevt. zh. 2007. №4. P.3-8. Allison R.R., Sibata C.H. / Photodiag. Photodyn. Ther. 2010. V. 7. P.61-75. Meerovich I.G, Smirnova Z.S., Oborotova N.A. / Bul. Exper. Biol. Med. 2005. V.139. P.427-430.