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The review analyzes up-to-date information about specific characteristics of anti-estrogen therapeutic agents with different mechanisms of action with regard to present knowledge of endocrine therapy for estrogen-positive breast cancer (ER+ BC). The paper presents some agents for anti-estrogen therapy of breast cancer - aromatase inhibitors and selective modifiers of biological reactions (SMBR) and their mechanisms of anti-proliferative action. The authors describe significant therapeutic and side effects as well as different options for anti-estrogen combinations. Special emphasis is made on national herbal estrogens/anti-estrogens that have no toxicity associated with the well-known SMBRs. The review presents the structure and characteristics of a perspective phyto-anti-estrogen sekoizolaricirezinol (SEKO), which demonstrated significant anti-proliferative activity with no pro-estrogen action in the in vivo models of ER+ BC.

Biodistribution of [125I]Aimpila (20 mg/kg) in the tumor and normal tissues, including the mammary gland tissue, after single oral dose was studied in BALB/c nude mice with T47D/ReCAF+++ human breast tumor sensitive to this drug and in closely related BALB/c nude+mice without tumors. The maximum concentration of [125I]Aimpila was in fact the same in the tumor and in the mammary gland, while the time course of its accumulation/elimination differed. The time of the maximum accumulation of the drug in the tumor was shorter and its persistence longer than in normal tissue. After 24 h, label concentration in the tumor was 4.5 times higher (p=0.002). Differences in the time course of label accumulation in the tumor were detected. The maximum ratio of tumor/blood concentrations of the preparation was recorded in 1 h after administration. [125I]Aimpila and [125I]alpha-fetoprotein accumulated in the tumor in comparable concentrations and were eliminated simultaneously at the same rate. The results of comparative analysis of accumulation of the labeled compounds in Aimpila-sensitive T47D/RECAF+++ tumor from 0.5 to 9.0 h after drug administration could be interpreted as a result of possible receptor-mediated binding of the complex with the tumor at the expense of the alpha-fetoprotein transporting part. Differences in the parameters of [125I]Aimpila biodistribution in the tumor and normal mammary tissue indirectly attested to selective antiproliferative activity of the complex.

Daily administration of tubuloclustin (1 mg/kg, 5 d, i.p.) to BDF1 mice with i.p. transplanted P388 leukemia extended statistically significantly by 45% their life spans compared with those of untreated controls (17 vs. 11.7 ± 3 d). The possibility in principle of preparing 2-methoxyestradiol analogs with a linker bonded through a steroid C6 ester was demonstrated. However, the resulting conjugates IIa and IIb were unstable with respect to a strong tendency for elimination from the C6–C7 bond. This may have been the reason for their low cytotoxicity in the MTT assay on A549 cell culture (IC50 > 10 μM). It was concluded that conjugates of higher stability must be synthesized as potential antitumor agents.

To study the tumour-promotion activity of cell environment the transformed embryonic rat fibroblasts (clone CL-1-1) were transfect to immunodeficient mice then the cells of the formed tumour were cultivated (clone CL-1-1). The cells before and after transplantation were compared by morphology, proliferation activity and gap junction intracellular communications. The clone CL-1 cells proliferated much faster than clone CL-1 cells. The CL-1-1 cells had changed morphology structure and unlike CL-1 the contract inhibition was absent in CL-1-1. The number of CL-1 cells in phase G1 was significantly greater than that of CL-1-1 cells, while the number of CL-1-1 cells in G2/M phases was much more the number of CL-1 cells. The activity of gap junction intercellular communications in both cell types was near the same. It was concluded that cell microenvironment act as a tumour-promoter and tumour progression factor in the case of cell transplantation to immunodeficient mice.

The physicochemical, catalytic, and antiproliferative activity of a recombinant L-asparaginase from Yersinia pseudotuberculosis (YpA) have been studied. The following results were obtained: the KM value for L-asparagine is 17 ± 0.9 μM, the optimal temperature is 60°C, pH is 8.0, pI is 5.4 ± 0.3, the L-glutaminase activity is no more than 5–6% of the L-asparaginase activity, and the antiproliferative activity on the Fisher L5178y lymphadenosis cell line comprised T/C = 136% (p < 0.001) at a 15% recovery rate. The described characteristic allows one to regard YpA as an antitumor enzyme with biological features similar to the L-asparaginase of E. coli.

Authors’ concepts on the use of solid-phase sonosensitizer nanoinclusions in biological structures as ultrasonic energy concentrators in the therapy of oncological diseases are developed. The possibility of directed synthesis of nanoparticles and their aggregates in tumor tissue depending on its growth features is discussed. It was found that acoustic effects in polymer structures containing solid-phase inclusions depend on the nature of these inclusions and their bond with the polymer matrix. Using model gel systems, it was shown that solid-phase sonosensitizers enhance local thermal effects and amplitude-dependent scattering of ultrasound during its propagation in gel. Experimental studies on animals showed that the ultrasound exposure of malignant tumors containing nanoparticles of gold and some complex compounds results in a significant therapeutic effect.

The bone marrow myelopeptide MP-2 (Leu-Val-Val-Tyr-Pro-Trp), exhibiting antitumor activity, and its retro-analogue (Trp-Pro-Tyr-Val-Val-Leu) were synthesized, and their properties were studied. The in vitro and in vivo activities of retro-MP-2 were comparable with those of MP-2. Both peptides equally restored the functional activity of T-lymphocytes inhibited by toxins released by HL-60 cells and inhibited by 70-82% the growth of various types of transplantable solid tumors: Ca-755 adenocarcinoma of the mammary gland, Lewis adenocarcinoma of the lung, and S180 sarcoma. The positions and intensities of the Cotton effects in CD spectra of the MP-2 peptide and its retro-analogue in various solvents are almost indistinguishable. The positions of extrema and integral intensities of the amide I and amide A bands in IR spectra of both peptides were practically identical. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 3; see also http://www.maik.ru.

Synergism effects of cisplatin and L-lysine-alpha-oxidase (LO), while sequential (no interval) administration of drugs depends on the tumor model and duration of treatment. Synergism is identified at intraperitoneal daily (during 3 days) administration of cisplatin to experimental animals in single doses of 1.5 or 3.0 mg/kg and intravenously 5-fold after 48 h administration of LO and also administered intravenously in cumulative doses of 300-600 E / kg discretely, the first dose--doubled. Synergism of cisplatin and LO is showed by significant (p0.05) therapeutic gain against cisplatin at such indicators as increased survival of mice with P388 tumor and increased inhibition of primary tumor melanoma B16.

To study the tumour-promotion activity of cell environment the transformed embryonic rat fibroblasts (clone CL-1-1) were transfect to immunodeficient mice then the cells of the formed tumour were cultivated (clone CL-1-1). The cells before and after transplantation were compared by morphology, proliferation activity and gap junction intracellular communications. The clone CL-1 cells proliferated much faster than clone CL-1 cells. The CL-1-1 cells had changed morphology structure and unlike CL-1 the contract inhibition was absent in CL-1-1. The number of CL-1 cells in phase G1 was significantly greater than that of CL-1-1 cells, while the number of CL-1-1 cells in G2/M phases was much more the number of CL-1 cells. The activity of gap junction intercellular communications in both cell types was near the same. It was concluded that cell microenvironment act as a tumour-promoter and tumour progression factor in the case of cell transplantation to immunodeficient mice.

The physicochemical, catalytic, and antiproliferative activity of a recombinant L-asparaginase from Yersinia pseudotuberculosis (YpA) have been studied. The following results were obtained: the K(M) value for L-asparagine is 17 +/- 0.9 microM, the optimal temperature is 60 degrees C, pH is 8.0, pI is 5.4 +/- 0.3, the L-glutaminase activity is no more than 5-6% of the L-asparaginase activity, and the antiproliferative activity on the Fisher L5178y lymphadenosis cell line comprised T/C = 136% (p0.001) at a 15% recovery rate. The described characteristic allows one to regard YpA as an antitumor enzyme with biological features similar to the L-asparaginase of E. coli.

The bone marrow-derived peptide Phe-Leu-Gly-Phe-Pro-Thr (MP-1) has been synthesized by the classical methods of peptide chemistry in solution, and its antitumor properties have been studied. It has been shown that MP-1 enhances the efficacy of the cytostatic therapy of lympholeukosis P388, increases the latent period of the growth of P388 tumors implanted in irradiated mice, and reduces the recurrence of the breast adenocarcinoma Ca-755 in mice after the surgery.

Data are presented on evaluation of use of combinations of aranosa (Ar), irinotecan (I) and cisplatin (C) in treatment of Lewis lung carcinoma. The drugs were administered i.p. simultaneously, in single doses: irinotecan 20-100 mg/kg, single dose, cisplatin 2.5 3.0 mg/kg and aranosa 100-200 mg/kg, three doses. High synergism (IP, PAr, IPAr) and sufficient tolerance were reported. Efficiency of IPAr regimen was significantly higher while hematotoxity prognosis - comparable to those of IP.

The basidiomycetes Ganoderma lucidum, Hericium erinaceus, Lentinus edodes and Trametes versicolor were used for preparation of aqueous extracts. A polysaccharide preparation (VPG) was isolated from the G. lucidum aqueous extracts. The mycelium was grown under submerged conditions according to an original procedure. Preliminary exposure of mice with tumors to cyclosphosphamide in a low dose for prolonged elimination of T-suppressors and rapid recovery of T-killers induced an increase in the efficacy of the H. erinaceus and L. edodes extracts. Investigation of the aqueous extracts and VPG on different tumor strain lines for the potential Modifiers of Biological Response (Ca755, s/c P388, s-180) demonstrated antitumor activity and satisfactory tolerabily after oral administration. Inhibition of the tumor growth by the H. erinaceus and T. versicolor extracts and VPG amounted to 88-99% and that of s-180 treated with the L. edodes aqueous extract amounted to 66-75%. Compositions 1, 2, 4 amd 5 were significantly more active by the duration and value of the effect on the animal tumor nodes as compared to the aqueous extracts and VPG included to the compositions and composition 4. Composition 5 (T. versicolor + H. erinaceus + G. Lucidum) proved to be the most efficient by all the criteria. The results of the design of the technologies for cultivation of the mycelum of the medicinal basidiomycetes, investigation of the antumor properties of the extracts and polysaccharide fraction of the mycelium and development of efficient compositions on their basis are summarized. Composition 5 proved to be the most promising for the clinical trials.

Bone marrow multipotent mesenchymal stromal cells represent a perspective material for engineering of human three-dimensional transplants of cartilage tissue. We are demonstrated the opportunity of the directed differentiation of BM MMSC in cells of cartilage tissue by culturing them in three-dimensional scaffolds, presented by polymer OPLA in medium with inductors of chondrogenesis. For loading cells in porous scaffolds used method which essence consist in saturation of polymeric blocks by cellular suspension with the subsequent centrifugal force of cells in scaffolds and culturing of engineering constructs for 28 days in chondrogenic medium. Histological analysis derived in vitro of three-dimensional transplants showed uniform distribution of cells in the matrix with morphologically distinct chondrocytes-like cells of hyaline cartilage. Immunohistochemical analysis detected aggrecan and collagen type II within the extracellular matrix. Preclinical the researches lead on a livestock of immunodeficient mice have shown not toxicity of the engineering constructs.

The significant difference between biological properties of L-lysine-alpha-oxidase from Trichoderma harzianum Rifai (LO) and L-asparaginase from E. coli has been observed in vitro and in vivo. High antitumor activity was shown against 8 types of murine and rat transplanted tumors with a wide range of LO therapeutic doses: 35-350 U/mg. The LO conjugates with monoclonal antibodies CD5 specific to the surface of cell line Yurkat were obtained without significant loss of either enzymatic and cytotoxic activity or immunological specificity. The further perspective investigation for the clinical application of the native or conjugated enzymes is discussed.

We studied the effect of combination treatment with T-activin and vitamin E on acute toxicity and antitumor activity of cyclophosphamide in mice. Combined administration of these preparations 1.37-fold increased the maximum permissible dose of cyclophosphamide without affecting its LD(50)and delayed mouse death from cyclophosphamide toxicity. Most mice died only 3 days after combination treatment with the test preparations and cyclophosphamide in doses of LD(16)-LD(84). The second peak of death from hematologic toxicity of cyclophosphamide was absent under these conditions. T-activin and vitamin E did not abolish the antitumor effect of cyclophosphamide on mice with subcutaneously implanted P-388 lympholeukemia. Tumor growth was suppressed by 100%.

New neoplastic models such as orthotopic solitary hepatic tumor (cholangiocellular cancer PC-1) as well as different strains of malignant pleuritis (hemoblastosis and ascitic tumors) have been evolved by transplanting tumor cell suspension to rat liver or murine pleural cavity. Intrahepatic cancer PC-1 has a solid mucosa-excreting structure and is characterized by low activity of detoxication enzymes of such xenobiotics as glutathione-S-transferase, NAD(p)N-chinonoxyreductase and aldehyde dehydrogenase. Orthotopic hepatic tumor PC-1 may be used for evaluating systemic and regional therapy. Models of tumorous pleuritis described with respect to their response to chemotherapy, may have an application in screening and preclinical examination of newly-developed antitumor drugs.

The influence of persistent infection with Tahyna virus on the natural antitumor resistance of the hosts was studied in mature mice. The infection was shown to suppress the host natural antitumor resistance. The development of infection was accompanied by a decrease of natural killer cell cytotoxicity against YAC-1 cell line within 7 days after virus inoculation. In this period, the transplantation dose of tumor cells decreased from 10(1.73) to 10(0.82). This indirectly indicates a potential ability of viruses with immunosuppressive activity to increase the frequency of development of malignant tumors.

On the basis of the supposed difference in the mechanisms of action of copper (II) complexes with alpha-amino acids and of alkylating agents, the antitumor activity of Cu-2 when given in conjunction with cis-diamminedichloroplatinum (DDP) is studied. The DNA precursor C 14-thymidine was injected into mice 30 min before sacrifice. Doses of the substances appropriate as regards toxicity were used: Cu-2 9 mg/kg, DPP 4 mg/kg. The antitumor effect was assessed as inhibition of tumor growth, calculated relative to the mean volumes of the tumor in the experimental animals, was compared with the controls over a period of time. Toxicity was recorded as the percentage of mice which died and changes in the mean weight of the spleen. The investigations show that Cu-1 does not induce direct inhibition of DNA synthesis in the tumor cell, unlike DDP and sarcolysin. Combined administration of Cu-2 and DDP leads to summation of their antitumor effect without any increase in toxicity.

There was no direct inhibition of DNA synthesis in ascites hepatoma 22A cells after intraperitoneal injection of single doses of copper (II) complexes with amino acids into tumor-bearing C3HA mice. Meanwhile cis-dichlorodiamine platinum (II) (DDP) as well as sarcolysine showed such inhibition. Copper (II) complexes with alpha-amino acids displayed as significant superoxide dismutase-like activity at concentrations corresponding to therapeutic doses of these compounds. The complexes of copper (II) combined with DDP give an additive antitumor effect in solid tumors of mice.

Dicarbamin-assisted mono- and combination chemotherapy (cyclophosphamide + carboplatin + cisplatin) for transplantable tumors born by linear or hybrid mice of both sexes was investigated. It was shown that long-term oral administration contributed to the effect of a range of cytostatic therapeutic dosage rather than adversely affected it. Our findings were used to make a case for clinical studies of dicarbamin for its potential of lowering hematological toxicity of antitumor therapy.

The Val-Val-Tyr-Pro-Asp bone marrow peptide (MP-5) and an analogue (MP-5-Lys) were synthesized. Fluorescent derivatives, Ftc-MP-5 and MP-5-Lys(Ftc), were prepared. The biological activity of MP-5 and MP-5-Lys was studied in vitro and in vivo. The MP-5 peptide caused 60-84% inhibition of growth of the following mouse cancers: lymphatic leukemia P-388, melanoma B-16, and cervical carcinoma CUC-5. These peptides also restored functional activity of T lymphocytes that was inhibited by metabolic products of the HL-60 leukemic cell line. MP-5-Lys(Ftc) was shown to preserve the functional properties of MP-5 toward T lymphocytes, but Ftc-MP-5 was practically inactive.

The effects of dicarbamine (r) and polytransretinoic acid (PTRA) on human melanoma MEL-6 transplanted into Balb/c nude female mice have been compared by histological and electron microscopic procedures. It was discovered that long-term administration of 1.5 mg/kg dicarbamine caused melanoma MEL-6 cells to undergo terminal differentiation. As a result, the number of melanosome-containing cells was 3-4 times and the number of melanosomes in them--5 times those in intact controls. Dicarbamine effect was double that of PTRA.