REPRODUCTIVE FUNCTION AND ANTITUMOR ACTIVITY: DIFFERENT ROLES FOR THE HYPOTHALAMIC HORMONE GnRH

The decapeptide GnRH (Gonadotropin-Releasing Hormone), whose amino acidic sequence was discovered by Dr. A.V. Schally, was initially identified as the key hypothalamic hormone involved in the control of reproductive functions. GnRH, by binding to specific receptors (GnRH-R) at the pituitary level, stimulates the synthesis and secretion of the two gonadotropins (LH, luteinizing hormone and FSH, follicle stimulating hormone) and the downstream production of steroid hormones at the gonadal level. At present, these receptors represent the molecular targets of the standard pharmacological treatments for hormone-related tumors, such as androgen-dependent prostate cancer. Actually, chronic administration of synthetic GnRH agonists induces the desensitization of pituitary receptors and, subsequently, the suppression of testicular androgen production. The physiological role of GnRH in reproductive functions, and its regulation, represented a very important line of research for professor Martini and His colleagues. In the last three decades it has become increasingly clear that GnRH-R are expressed also in a wide range of tumors, both related and unrelated to the reproductive system; in particular GnRH-R are expressed in prostate cancers after development of resistance to androgen ablation therapy (castration resistant prostate cancer, CRPC), a tumor known to be refractory to standard chemotherapy. Activation of these receptors by means of GnRH agonists is associated with a significant antiproliferative/antimetastatic/antiangiogenic activity. These different biological effects at pituitary vs. prostate tissues are related to specific intracellular signal transduction pathways. Based on these observations, tumor GnRH-R are presently considered an effective molecular target for novel therapies (‘targeted’ therapies). In particular, GnRH-based bioconjugates, in which a standard cytotoxic drug is linked to a GnRH analog, have been developed. The rationale for this ‘targeted’ therapy is that the GnRH analog behaves as the targeting moiety by binding to GnRH-R in tumors, thus specifically delivering (targeting) the cytotoxic drug to tumor cells. At the level of tumor cells, the bioconjugate is internalized and degraded at the lysosomal level; in this way the anticancer drug is specifically released into the tumor cells to exert its cytotoxic effects, while sparing normal cells. In conclusion, GnRH-R are expressed not only at the pituitary level but also in a wide range of tumor tissues; these receptors are at present under investigation as an effective molecular target for the development of novel therapeutic strategies.

FEATURES OF THE TECHNOLOGY OF LIPOSOMAL FORMULATION OF A ANALOGUE HYPOTHALAMIC HORMONE SOMATOSTATIN

Background. In connection with the prospect of the use of an analog of the hypothalamic hormone somatostatin synthesized by the laboratory of chemical synthesis Institute of experimental diagnostics and chemotherapy of FSBI «N.N. Blokhin Russian Cancer Research Center» and showed a high anti-tumor activity as a drug arises a need to establish an optimal technology of its receipt. In preliminary studies in a modelformulation for an analog of the hypothalamic hormone somatostatin selected liposome technological process of which has a series of specific steps comprising. Objective. Development of technology for obtaining liposomal formulation hypothalamic hormone somatostatin analogue. Materials and methods. Liposomes analog of the hypothalamic hormone somatostatin obtained by method Bengema in modification for hydrophobic substances. To reduce the diameter of the liposome are used methods extrusion, homogenization and ultrasonic. Analysis of the size of the liposomes was performed by correlation spectroscopy light scattering using nanosizer. The pH of the liposomal dispersion was determined by potentiometry. The quantitative content of the drug substance was determined by spectrophotometry using a standard sample with X (282 ± 3) nm and an alcoholic solution of empty liposomes as a reference solution. Amount of incorporated drug was calculated as the ratio of the concentration of drug in the liposome dispersion after filtration to the concentration of drug in the dispersion after preparation. Results and Conclusion. The hydrophobic nature of the substance causes an analog of the hypothalamic hormone somatostatin technological features of obtaining liposomal formulation. Since the step of forming a film of the lipid substance is dissolved in an organic solvent together with lipids, film is hydrated by a solution of cryoprotectant. Grinding liposomes an analog of the hypothalamic hormone somatostatin appropriate to be carried out using homogenization or extrusion methods, due to the high efficiency of these methods, the preservation stability of the liposomes and a high percentage of inclusion an analog of the hypothalamic hormone somatostatin, included in the liposomal bilayer. At the stage of separating the non-inclusion of substance an analog of the hypothalamic hormone somatostatin due to the insolubility of the substance in the water, you can use the filtering method, without the need for complicated procedures gel filtration, dialysis, etc. Furthermore the process of separating a substance not included can be combined with the sterilization of the liposome dispersion by selecting a particular filter material.

DEVELOPING A MODEL OF LIPOSOMAL FORMULATION OF A NEW NATIONAL ANALOGUE HYPOTHALAMIC HORMONE SOMATOSTATIN, WHICH HAS ANTI-TUMOR ACTIVITY

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.

Klinicheskiy sluchay narusheniyavodno-elektrolitnogo obmena kak pervogosimptoma rasprostranennogo metastaticheskogoprotsessa: osobennosti diagnostiki i lecheniyapreparatom sinteticheskogo analogavazopressina (Presayneks)

The main manifestations of central diabetes insipidus (CDI), a disease of absolute deficiency of hypothalamic hormone vasopressin, are severe thirst and polyuria, which severely interferes with normal life of patients. In some cases CDI may be the first sign of wide spread metastatic process, appearing many years after successful treatment of oncological diseases.

Sandostatin i Sandostatin LAR pri metabolicheskikh, neyroendokrinnykh i onkologicheskikh zabolevaniyakh

Octreotide is a synthetic analog of hypothalamic hormone somatostatin. This neuropeptide is widely distributed in humans and animals in central nervous system and periphery, which defines its potential regulatory functions. In 1987 the first registration was received for octreotide preparation, Sandostatin, for treatment of acromegaly and carcinoid tumors. In 1997 a long lasting form of octreotide appeared - Sandostatin LAR. At the present time both preparations have found their use in multiple areas of medicine for treatment of different metabolic, neuroendocrine and oncologic diseases.