Chimeric peptide for epithelial and mesenchymal malignant neoplasms treatment

FIELD: medicine.

SUBSTANCE: invention relates to medicines, particularly to the use of chimeric peptide VP-22_p16INK4a for epithelial and mesenchymal malignant neoplasms treatment. The claimed chimeric peptide VP-22_p16INK4a contains two amino acid sequences. The first sequence comprises inhibitor of cycline kinases as active fragment p16INK4a as therapeutic agent and the second sequence comprises peptide VP22 of herpes simplex virus as carrier agent to deliver cycline kinase inhibitor into target cells.

EFFECT: enlarging the application range of medicine.

9 dwg

 

The invention relates to medicine, namely to chimeric peptides containing transport (chimeric, in the world literature there is also the term "cell penetrating peptides" - RAF) part and the functional part, intended for the treatment of epithelial and mesenchymal malignant neoplasms (i.e. malignant neoplasms of non-lymphoid origin).

The creation of chimeric peptides with cytostatic and cytotoxic activity, is a promising direction of development of modern therapy of malignant tumors of non-lymphoid origin.

From the description of the patent RU 2297241 C2 invention Chimeric protein for the treatment of malignant lymphomas" (published 20.04.2007) it is known that one of the areas of treatment of neoplastic diseases is the use of inhibitors ticinovic kinases, for example protein family INK4a affecting the cell cycle. It is also known that it is desirable that the molecular constructs were delivered into the cell "address" and hit it on a specific intracellular signal or function. From the above document is also known that depending on the structure of different peptides may accumulate in different compartments of the cell, which gave a theoretical possibility to construct after which outlinesthe with a target delivery to different organelles of the cell.

Chimeric peptide VP-22_p16INK4a the patent RU 2297241 C2 has a higher biological effect due to the improved transport properties of the agent and is intended for the treatment of malignant lymphomas, however, is known of the possibility of its use for the treatment of epithelial and mesenchymal malignant tumors.

The present invention is the expansion of the use of the chimeric peptide VP-22_p16INK4a and the application of this peptide for the treatment of epithelial and mesenchymal malignant tumors.

The technical result of the invention is medical-biological effect, objectively manifested in the use of this chimeric peptide consists of the solution of the stated problem.

The technical result is achieved due to the use for the treatment of non-lymphoid neoplasms of origin chimeric peptide VP-22_p16INK4a containing two amino acid sequences, the first of which includes the inhibitor ticinovic kinases in the form of an active fragment of p16INK4a (amino acid residues 84-103 or 84-106) as a therapeutic agent, and the second includes the VP22 peptide (amino acid residues 140-301) of herpes simplex virus as a transport agent for transfer inhibitor ticinovic kinases inside the target cells.

Himem the th peptide VP-22_p16INK4a contains the following amino acid sequence: D-A-A-T-A-T-R-G-R-S-A-A-S-R-P-T-E-R-P-R-A-P-A-R-S-A-S-R-P-R-R-P-V-E- D-A-A-R-E-G-F-L-D-T-L-V-V-L-H-R-A-G-A-R(hereinafter referred to SEQ ID NO. 1, underlined sequence of the P16).

Control and synchronization of events in the process of cell division is a large complex molecules, one of the key participants in this process are cycline, activating the so-called cyclin dependent kinases (CDK). During the cell cycle is a sequential activation of transcription of specific cyclina with the subsequent formation of the active complex of the cyclin-CDK. Stop cell division in the control (restriction) points (G1, S, G2) is the inhibition of the corresponding zaklinivalo complex through specific proteins. A family of proteins, inhibiting cyclin D (controlling the transition of G1-S) refers to the peptides INK4a.

The most studied of this group p16INK4a peptide. This peptide inhibits the activity of CDK4 and CDK6, included in the complex with cyclin D, which inhibits pRb phosphorylation and the release of E2F, and leads to cell cycle arrest at the border of the G1-S transition. Structural and functional studies of this protein have revealed active fragment of p16INK4a (amino acids 84-103 or 84-106), which is responsible for the inhibition of CDK4 and CDK6, included in the complex with cyclin D.

The p16INK4a peptide plays an important role in the process of differentiation and aging of cells, in addition, this peptide is not functional is h or absent in many tumor tissues. For malignant neoplasms of non-lymphoid origin characterized by impaired function of p16INK4a peptide and overexpression of Zilina D. Thus, in malignant tumors of non-lymphoid origin there is impaired control restriction point R1 (G1-S transition).

As mentioned in the description of the patent RU 2297241 C2, the ability to use natural inhibitors ticinovic kinases to control proliferation occurred after the discovery of the ability of some proteins to the TRANS-activation. That is, proteins synthesized in the same cell, could go out and penetrate into a different cell, lead to the activation of certain genes. The study of the structure of these proteins allowed us to identify short (10 to 30 amino acids) amino acid sequences responsible for intracellular transport. It was shown that the addition of such a sequence in the structure of an arbitrary protein confers properties of intracellular and intranuclear internalization. Currently, there are about 30 known sequences of such peptides.

Constructed chimeric molecule peptide comprising VP22 protein fragments and a fragment of the protein p16INK4a inhibitor ticinovic kinase, previously used exclusively for the treatment of malignant lymphomas. Currently, however, there are experimental the data validate the use of the chimeric peptide VP-22_p16INK4a and for the treatment of epithelial and mesenchymal malignant tumors.

The possibility of carrying out the invention with the implementation of the specified destination confirm these results.

Materials and methods. Examples

Working with cell cultures

Cells were cultured at 37°C in 5% CO2 atmosphere in DMEM (Paneco, Russia)containing 10% fetal bovine serum (FSB) (Paneco, Russia), 10 μg/ml of antibiotic-antimycotics gentamicin (Paneco, Russia) and 2 mm L-glutamine (Paneco, Russia).

Chimeric peptide and anticancer drugs were dissolved in culture medium and added to cells at changing environment. The effect was evaluated after 24 hours of incubation.

Short-term culture of human cancers

To assess the effectiveness of the cytotoxic effect of chimeric peptide VP-22_p16INK4a on tumor person used short-term cultures derived from operational material breast cancer, cancer of the body of the stomach, cancer of the cervix and kidney cancer. It was also evaluated the effect of chimeric peptide in short-term cultures of skin, unchanged mucosa of the stomach, unmodified endometrium and unmodified kidneys. Short-term culture was obtained by mechanical disaggregation of the operational material, the cells were incubated 24 hours at 37°C in a 5% atmosphere of CO2in medium RPMI (Paneco, Russia)containing 5% fetal bovine serum (FSB) (Paneco, Russia) and d is I the growth components. Next was replacing the medium on the medium containing chimeric peptide VP-22_p16INK4a at a concentration of 40 μm. The effect was evaluated after 24 and 48 hours of incubation with the peptide.

When working in vitro effects on the cells of chimeric peptides was evaluated using the method of flow cytofluorimetry (flow cytometer DAKO Galaxy). We studied the level of apoptosis, the number of dead cells by staining AnnexinV-PI (propedy iodide) and quantitative distribution of cells in cell cycle phases in coloration PI.

Coloring on AnnexinV. Used set of AnnexinV KIT (Caltag laboratories LI 2004). Cells were washed from the environment in cold phosphate-buffered saline (PBS), resuspendable in 1 × Binding Buffer at a concentration of 106 cells per ml were Collected and 100 μl of the resulting suspension was added to 5 μl of AnnexinV-FITC and 10 μl PI. Incubated in the dark at room temperature for 15 minutes. Added 400 μl of 1 × Binding Buffer and analyzed on a flow cytometer.

Colour PI. Cells were washed from the serum twice by centrifugation in 1 ml PBS (4 minutes at 2000 rpm). Removed supernatant, was added 300 μl of PBS was added dropwise to 700 μl of ice-cold 70% ethanol and kept at -20°C overnight (fixation). Fixed cell samples were besieged by centrifugation (4 min at 2000 rpm), washed with 1 ml PBS and repeat the centrifugation. To the precipitated cells were added 100 μl of PBS and 20 μl of RNA is PS (1 mg/ml) and incubated for 30 minutes at 37°C. Further to the suspension was added to 30 μl of PI and incubated for 40 minutes at room temperature in the dark. After the incubation was finished, the volume of sample to 1 ml with PBS.

In the study of chimeric peptides in vivo antitumor effect was evaluated in Nude mice (nude) with inoculated tumor human cell lines A (lung cancer) and HCT-116 (colon cancer person).

To study the effects on human tumors used method of short-term cultures.

Investigation of the effect of chimeric peptide in short-term culture of breast cancer, stomach cancer, kidney cancer. It is shown that for this model the most sensitive option tumor is a cancer of the kidney.

Experiments in vivo

In Nude mice (Nude) studied the antitumor activity of chimeric chimeric peptide VP-22_p16INK4a. Mice were subcutaneously inoculated tumor human cell culture lines A (lung cancer) and HCT-116 (colon cancer) in an amount of about 1 million cells per mouse. Introduction peptide was started after detection of the tumor site (3-4 mm) on 4-6 day after inoculation of the tumor. Introduced 100 (first group) or 200 μg (second group) of the peptide through the day. For both tumor lines received a 50% inhibition of tumor growth. Differences in the effect for doses of 100 and 200 µg not found.

The results of issledovaniye malignant neoplasms of non-lymphoid origin using chimeric peptide VP-22_p16INK4a explained by the following drawings:

Figure 1: the level of apoptosis in short-term cultures unchanged renal tissue (normal) and renal carcinoma (cancer) when incubated with the chimeric peptide VP-22_p16INK4a at a concentration of 40 μm for 24 hours. Mean values from 4 experiments. The number of apoptotic particles was determined as positive for AnnexinV with dual color AnnexinV-PI;

Figure 2: cytotoxic effect of chimeric peptide VP-22_p16INK4a short-term culture unchanged renal tissue (normal) and renal cancer (cancer). The average number of particles, positive for AnnexinV and particles, including PI, double color AnnexinV-PI on four experiments. Incubation with chimeric peptide for 24 hours;

Figure 3: the level of apoptosis in short-term cultures unchanged tissue of the gastric mucosa (normal) and gastric cancer (cancer) when incubated with the chimeric peptide VP-22_p16INK4a at a concentration of 40 μm for 24 hours. Mean values from 4 experiments. The number of apoptotic particles was determined as positive for AnnexinV with dual color AnnexinV-PI;

Figure 4: the cytotoxic effect of chimeric peptide VP-22_p16INK4a short-term culture unmodified tissue of the gastric mucosa (normal) and gastric cancer (cancer). The average number of particles, positive for AnnexinV and particles, including PI, double color AnnexinV-PI on four experiments. Incubation with himem the m peptide for 24 hours;

Figure 5: level of apoptosis in short-term cultures unmodified body tissue of the uterus (the norm) and cervical cancer (cancer) when incubated with the chimeric peptide VP-22_p16INK4a at a concentration of 40 μm for 24 hours. Mean values from 4 experiments. The number of apoptotic particles was determined as positive for AnnexinV with dual color AnnexinV-PI;

6: the cytotoxic effect of chimeric peptide VP-22_p16INK4a short-term culture unmodified body tissue of the uterus (the norm) and cervical cancer (cancer). The average number of particles, positive for AnnexinV and particles, including PI, double color AnnexinV-PI on four experiments. Incubation with chimeric peptide for 24 hours;

Fig.7: the level of apoptosis in short-term cultures unchanged tissue skin breast (normal) and breast cancer (cancer) when incubated with the chimeric peptide VP-22_p16INK4a at a concentration of 40 μm for 24 hours. Mean values from 4 experiments. The number of apoptotic particles was determined as positive for AnnexinV with dual color AnnexinV-PI;

Fig: the cytotoxic effect of chimeric peptide VP-22_p16INK4a short-term culture unmodified tissue skin breast (normal) and breast cancer (cancer). The average number of particles, positive for AnnexinV and particles, including PI, double color AnnexinV-PI on four set of experiment is. Incubation with chimeric peptide for 24 hours;

Figure 9: change in the volume of tumor in nude mice. Mice were inoculated subcutaneously cells HCT-116 (colorectal cancer) is the number of 1 million Chimeric peptide VP-22_p16INK4a dose of 0.1 mg was administered to the experimental group (experience) in the area of the tumor site, the control group (control) in the area of the tumor site was injected with saline. The first injection was made on the 6th day after inoculation of the cells HCT-116.

The results of the experiments shown in figures 1 to 9, which shows an increase in the level of apoptosis and necrosis in malignant tumors of non-lymphoid origin when using chimeric peptide VP-22_p16INK4a confirm pronounced cytostatic and cytotoxic effect against non-lymphoid tumor Genesis in both in vitro and in animal models.

The described experiments on the intratumoral injection of peptides in subcutaneous variant inoculation of the tumor were the first in the world. In the literature are not described similar experiments.

The results on short-term models of human tumors obtained for the first time in the world. First it is shown that the peptide with the structure of VP-22_p16INK4a can be applied for the treatment of malignant tumors of non-lymphoid origin.

The use of chimeric peptide VP-22_p16INK4a containing the amino acid sequence of SEQID NO.1, for the treatment of epithelial and mesenchymal malignant tumors.



 

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