The antitumor vaccine RESAN contains imitators of mainly three major groups of tumor antigens due to which it acts as cancer vaccine triggering immune responses against wide types of tumors. The three groups of tumor antigens against which the vaccine RESAN is directed to act upon are: 
1. 22 peptide fragments of the Homo sapiens telomerase ferment (hTRT);
2. Cytokeratin-19 (CYFRA21-1);
3. Peptide fragments of 40 most common cancer specific antigens.

1. Homo sapiens telomerase ferment (hTRT)

Homo sapiens telomerase reverse transcriptase (hTRT) is a tumor-associated antigen expressed in the vast majority of human tumors and is presently one of the most promising target candidates for a therapeutic cancer vaccine [22, 23, 24, 25]. (This enzyme is in silent/inactive in normal tissues except in some body cells-like stem cell, basal cells of epidermis, male and female reproductive cells but it is most active in more than 85% of the cancer cells) [24].

It is this very enzyme, which enables the cancer cells to under go endless cell divisions. The fragments of this enzyme in complex with HLA molecules are located on the cancer cell membranes. The vaccine RESAN, in its basic composition, include glycoproteins which are analogous to 22 peptide fragments of the telomerase enzyme (hTRT). Due to this, the vaccine possesses a broad spectrum of antitumor activities.

In the amino acidic sequence of hTRT (Table 1), the peptide fragments are shown  in orange colour which are present in the vaccine RESAN  (the  international single-letter designation of amino acids is illustrated).

Table 1. 

The administration of vaccine RESAN in an organism triggers the immune mechanism to form specific antitumoral T-lymphocytes (CTLs) against the cells with active telomerase enzyme i. e. cancer cells. The specific antitumoral T-lymphocyte  recognizes the tumor peptides (each with 8-10 amino acids) represented in a complex HLA class I molecule on the cancer cell membranes and destroy them.

2. Cytokeratin fragment 19 (CYFRA 21-1)

Most of the malignant tumors are hard in consistency. This is due to the presence
of a strong cellular structure known as the cytoskeleton, which consists of
proteins – cytokeratins. There are more than 20 known types of cytokeratins. For
example – the cytokeratin fragment 19  is located in many of the epithelial malignant cells. With the help of these strong cytokeratins, the cancer cells displace the normal cells invading new spaces for their growth into the healthy tissues. 

In a healthy person the concentration of cytokeratin-19 in blood serum may deviate from 0.1 to 3.3 ng/mL; thus the normal (average) concentration of cytokeratin-19 is considered as 2.1 ng/mL [21]. Today the cytokeratins-19 test is used as a standard tumor marker for the diagnosis of metastatic growths of cancers from epithelial cells; this tumor marker has been found elevated in different types of epithelial cancers: prostate cancers [1], hepatocellular carcinoma [2, 3, 4], pancreatic carcinoma [5, 6], breast cancer [7, 8, 9], ovarian adenocarcinoma [10, 11], basal cell carcinoma [12], thyroid tumors [13], colorectal cancer [7, 14], squamous cell carcinoma of head and neck [7, 15], neoplastic lymphadenopathies [20], lung carcinoma [7, 17, 18, 19, 20].

The vaccine RESAN is the first cancer vaccine, which contains, in its chemical composition, the imitators of the protein fragments of the cellular cytoskeleton located in the malignant tumors. With the help of Enzyme-Linked Immunosorbent Assay (ELISA) kit (Hoffman-La Rosch CYFRA 21-1), it was determined that in a single vial of the vaccine RESAN (200 mg) the concentration of the cytokeratin-19 was 20 times higher than in the blood serum of a healthy person. This allows us to use the vaccine to trigger specific antitumor immune responses against various types of human epithelial tumors. Thus, the presence of the cytokeratin-19 imitators in the vaccine composition is one more important factor, which makes it "a cancer vaccine of wide spectrum". 

 3. Peptide fragments of 40 most common cancer specific antigens

In order to intensify and widen the spectrum of the anti tumor immune responsing capacity of the vaccine even more, other additional glycoproteins are included in the composition of  vaccine RESAN whose (glycoproteins) peptide fragments are analogous to some particular fragments of 40 most common cancer antigens (Table 2).

Table 2.

These glycoproteins included in the composition of the vaccine imitate 6-50 different peptide fragments (each with 7-30 amino acids) of each cancer antigens illustrated above.

References

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8. Kruger W. et al. Reverse transcriptase/polymerase chain reaction detection of cytokeratin-19 mRNA in bone marrow and blood of breast cancer patients. / J. Cancer Res. Clin. Oncol. 1996, 122 (11), 679-686.

9. Ethier S. P. et al. Differential isolation of normal luminal mammary epithelial cells and breast cancer cells from primary and metastatic sites using selective media. / Cancer Res. 1993, 53 (3), 627-635.

10. Gorai I. et al. Establishment and characterization of two human ovarian clear cell adenocarcinoma lines from metastatic lesions with different properties. / Gynecol. Oncol. 1995, 57 (1), 33-46.

11. Mobus V. et al. Morphological, immunohistochemical and biochemical characterization of 6 newly established human ovarian carcinoma cell lines. / Int. J. Cancer 1992, 52 (1), 76-84.

12. Kooy A. J. W. et al. Expression of cytokeratin 8 and low molecular weight cytokeratins in human basal cell carcinoma. / Anticancer Res. 1995, 15, 241-248.

13. Raphael S. J. et al. Brief report: detection of high-molecular-weight cytokeratins in neoplastic and non-neoplastic thyroid tumors using microwave antigen retrieval. / Modern Pathol. 1995, 8 (8), 870-872.

14. Braun S. & Pantel K. Immunodiagnosis and immunotherapy of isolated tumor cells disseminated to bone marrow of patients with colorectal cancer. / Tumori 1995, 81 (Suppl.), 78-83.

15. Doweck I. et al. CYRFA 21-1. A new potential tumor marker for squamous cell carcinoma of head and neck. / Arch. Otolaryngol. Head Surg 1995. 121, 177-181.

16. Gould V. E. et al. Increased numbers of cytokeratin-positive interstitial reticulum cells (CIRC) in reactive, inflammatory and eoplastic lymphadenopathies: hyperplasia or induced expression. / Virch. Arch. 1995, 425, 617-629.

17. Muraki M. et al. Assessment of serum CYFRA 21-1 in lung cancer. / Cancer 1996,  77, 1274-1277.

18. Niklinski J. et al. Diagnostic and prognostic value of the new tumour marker CYRFA 21-1 in patients with squamous cell lung cancer. / Eur. Respir. J. 1995, 8, 291-294.

19. Trevisani L. et al. Cytokeratin tumor marker levels in bronchial washing in the diagnosis of lung cancer. / Chest 1996, 109, 104-108.

20. Molina R. et al. Study of a new tumor marker, CYRFA 21-1, in malignant and nonmalignant diseases. / Tumor Biol. 1994, 15, 318-325.

21. Behbehani A.I., Mathew A., Farghaly M., A.Van Dalen. Reference levels of the tumor markers carcinoembryonic antigen, the carbohydrate antigens 19-9 and 72-4, and cytokeratin fragment 19 using the ®Elecsys Relecsys 1010 analyzer in a normal population in Kuwait. The importance of the determination of local reference levels. / The International Journal of Biological Markers, 2002, Vol. 17 (1), 67-70.

22. Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells.
 Hernandez J., Garcia-Pons F., Lone Y.C., Firat H., Schmidt J.D., Langlade-Demoyen P., Zanetti M. / Proc Natl Acad Sci USA 2002 Sep17; 99(19): 12275-80. / Department of Medicine and Cancer Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0837, USA.

23. Tumour immunotherapy: new tools, new treatment modalities and new T-cell antigens.
Schultze J.L., Maecker B., Von Bergwelt-Baildon M.S., Anderson K.S., Vonderheide R.H. / Vox Sang 2001 Feb; 80(2):81-9. / Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, D540C, Boston, MA 02115, USA.

24. Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells.
Nair S.K., Heiser A., Boczkowski D., Majumdar A., Naoe M., Lebkowski J.S., Vieweg J., Gilboa E. / Department of Surgery, Center for Genetic and Cellular Therapies, Duke University Medical Center, Durham, NC 27710, USA.

25. Cytotoxic T cell immunity against telomerase reverse transcriptase in humans.
Minev B., Hipp J., Firat H., Schmidt J.D., Langlade-Demoyen P., Zanetti M. / Proc Natl Acad Sci USA 2000 Apr 25; 97(9): 4796-801. / Departments of Medicine and Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0368, USA.

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