Telomerase as a tumor marker in diagnosis of prostatic intraepithelial neoplasia and prostate cancer.

BACKGROUND: Early diagnosis of prostate cancer (CaP) can be addressed by studying prostatic intraepithelial neoplasia (PIN) as precancer (high-grade PIN or HGPIN). This article attempts to analyze the diagnostic role of telomerase as an early marker of carcinogenesis. METHODS: Complex urological patient evaluation and assessment of telomerase activity. RESULTS: Out of 92 patients 44% were diagnosed with CaP, 49% with low-grade PIN (LGPIN) in association with benign prostatic hyperplasia (BPH), and 7% with HGPIN in association with BPH. Active telomerase (AT) in prostate biopsy specimens was detected in 98% of patients with CaP, in 33% of patients with HGPIN, and in 20% of patients with LGPIN. In the event of simultaneous detection of AT and PIN in initial prostate biopsy specimens, further monitoring for 0.5-4.0 years revealed CaP development in 50-56% of cases. Further follow-up of patients with PIN and absent telomerase activity in initial biopsy specimens did not demonstrate the development of CaP. The PSA level was significantly higher in patients with active telomerase in the prostate tissue than in telomerase negative patients. CONCLUSIONS: Telomerase activity in the prostate tissue increases the risk of CaP development in patients with PIN. Detection of telomerase activity in prostate biopsy specimens from patients with PIN enables selection of a group of patients with high risk of CaP development and reduction of the number of prostate biopsies performed in other patients.

[Prostate-specific antigen and telomerase in prostatic cancers].

A correlation between the blood level of prostate-specific antigen (PSA) and the prostatic tissue activity of telomerase was analyzed in prostate cancer (PC), low- and high-grade prostatic intraepithelial neoplasia (LG PIN, HG PIN) and in benign prostatic hyperplasia (BPH). The study was based on the results of a comprehensive examination of 92 patients from the Clinic of Urology, I. M. Sechenov Moscow Medical Academy. 44% of the patients were diagnosed as having PC; 49% had LG PIN and BPH; 7% had HG PIN and BPH. Active telomerase in the prostate biopsy specimens was found in 98% of the patients with PC, in 33% of those with HG PIN, and in 20% of those with LG PIN. When active telomerase was detected in the prostate biopsy specimens of patients with urological cancer (PC, PIN, BPH, the blood content of total PSA) was statistically significantly higher than that in the absence of this enzyme.

[Hormonal and molecular biological factors in pathogenesis of prostate cancer]. / Gormonal'nye i molekuliarno-biologicheskie faktory patogeneza raka predstatel'noi zhelezy.

Moleculo-genetic pathways of development and progression of prostate cancer have been studied. In the norm, paracrine regulation of the glandular secretory epithelium are predominant due to the influence of hormonal and protein factors of the stroma. The altered prostatic epithelium becomes independent from the stroma and androgens and, consequently, prone to metastasizing, following activation of protooncogenes (growth factor genes), inactivation of gene-suppressors, hyperexpression of certain growth factors and apoptosis inhibitor Bcl-2, and inactivation of androgen receptor. In inoperable prostate cancer, palliative treatment should include antiandrogen therapy, inhibition of growth factors and activation of apoptosis. Prevention and medication for prostate cancer targeting apoptosis, growth factors and androgens should be based on recent achievements in experimental genotherapy and selective use of proliferation inhibitors and apoptosis activators which are to be fed to the gland via viral and non-viral vectors. Molecular-biological markers of risk for cancer, its early detection, prognosis of clinical course and effectiveness of treatment are discussed. A modality for laboratory diagnosis and complex treatment of prostate cancer offering maximum survival so far has been suggested.

["Prostatic" kallikreins, sex hormones and insulin-like growth factors: complex of male and female regulatory elements in health and carcinogenesis]. / "Prostaticheskie" kallikreiny, polovye gormony, insulinopodobnye faktory rosta-kompleks reguliatornykh élementov u muzhchin i zhenshchin pri fiziologicheskikh protsessakh i kantserogeneze.

Publications (up to the year 1997) on the interactions of "prostatic" kallikreins (prostatic specific antigen-PSA, etc.), sex hormones, insulin-like growth factors (IGF) and proteins binding them (IGFBP) in physiological processes (ageing, menstrual cycle, pregnancy) and oncogenesis (prostatic and mammary cancer) are reviewed. The concentrations of PSA, IGF, and IGFBP in organs and liquid media of men and women are presented. A concept of similarity in the mechanisms of interactions of sex hormones (dihydrotestosterone in men and progesterone in women), PSA, IGFBP, and IGF during activation of anabolic and proliferative processes in health and carcinogenesis is presented as a scheme. The diagnostic and prognostic value of PSA as a cancer marker should not be confined to male tumors (prostatic cancer and benign prostatic hyperplasia). Our data permits us to regard PSA as an oncofetal marker for men and women, indicating normal and neoplastic proliferative processes in the prostatic, mammary, salivary, and other glands and in the lungs and endometrium. Diagnostic and prognostic significance of PSA in breast cancer is shown. The traditional name "PSA" does not reflect its physiological and pathogenetic role as a member of the kallikrein family with chymotrypsin-like activity. PSA is not absolutely specific towards the producer organ and sex. Its relative specificity for the prostate is undoubted, because the content of PSA in prostatic tissue and seminal plasma is 10(6)-10(8) times higher than in the serum and other organs of men and women. Therefore, although the terms "prostatic, "specific", and "antigen" now became trivial and it is difficult to refuse from them, they can be used only in quotation marks.

[Molecular mechanisms of prostatic oncogenesis]. / Molekuliarnye mekhanismy onkogeneza predstatel'noi zhelezy.

A model of effector and regulatory determinants of the rate and coordination of proliferation of epithelial and stromal cells in the normal prostate in benign hyperplasia and cancer of the prostate was developed. The direct effector factors-protein growth factors, the regulatory factors: activators (5-alpha-reductase, dehydrotestosterone, prostatic specific antigen) and inhibitors (tumor suppressors and metastatic suppressors, insulin-like growth factor-binding protein type 3) were analyzed and systematized. The molecular mechanisms responsible for the occurrence and progression of prostatic tumors, the role of the above factors, genetic changes in the chromosomes and genes, impaired coordination in the action of oncogenes and antioncogenes were under investigation. Directions of experimental search for the earlier unknown links in the analyzed system are outlined. The prospects for designing and using new diagnostic and prognostic omcomarkers and new means for the prevention and treatment of benign hyperplasia and cancer of the prostate are defined.

[Biochemical and immunochemical study of antigen preparations of Rickettsia prowazekii]. / Biokhimicheskoe i immunokhimicheskoe izuchenie antigennykh preparatov rikettsii Provacheka.

The biochemical and immunochemical study of the qualitative composition of R. prowazekii antigenic preparations, isolated and purified by different methods, indicates that these preparations contain high-molecular polypeptide 3 (133600 D), morphologically linked with the cell membrane of R. prowazekii. The method of adsorption chromatography on calcium phosphate permits obtaining specific rickettsial antigens with a greater degree of purification from ballast admixtures than the methods of acid precipitation and gel filtration on Sephadex G-200.

[Polypeptide and phospholipid composition of the Rickettsia prowazekii membrane and its immunogenic properties]. / Polipeptidnyi i fosfolipidnyi sostav obolochki Rickettsia prowazekii i ee immunogennye svoistva.

The composition of the cell membrane in R. prowazekii strain Breinl has been studied by the methods of electrophoresis in 7.5% polyacrylamide gel with 0.1% sodium dodecyl sulfate, iodination with Na125I in the presence of chloramine T or lactoperoxidase and the thin-layer chromatography of the common lipid fraction. Of six major polypeptides contained in whole rickettsial particles (3, 16, 26, 27, 28, 29), five polypeptides (3, 26, 27, 28, 29) making up 54% of all polypeptides of purified rickettsiae have been detected in membrane preparations obtained by either treatment. The molecular weights of these membrane polypeptides are, respectively, 133600, 34000, 29600, 21500 and 12400 daltons. The main membrane phospholipids are phosphatidylethanolamine (68.4%), phosphatidylglycerol (17.2%), phosphatidylcholine (5.1%) and cardiolipin (2.1%). The presence of cholesterol has also been established. The preparations of R. prowazekii membranes and individual membrane polypeptides are immunogenic and induce the formation of specific antibodies in white mice. The preparations of both membranes and surface polypeptide 3 (glycoprotein) have been found to possess a certain protective activity: the effect of the protection of white mice inoculated with R. prowazekii culture has proved to be 64%.

[Protective antigens of the vaccinia virus]. / Izuchenie protektivnykh antigenov virusa vaktsiny.

The comparison of the polypeptide composition of 3 vaccinia virus strains, L-IVP, B-51 and CM-63, has revealed that strains L-IVP and B-51 are similar in their polypeptide composition, while in strain CM-63 capsid polypeptide with a molecular weight of 34000 daltons is absent or has altered electrophoretic mobility. As the result of the isolation of vaccinia envelopes (from strain L-IVP) and the electrophoretic separation of their polypeptides in plates with polyacrylamide gel 10 polypeptides have been obtained in 7 fractions, each containing 1 or 2 polypeptides. The immunization of rabbits with individual fractions has demonstrated that the formation of virus-neutralizing antibodies is induced mainly by 4-5 polypeptides in 3 fractions, having the highest molecular weight (54000-31000 daltons) and constituting about 19% of all proteins in the whole virion. The low-molecular envelopes polypeptides have been found to play no essential role in inducing the formation of virus-neutralizing antibodies. The highest antibody titers (1: 15625) have been detected in antisera to the preparations of whole vaccinia virus envelopes.

[Rickettsia prowazekii polypeptide composition and protective antigens]. / Izuchenie polipeptidnogo sostava i protektivnykh antigenov rikketsii Provacheka.

Serologically active preparations of R. prowazekii membranes were obtained by the lysis of purified R. prowazekii with ether and by differential and gradient centrifugation. Purified R. prowazekii and their membranes were analyzed by the method of electrophoresis in acrylamide gel. The former contained not less than 30 proteins with molecular weights of 10 000-169 000 daltons, while the membrane preparations contained 5 main polypeptides with molecular weights of 12400, 21500, 29600, 34000 and 133600 daltons. Antisera obtained after the immunization of rabbits with the membrane preparation were found to contain antibodies reacting in the complement fixation test and neutralizing rickettsial toxin.

[Primary structure of functions of RNA terminals]. / Pervichnaia struktura i funktsii kontsevykh uchastkov ribonukleinovykh kislot.

Primary structure of tRNA, rRNA, nRNA, mRNA and viral RNA terminals has been studied. Various RNAs responsible for similar functions have been shown to possess some common features. Previously obtained data on the functional role of RNA terminal sequences, mechanisms of their biosynthesis, the stabilizing role of 5'- and 3'-sequences for the molecules of translated eukaryotic RNAs and some viral RNAs are reviewed.