[First experience of using positron emission tomography with 11C-choline in prostate cancer (PC)].

Introduction into clinical practice of combined positron emission technology and computer tomography (PET/CT) allows in one study to identify structural and functional abnormalities. The study involves 32 patients who underwent PET/CT with "C-choline, including 5 patients with prostate cancer (PC), 3--with chronic prostatitis and 24--with biochemical PC recurrence. PET/CT with 11C-choline has a high diagnostic efficacy in detection of local recurrence and PC metastases in patients with biochemical PC recurrence. The results of visual analysis do not permit to distinguish PC from benign prostate diseases.

[The proliferative properties and regulators of the mitotic cell cycle of prostate adenocarcinoma].

The authors have made an immunohistochemical determination of Ki-67, topoisomerase IIalpha, cyclins D1, A, and B1, and calculated their indices in 145 acinar adenocarcinomas of the prostate. This tumor is characterized by a wide range of Ki-67 index (from 3 to 90% or more) although 90% of cases are in the range of 5-35%. Other study proliferative markers are distributed in the following descending order: cyclin D1 (1.32 to 63.27%), topoisomerase IIalpha (0.47 to 53.17%), cyclin A (0.46 to 28.09%), and cyclin B1 (0.29 to 9.34%). The indices of the study markers are increased as the Gleason grade is higher. The exception is cyclin D1 that shows high expression in intact and tumor tissues, which is frequently greater than that of Ki-67, and its stable expression independent of the Gleason score.

[Positron emission tomography with 18-fluorine deoxyglucose in the diagnosis and assessment of prostate cancer].

Results of PET studies using 18-fluorine deoxyglucose (18-FDG) in patients with large-size masses (51) are discussed. Histologically-confirmed prostate cancer was diagnosed in 36 (70.5%), benign hyperplasia--12 (23.5%) and chronic prostatitis--3(6%). 18FDG PET was conducted as whole body irradiation. Our results established its high predictive significance in identifying the scope of tumor involvement. However, the latter's potential is limited in diagnosis of primary tumor node due to low rate of glycolysis in it.

[Predictive value of serum PSA in detection of prostate cancer by fine needle biopsy].

Parallel study of PSA and needle biopsy were performed in 356 men, aged 42-92 years; prostate cancer was detected in 182 cases while no cancer--in 174. When PSA level ranged 4-20 ng/ml, at density of 0.1-0.3, its specificity was low and cancer detection was under 50%. There was a direct correlation between the PSA indices and cancer detection rate, and nearly 100% of tumors were detected at the values of 25-30 ng/ml and 0.5-0.9 respectively. PSA level and especially results of morphological examination by means of prostate needle biopsy (Gleason) offer possibility to visualize tumor size and its malignant potential.

Arginine-rich cell penetrating peptides: design, structure-activity, and applications to alter pre-mRNA splicing by steric-block oligonucleotides.

Rerouting the splicing machinery with steric-block oligonucleotides (ON) might lead to new therapeutic strategies in the treatment of diseases such as beta-thalassemia, Duchenne muscular dystrophy, or cancers. Interfering with splicing requires the sequence-specific and stable hybridization of RNase H-incompetent ON as peptide nucleic acids (PNA) or phosphorodiamidate morpholino oligomers (PMO). Unfortunately, these uncharged DNA mimics are poorly taken up by most cell types and conventional delivery strategies that rely on electrostatic interaction do not apply. Likewise, conjugation to cell penetrating peptides (CPPs) as Tat, Arg9, Lys8, or Pen leads to poor splicing correction efficiency at low concentration essentially because PNA- and PMO-CPP conjugates remain entrapped within endocytotic vesicles. Recently, we have designed an arginine-rich peptide (R-Ahx-R)4 (with Ahx for aminohexanoic acid) and an arginine-tailed Penetratin derivative which allow sequence-specific and efficient splicing correction at low concentration in the absence of endosomolytic agents. Both CPPs are undergoing structure-activity relationship studies for further optimization as steric-block ON delivery vectors.

Cell-penetrating-peptide-based delivery of oligonucleotides: an overview.

Cationic CPPs (cell-penetrating peptides) have been used largely for intracellular delivery of low-molecular-mass drugs, biomolecules and particles. Most cationic CPPs bind to cell-associated glycosaminoglycans and are internalized by endocytosis, although the detailed mechanisms involved remain controversial. Sequestration and degradation in endocytic vesicles severely limits the efficiency of cytoplasmic and/or nuclear delivery of CPP-conjugated material. Re-routing the splicing machinery by using steric-block ON (oligonucleotide) analogues, such as PNAs (peptide nucleic acids) or PMOs (phosphorodiamidate morpholino oligomers), has consequently been inefficient when ONs are conjugated with standard CPPs such as Tat (transactivator of transcription), R(9) (nona-arginine), K(8) (octalysine) or penetratin in the absence of endosomolytic agents. New arginine-rich CPPs such as (R-Ahx-R)(4) (6-aminohexanoic acid-spaced oligo-arginine) or R(6) (hexa-arginine)-penetratin conjugated to PMO or PNA resulted in efficient splicing correction at non-cytotoxic doses in the absence of chloroquine. SAR (structure-activity relationship) analyses are underway to optimize these peptide delivery vectors and to understand their mechanisms of cellular internalization.

[Achievements in morphological diagnosis of prostatic cancer: alpha-methylacyl-coenzyme-A-racemase--a new marker of malignant cell transformation].

Gene P504S is considered as the most specific for prostatic carcinoma and its protein (alpha-methylacyl coenzyme A racemaze (AMACR/P504S) is higly sensitive and specific marker not only for adenocarcinoma cells but also for preceding changes - prostatic intraepithelial neoplasm (PIN). AMACR/P504S seems to be the first marker of malignant transformation and tumor progression. Use of immunohistochemical method for revealing this marker together with methods of basal prostatic cells observation (cytokeratin of a high molecular weight, cytokeratin 5/6, p63) improves morphological diagnosis of prostatic carcinoma, particularly on the material of needle biopsies. This combination allows one to identify neoplastic nature of some difficult lesions.

[Prognostic and predictive factors in breast cancer].

Recent data on prognostic and predictive significance of breast cancer-associated molecular markers are presented and their clinical value in making individual prognosis and choosing adequate therapy is discussed. Markers of tumor proliferation, steroid hormone receptors, factors of epidermal cell growth, plasminogen activators and inhibitors, factors influencing angiogenesis and apoptosis and genome characteristics are considered. It is concluded that only Ki-67, ER, PR and Her-2/neu may be recommended for clinical use.

[Positron emission tomography in oncourology].

The authors present the results of the examination of 61 patients with genitourinary space-occupying lesions, using 18F- fluorodeoxyglucose positron emission tomography (PET) in whole body mode. In all cases the diagnosis was verified morphologically. The results demonstrated high diagnostic accuracy of PET, including possibility to determine the extent of oncourological cancer. However, the method displays poor efficacy in cases of hypernephroid cancer due to low level of glycolysis in this type of tumor.

[Prognostication of hematotoxicity for radio- and chemotherapy in patients with breast cancer]. / Prognozirovanie gematotoksichnosti pri luchevoi i khimioterapii u bol'nykh rakom molochnoi zhelezy.

The effectiveness of radiation and chemotherapy for breast cancer depends on individual response to drug-induced toxicity. The response can be evaluated by means of myelodepression. To this end, changes in leukocyte DNA level after ex vivo gamma radiation test were used as a criterion. Patients, aged 29-78, with tumors stage IIIB-IV received standard radiotherapy (50 Gy) or cyclophosphamide-methotrexate-5-fluorouracil (CMF). Clodronate alone was given to 26 patients and prior to a CMF course. The method proved prognostically effective since it revealed a significant inverse relationship between S-index and leukocyte nadir for both modalities. However, chemotherapy resulted in more pronounced leukopenia. With clodronate administration, the correlation was not significant. When clodronate was supplemented with CMF chemotherapy involved a significant relationship was observed between the two factors.

Inhibition of HIV-1 Tat-dependent trans activation by steric block chimeric 2'-O-methyl/LNA oligoribonucleotides.

The HIV-1 trans-activation responsive element (TAR) RNA 59-residue stem-loop interacts with the HIV trans-activator protein Tat and other cellular factors to stimulate transcriptional elongation from the viral long terminal repeat (LTR). Inhibition of these interactions blocks full-length HIV transcription and hence replication. We have found that three types of 12-residue oligonucleotide analogues, namely, a 2'-O-methyl oligoribonucleotide (OMe), a chimeric oligonucleotide containing 7xOMe and 5x5-methyl C locked nucleic acid (LNA) residues, and a peptide nucleic acid (PNA), inhibit Tat-dependent in vitro transcription in HeLa cell nuclear extract equally efficiently (50% inhibition at 100-200 nM) and sequence specifically. The results are correlated with surprisingly similar binding strengths to a model 39-residue TAR under transcription conditions. A 12-mer containing 11 contiguous LNA residues was less effective in both Tat-dependent transcription inhibition and TAR 39 binding. Anti-TAR 3'-carboxyfluorescein- (FAM-) labeled OMe and OMe/LNA chimeric 12-mers were also efficient Tat-dependent in vitro transcription inhibitors as were 3'-FAM-labeled OMe oligonucleotides containing some phosphorothioate (PS) linkages. By use of a HeLa cell line containing stably integrated plasmids expressing firefly luciferase under HIV-LTR/Tat dependence as well as a Renilla luciferase constitutive control, we showed submicromolar, selective, dose-dependent, and sequence-dependent intracellular inhibition of Tat-TAR trans activation by the anti-TAR 3'-FAM 12-residue 7xOMe/5xLNA oligonucleotide when delivered by cationic lipid. No intracellular activity was observed for the corresponding anti-TAR 3'-FAM OMe 12-mer. An alternating PS-containing 3'-FAM OMe 12-mer oligonucleotide exhibited partial inhibition of trans-activation activity, but this was correlated with a similar effect on control gene expression, suggesting nonspecific inhibition.

Oligonucleotide analogue interference with the HIV-1 Tat protein-TAR RNA interaction.

The HIV-1 Tat protein interaction with its RNA recognition sequence TAR is an important drug target and model system for the development of specific RNA-protein inhibitors. 2'-O-methyl oligoribonucleotides complementary to the TAR apical stem-loop effectively block Tat binding in vitro. Substitution by 5-propynylC or 5-methylC LNA monomeric units into a 12-mer 2'-O-methyl oligoribonucleotide leads to stronger inhibition, as does a 12-mer PNA. 10-16 mer 2'-O-methyl oligoribonucleotides give sequence- and dose-dependent inhibition of Tat-dependent transcription of an HIV DNA template in HeLa cell nuclear extract. Inhibition is maintained for the substituted 12-mer analogues but is poorer for PNA and is not correlated with TAR binding strength.

[Clinical experience with positron emission tomography with 2-fluorine, 18F-2-deoxy-d-glucose used for the diagnosis of malignant breast neoplasms]. / Klinicheskii opyt primeneniia pozitronnoi emissionnoi tomografii s 2-ftor, 18F-2-dezoksi-d-glukozoi dlia diagnostiki zlokachestvennykh novoobrazovanii molochnoi zhelezy

The aim of the study was to evaluate sensitivity and specificity of positron emission tomography (PET) and 18F-fluorodesoxyglucose (18F-FDG) in breast cancer diagnosis and to assess tumor dissemination. Sixty two patients were examined: 10 without mammary disease, 10 with fibrous cystic mastopathy, and 42 with breast cancer, which was hystologically verified. PET scanning was recorded in the "Whole body" mode 70-90 min later administration of 370-420 MBq 18F-FDG. It was shown that PET has a high diagnostic accuracy in breast cancer detection. There were no False-positive cases in our investigations. PET scanning in the "Whole body" mode was allowed to assess dissemination of tumor process with high accuracy. Metastatic involvement of local lymph nodes was detected in 82.8% cases and bone metastases--86% in cases.

Synthesis, anti-HIV activity, and stability studies of 5'-phosphorofluoridate derivatives of AZT.

The synthesis, in vitro anti-HIV activity and stability studies of the 5'-fluorophosphate derivative of 3'-azido-3'-deoxythymidine (AZT) are reported. The results support the hypothesis that this phosphorylated entity exerts its biological effect via the delivery of the corresponding 5'-mononucleotide through an enzymatic process. However, the antiviral evaluation in thymidine kinase-deficient CEM cells as well as the stability studies in culture medium and cell extract showed that this bioconversion is not specific to the intracellular medium. Attempts to improve the biological activity of mononucleoside 5'-fluorophosphates by the use of the S-pivaloyl-2-thioethyl (tBuSATE) group as biolabile phosphate protection are reported.

[Adjuvant chemotherapy with anthracyclines in comparison with the standard combination of CMF in breast cancer with high risk of relapse]. / Antratsiklin-soderzhashchaia ad''iuvantnaia khimioterapiia v sravnenii s klassicheskoi skhemoi CMF u bol'nykh rakom molochnoi zhelezy s vysokim riskom retsidiva.

The effectiveness of adjuvant therapy with adriablastin and doxorubicin for breast cancer has been compared to that of standard CMF. During 1985-1990, the study included 349 patients with T1-2N2M0 and T3N0-2M0 tumors; mean age--46 yrs; mean follow-up--96.7 months. Overall survival rate in the doxorubicin group was 73%, CMF--62%; relapse-free survival--62.1 and 55%, respectively. The absolute difference in overall survival rates (11%) proved barely significant (p = 0.056). However, the difference in overall survival (p < 0.05) after anthracyclines and CMF in patients with tumors T1-2N2M0 and T3N1M0 was significant and in favor of the former. As far as frequency and degree of side-effects is concerned, their patterns were practically identical in both groups, except for the significantly higher frequency of cardiotoxity and complete alopecia in doxorubicin therapy. Cardiotoxic complication rate was significantly reduced from 13.8 to 3.9% by cardioxane treatment.