Eugenii S. Severin

The neuroleptic activity of haloperidol increases after its solubilization in surfactant micelles: Micelles as microcontainers for drug targeting

It has been suggested to use surfactant micelles as microcontainers for increasing the efficiency of neuroleptic targeting from blood flow into the brain. The neuroleptic action of haloperidol, intraperitoneally injected into mice in micellar solution of non‐ionic block copolymer surfactant (pluronic P‐85) in water, increased several‐fold if compared with that observed for haloperidol aqueous solution. Incorporation of brain‐specific antibodies into haloperidol‐containing micelles resulted in additional drastic increase (more than by 2 orders of magnitude) in the drug effect.

Fatty acid acylated antibodies against virus suppress its reproduction in cells

A method for suppression of virus reproduction in cells using fatty acylated antiviral antibodies, which in contrast to non‐modified antibodies are capable of intracellular penetration, has been suggested. The addition of stearoylated antiviral antibodies to influenza A/Chili virus‐infected cells causes a 100‐fold suppression of virus reproduction. Non‐modified antibodies do not produce any effect on virus reproduction.

Antitumor activity of conjugates of the oncofetal protein alpha-fetoprotein and phthalocyanines in vitro.

The several conjugates of aluminium and cobalt complexes of phthalocyanines with human alpha‐fetoprotein have been synthesized. Their cytotoxic activity against tumor cells and human peripheral blood lymphocytes was studied. The experimental data demonstrate that the cytotoxic activity of alpha‐fetoprotein‐phthalocyanine conjugates against three types of tumor cells of various origin is much higher (for aluminium and cobalt complexes more than 1000 and 50 times, respectively) in comparison with phthalocyanines themselves. The application of phthalocyanines as conjugates with alpha‐fetoprotein makes it possible to markedly enhance the selective toxicity of phthalocyanines against human tumor cells.

Platelet-activating factor stimulates receptor-mediated formation of reactive oxygen intermediates in human monocytes

Stimulation of production of reactive oxygen intermediates (ROI) was examined in human peripheral blood monocytes by luminol-dependent chemiluminescence. The dose-response cureve characterizing the dependence of ROI production on the concentration of platelet-activating factor (PAF) showed that stimulation occurred within a concentration range of 2×10−9M to 5×10−6M. Transformation of the dose-response curve to an Eadie-Hofstee plot indicated that the process is characterized by two Km values. The Km value corresponding to the high-affinity branch of the curve is 1.3±0.14 nM. In the same cells, the dissociation constant for the [3H]PAF/receptor complex was determined. The Kd value was 0.8±0.1 nM, which agreed quite well with the high-affinity Km value obtained in the Eadie-Hofstee plot. The data indicate that stimulation of ROI generation is mediated through PAF binding at specific receptor sites at nanomolar PAF concentrations. Along with the specific receptor-mediated ROI generation, a nonspecific effect of PAF at a high concentration was demonstrated.

Mutual arrangement of histone H1 molecules in extended chromatin: Chymotryptic digestion of cross-linked H1 histone dimers

Mutual arrangement of histone H1 molecules in chromatin extended in low salt—EDTA buffer and additionally in the presence of urea was studied by means of reversible cross‐linking combined with chymotryptic digestion. In the chromatins tested, the chymotryptic halves of H1 were cross‐linked in all possible combinations; i.e., C—C, C—N and N—N. The results imply that the mutual arrangement of H1 histones is determined by the structure of extended nucleosomal chain, rather than chromatin superstructure.

Calmodulin-dependent enzymes as a target of staphylococcal enterotoxin A

The response of lymphoid and nerve cells to the action of SEA has been investigated. It has been established that the toxin acts as a mitogen with respect to resting cells and suppresses the DNA biosynthesis in proliferating cells. Interaction of SEA with the systems of second messengers in lymphoblastoid cells has been studied. The results obtained suggest a mechanism of the antiproliferative action of SEA on these cells. Studies on the structural organization of the toxin molecule have revealed that the latter contains a polypeptide (BacM) capable of activating calmodulin-dependent enzymes both in the presence and absence of Ca2+. These findings permit us to assume that the cytostatic effect of SEA is conditioned by the formation of BacM and phosphorylation of elongation factor 2.

Inactivation and sensitization of tumor cells after transfection with gene Bax

Experiments on the transfection of cultured SKOV3 tumor cells of human ovarian adenocarcinoma and HeLa cells of human cervical carcinoma with gene Bax have demonstrated that SKOV3 cells are highly sensitive to the protein product of this gene, whereas the sensitivity of HeLa cells is substantially lower. HeLa cells obtained as a result of Bax transfection and subsequent selection are characterized by an extremely high Bax protein content and a hypersensitivity to doxorubicin. All Bax-transfected SKOV3 cells with an increased Bax content have died. In the SKOV3 cell line, a Bax exon 3 mutation has been found that corresponds to genotype G7/G9, whereas the native type of the Bax gene corresponds to genotype G8/G8. The results suggest that the G7/G9 mutation in Bax exon 3 deprives the Bax protein of proapoptotic activity.

Characterization of benzodiazepine receptors of human lymphocytes

It is demonstrated that benzodiazepine binding sites on human peripheral blood lymphocytes are the peripheral type receptors. The binding sites for the selective agonist3H-Ro 5-4864, but not for the antagonist3H-PK 11195, are completely inactivated by freezing-thawing of lymphocytes. The binding of3H-Ro 5-4864 to intact lymphocytes is activated by GABA and (+)baclofen. It is shown that the selective ligands Ro 5-4864 and PK 11195 bind to different subtypes of benzodiazepine receptors on human peripheral blood lymphocytes.

Respecrin — A New Approach to Constructing Drugs with Targeted Action

The directed or targeted transport of drugs to sites of disease was first suggested by Ehrlich more than 100 years ago (Himmelweit, 1960). There is no doubt that drugs are most effective, and have fewest side effects, when their activity becomes manifest only upon contact with affected organs or cells. This is especially important in tumour therapy, where cytotoxic and highly antigenic protein factors are administered.