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Biomedical subjects

S E Severin

Publications and source records attributed to S E Severin.

At least 19 recordsLinked to original sources
PubMed2004

[Analysis of virulent and avirulent strains of Vibrio cholerae by the nest polymerase chain reaction].

The detection of cholera enterotoxin in environmental objects and isolation of patients are considered to be the most reliable indices of that the cholera agent is present. Described in the case study is a method of nested polymerase chain reaction (PCR) based on amplifying the ctxA gene fragment coding subunit A of enterotoxin. A possibility was shown to use the above method to confirm the virulence of strains Vibrio cholerae isolated from different sources. The method was tested with 18 virulent and avirulent strains V. cholerae as well as (for the sake of verifying the analysis specificity) with DNAs of other human-pathogenic microorganisms and with the human genome DNA. The results showed a high efficiency of nested PCR in detecting the pathogenicity of cholera-agent strains.

Humans↗
PubMed2003

Molecular mechanisms of tumor angiogenesis.

The maintenance of growth of malignant tumors is closely related with the development of the vascular network supplying the tumor with blood. The vascularization of tumor tissue is similar to physiological angiogenesis, but in tumors it has some specific features. During the last 25 years a vast number of biomolecules have been found and described which are involved in the regulation of tumor angiogenesis. This review considers the action mechanisms and specific features of expression of the main angiogenic growth factors, such as the vascular endothelium growth factor (VEGF), angiopoietins (Ang-1, Ang-2), and the basic fibroblast growth factor (bFGF). The roles of cytokines, growth factors, proteolytic enzymes, and cell adhesion molecules in the regulation of the key steps of blood vessel generation in the tumor are considered. The significance of angiogenesis in the treatment of oncological diseases and possible approaches for inhibition of the regulatory signals of angiogenic factors are discussed.

Angiogenesis Inducing Agents↗
PubMed2003

Tumor angiogenesis inhibitors.

Formation of the blood supply system is a critical step in malignant transformation of neoplasms which results in the penetration of tumor cells into neighboring tissues and metastatic growth. Significant progress in the elucidation of mechanisms underlying tumor angiogenesis and the discovery of a great diversity of biomolecules involved in its regulation have culminated in the development of a radically new approach to antitumor therapy based on the search for efficient inhibitors of tumor angiogenesis. This review is devoted to the analysis of action mechanisms and expression of the major endogenous inhibitors involved in regulation of tumor and physiological angiogenesis. The antiangiogenic effects of the majority of currently known synthetic inhibitors are considered in the context of their roles in the main steps of tumor angiogenesis. Possible applications of antiangiogenic therapy in the chemotherapy of cancer diseases are discussed.

Angiogenesis Inhibitors↗
PubMed2003

The tumor cell and telomerase.

Imbalanced activity of the mechanism that controls cell division is a prerequisite for malignant transformation of a normal cell. The present review considers this multi-step mechanism, which is usually called the G1-S checkpoint. Besides, tumor cells are characterized by the presence of telomerase, an enzyme responsible for restoration of chromosome ends after replication and thus providing for unlimited cell division. The main point of the present article is to find out whether the activation of telomerase is controlled by the G1-S checkpoint or does not depend on it. The principal components of the G1-S checkpoint, such as cyclin-dependent kinases, retinoblastoma and E2F proteins, control the activity of telomerase. In their turn, they accumulate and transmit signals from various sources inside and outside the cell. Thus, various changes in tumor cells can activate telomerase through the G1-S checkpoint. Such are the suggested effects on telomerase of Myc, p53, Waf1, protein kinases B and C, Wnt5A, TGFbeta, WT1, and estrogens. However, Myc, p53, WT1, estrogens, protein kinases B and C, and TGFbeta can also directly influence telomerase independently of the G1-S checkpoint mechanism. Moreover, in 30% of human tumors the gene of the key subunit of telomerase (hTERT) is amplified, possibly due to chromosomal rearrangements unassociated with the activity of the G1-S checkpoint. Thus, telomerase seems to be activated not by a single agent but due to combined action of various factors, both with involvement of the G1-S checkpoint mechanism and independently of it.

Animals↗
PubMed2003

[Use of the nested polymerase chain reaction in the differential diagnosis of human herpes simplex virus].

Herpes is one of the most widespread human viral pathologies. The article depicts a special modification of polymerized chain reaction--(PCR)--(referred to as "nested"), which has a higher sensitivity, specificity and reliability as compared to the ordinary PCR, and which is designed to detect the herpes viruses. The method was initially tested at purified preparation of viral DNA, and later--at clinical materials obtained from patients and healthy donors. Secretions from the urogenital tract (smears), scrapes from the urogenital tracts and urinal cellular samples were examined in patients. Herpes simplex was detected in all cases. As for the healthy people, the identical examinations produced in them mainly the negative findings. Therefore, the nested PCR is a simple, sensitive and effective instrument in the diagnostics and prevention of herpes; it can be recommended for a comprehensive usage in medical practice.

Diagnosis, Differential↗
PubMed2003

[Enhanced activity of rifampicin loaded with polybutyl cyanoacrylate nanoparticles in relation to intracellularly localized bacteria].

Association of rifampicin with polybutylcyanoacrylate nanoparticles provided considerable enhancement of drug antibacterial activity. In vitro nanoparticle-loaded rifampicin was more active against Staphylococcus aureus and Mycobacterium avium, localized in isolated alveolar macrophages. Level of rifampicin in macrophages increased 2-3-fold after incubation with rifampicinloaded nanoparticles comparing to the free drug. High therapeutic efficacy of colloidal rifampicin was demonstrated in vivo. Use of nanoparticles provided 2-fold increase in rifampicin efficacy, comparing with the free drug at treatment of staphylococcus sepsis in mice. Single administration of nanoparticulate rifampicin in the dose 25 mg/kg resulted in 80% survival of mice with salmonellosis, while 50 mg/kg of free rifampicin could provide only 10% survival. It may be considered that high antibacterial efficacy of rifampicin bound to nanoparticles is due to its effective delivery to macrophages.

Animals↗
PubMed2003

[Use of nested PCR in detection of the plague pathogen].

Causative agents of plague, i.e. bacterium Yersina pestis (in the subcutaneous tissues of rodents) and their cutaneous parasites need to be isolated to enable plague prevention. A comparatively new method of polymerase chain reaction (PCR) opens up new possibilities of determining Y. pestis just within several hours and without any cultivation. The article contains a description of the PCR-method, which makes it possible to distinguish the culture of Y. pestis from cultures of other microorganism, including speci of Yersina. The method is of the cluster-type, i.e. it is made up of subsequent PC reactions with the substrate for the second reaction being the product of the first one. The cluster nature of the method preconditions a higher sensitivity and specificity versus the ordinary PCR.

Humans↗
PubMed2002

Toxicological studies of doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles in healthy rats and rats with intracranial glioblastoma.

Polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles (NP) were shown to enable the transport of a number of drugs including the anti-tumour antibiotic doxorubicin (DOX) across the blood-brain barrier (BBB) to the brain after intravenous administration and to considerably reduce the growth of brain tumours in rats. The objective of the present study was to evaluate the acute toxicity of DOX associated with polysorbate 80-coated NP in healthy rats and to establish a therapeutic dose range for this formulation in rats with intracranially implanted 101/8 glioblastoma. Single intravenous administration of empty poly(butyl cyanoacrylate) NP in the dose range 100-400 mg/kg did not cause mortality within the period of observation. NP also did not affect body weight or weight of internal organs. Association of DOX with poly(butyl cyanoacrylate) NP did not produce significant changes of quantitative parameters of acute toxicity of the anti-tumour agent. Likewise, the presence of polysorbate 80 in the formulations was not associated with changes in toxicity compared with free or nanoparticulate drug. Dose regimen of 3x1.5 mg/kg on days 2, 5, 8 after tumour implantation did not cause drug-induced mortality. The results in tumour-bearing rats were similar to those in healthy rats. These results demonstrate that the toxicity of DOX bound to NP was similar or even lower than that of free DOX.

Animals↗
PubMed2002

Cytotoxic and antitumor activities of doxorubicin conjugates with the epidermal growth factor and its receptor-binding fragment.

The epidermal growth factor (EGF) receptor is expressed at high levels on many types of tumor cells, such as squamous carcinoma, breast cancer and endothelial cells. We studied targeted delivery of the anticancer drug doxorubicin (DOX) using EGF and its receptor-binding fragment (EGFfr) to cells able to overexpress EGF receptors. EGF-DOX and EGFfr-DOX conjugates were synthesized via a glutaraldehyde bridge. The cytotoxic activities (CTA) of the conjugates were studied in vitro in different tumor cell lines (MCF-7Wt, MCF-7AdrR, B16) and endothelial cells using MTT-test. The antitumor effects of the conjugates were examined in vivo in mice with a subcutaneous B16 model. In the case of MCF-7Wt cells, CTA of EGF-DOX and EGFfr-DOX conjugates exceeded 7.7- and 68-fold that of free DOX. Besides, the conjugates effectively decreased the drug resistance of MCF-7AdrR cells. CTA of the conjugates against endothelial cell cultures markedly exceeded that of free DOX. It is of note that proliferating endothelial cells were much more sensitive to the effects of the conjugates than confluent endothelial cells. Administration of EGF-DOX and EGFfr-DOX conjugates significantly inhibited tumor growth and increased the mean life span of experimental animals by 46 and 48.5%, respectively.

3T3 Cells↗
PubMed2001

[Optimization of "Photosens" pharmakokinetics by biodegradable nanospheres].

The present study is dedicated to investigation of pharmacokinetics of the colloidal delivery system based on polybutylcyanoacrylate nanoparticles for the II generation photosensitizer Photosense. Free or nanoparticle-bound Photosense was injected intravenously in healthy rats in the dose 15 mg/kg. It was shown that pharmacokinetic curve of the free drug was characterized by peak concentration while plasma concentrations of nanoparticulate Photosense were relatively steady. Elimination of nanoparticulate Photosense was more rapid comparing to the free drug. It is noteworthy that nanoparticles did not enhance liver uptake of the drug. Lung level of nanoparticulate drug was found to be lower and spleen uptake was enhanced. More important is the fact that nanoparticles provided two-fold decrease of Photosense skin concentration which is potentially important for decrease of drug-related skin phototoxicity. The above data provide evidence that optimization of Photosense pharmacokinetic parameters could be achieved by the use of nanoparticles.

Animals↗
PubMed2000

Cytotoxic action of conjugates of alpha-fetoprotein and epidermal growth factor with photoheme, chlorines, and phthalocyanines.

Covalently bound conjugates of alpha-fetoprotein (AFP) and epidermal growth factor (EGF) with photoheme (PH), 3-desvinyl-3-formylchlorine p6 (Chl p6), chlorine e6 (Chl e6), aluminum disulfochloride phthalocyanine (PC(Al)), and cobalt octa-4,5-carboxyphthalocyanine (teraphthal, TP(Co)) were synthesized. Their molar ratios were 1:4 for AFP-cytotoxin conjugates (cf. 1:10 for AFP-TP(Co)) and 1:2 for EGF conjugates (cf. 1:1 for EGF-PC(Al)). Dark toxicity of both protein conjugates with PH, chlorines, and PC(Al) was much lower than their phototoxicity. Studies on phototoxicity demonstrated that PC(Al) conjugates with AFP and EGF and also EGF-Chl p6 were the most effective. The cytotoxic activity (CTA) of AFP-PC(Al) and EGF-Chl p6 was 80% and of EGF-PC(Al) 64% higher than the CTA of the free drugs. Conjugates with TP(Co) were much more toxic on their activation with ascorbic acid (AA): in the presence of AA the CTA of AFP-TP(Co) and of EGF-TP(Co) was 19 and 61.1% higher, respectively, than the CTA of the free TP(Co).

Antineoplastic Agents↗
PubMed2000

Antitumor activity of alpha-fetoprotein conjugate with doxorubicin in vitro and in vivo.

alpha-Fetoprotein (AFP) was conjugated with doxorubicin (DR) using glutaraldehyde as a cross-linking agent. The protein/DR molar ratio in the conjugate is 1 : 2. Cytotoxic activities (CTA) of the AFP-DR conjugate and of the free DR were compared using human mammary gland carcinoma cells, both DR-sensitive (MCF-7Wt) and DR-resistant (MCF-7AdrR). The CTA of the AFP-DR conjugate was fivefold higher than the CTA of the free DR for sensitive cells of the MCF-7Wt line and sevenfold higher for resistant cells of the MCF-7AdrR line. The CTA of the AFP-DR conjugate was also studied in vitro using the proliferating endothelium taken for a model of endothelial cell lining of blood vessels that supply the tumor. The AFP-DR conjugate was shown to have a high CTA for the endothelial cells (IC50 = 2.5 nM); thus, the conjugate is suggested to manifest an anti-angiogenic effect in vivo. The antitumor activity of the AFP-DR conjugate was studied using mice with inoculated melanoma B16 tumors. The treatment of animals significantly inhibited the tumor growth (>97%) and increased by 60% the mean life span of the animals compared to the control. The high antitumor efficiency of the AFP-DR conjugate and the possibility to significantly decrease the tumor cell resistance to DR make this conjugate a promising chemotherapeutic agent.

Animals↗
PubMed2000

Cytotoxic activity, accumulation, and intracellular distribution of anthracycline antibiotics and their conjugates with the epidermal growth factor in sensitive and resistant MCF-7 cells.

Cytotoxic activities, accumulation levels and dynamics, and intracellular distribution of the anthracycline antibiotics doxorubicin (DR) and carminomycin (CM) in the free forms or within conjugates with the epidermal growth factor (EGF) were for the first time compared in human breast carcinoma cell lines MCF-7Wt and MCF-7AdrR. The cytotoxic activities of DR and CM conjugates with EGF were higher than the cytotoxic activities of the free antibiotics in both cell lines. The accumulation levels of the free anthracyclines in both cell lines were lower than those of the conjugates and significantly depended on the cell sensitivities to the antibiotics. On receptor-mediated endocytosis of the anthracycline-EGF conjugates, the accumulation levels did not significantly depend on the cell sensitivities to the antibiotics. Both DR and CM, either free or conjugated with EGF, were mainly accumulated in nuclei. The free drugs were accumulated more rapidly, and the accumulation rates of both free and EGF-conjugated CM were higher than those of DR preparations. The intracellular distribution of the free antibiotics significantly depended on the cell sensitivities to the anthracyclines, whereas the cell sensitivities had no effect on the distribution of the conjugates between the nucleus and cytoplasm. The rate of intracellular degradation of DR and CM delivered to target cells within conjugates with EGF was twice lower than that of the free antibiotics. The difference in the accumulation levels and dynamics and in the intracellular distribution of the free and conjugated DR and CM is likely to underlie the higher cytotoxic activities of the anthracycline conjugates with EGF compared to the free drugs.

Antibiotics, Antineoplastic↗
PubMed1999

Water-soluble 2,3,7,8-tetrachlorodibenzo-p-dioxin complex with human alpha-fetoprotein: properties, toxicity in vivo and antitumor activity in vitro.

The conditions for the formation of a non-covalent complex between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the human transport fetal protein, alpha-fetoprotein (AFP), have been studied. TCDD has been shown to form a stable complex with AFP in a 2:1 (TCDD:AFP) ratio. The apparent solubility of TCDD in water increases 10(5)-fold after complex formation. The toxicity of the TCDD:AFP complex injected into mice by the intravenous route is comparable with that of free TCDD administered in oil solution per os. The complex manifests very much higher toxicity (200-1400 times) against human tumor cells (CEM, MCF-7, HepG2) in vitro and surpasses TCDD in selectivity. AFP may facilitate TCDD transport in embryonic tissues and enhance its embryotoxic and teratogenic effects.

Animals↗
PubMed1999

[The targetted delivery of antitumor preparations by using protein vectors].

The prospects of the endocytosis-mediated targeted delivery of antitumor drugs to the target cells by means of vector proteins, such as nerve growth factor (NGF), epidermal growth factor (EGF), and the oncofetal protein alpha-fetoprotein (AFP), are discussed. The high selectivity and efficiency of antitumor effects of synthetic covalent EGF- and AFP-conjugates with chemical agents (antitumor antibiotics) and antisense oligonucleotides are compared with individual biologically active compounds in in vitro and in vivo animal studies. The molecular mechanisms of action of the above conjugates have been studied. Evidence is given for the fact that it is expedient to use them to overcome multidrug resistance in the clinical setting. The findings are the first important step in designing novel target antitumor drugs based on biologically active vector proteins showing their effects by receptor-mediated endocytosis.

Animals↗
PubMed1998

Inhibition of telomerase activity of melanoma cells in vitro by antisense oligonucleotides.

The effect of antisense oligonucleotides complementary to the RNA component of human telomerase on telomerase activity in cell extracts of the melanoma cell line SK-Mel-28 has been studied. It has been shown that the antisense oligonucleotide complementary to the hTR component in the region of the template synthesis of telomeric repeats is the most efficient inhibitor of telomerase activity in comparison with other antisense oligonucleotides. Pronounced inhibition of telomerase activity was observed at the oligonucleotide (Tel P5) concentration in the reaction mixture of about 5 nM. Complete inhibition of the enzyme occurs at the oligonucleotide concentration in the sample of about 20 nM.

Enzyme Inhibitors↗
PubMed1997

Alpha-fetoprotein-mediated targeting--a new strategy to overcome multidrug resistance of tumour cells in vitro.

The possibility of overcoming the multidrug resistance of human malignant cells by using doxorubicin conjugated to alpha-fetoprotein (AFP) was studied. It was shown that this type of antitumour drugs, penetrating the cell by receptor-mediated endocytosis with AFP as a vehicle, raises the sensitivity of the tumour cells that are resistant due to the expression of the multidrug resistance gene mdr1. The sensitivity of antibiotic-resistant cell lines SKVLB (a human ovarian carcinoma) and MCF-7 AdrR (a human breast carcinoma) increased by 10- and 4-fold, respectively, when AFP-conjugated doxorubicin was used. The rationale of using human AFP-antitumour drug conjugates for the development of new chemotherapeutic approaches to cancer treatment is discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗