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Biomedical subjects

E A Komarova

Publications and source records attributed to E A Komarova.

18 recordsLinked to original sources
PubMed2001

Chemoprotection from p53-dependent apoptosis: potential clinical applications of the p53 inhibitors.

The p53 tumor suppressor pathway is a key mediator of stress response that protects the organism from accumulating genetically altered and potentially cancerous cells by inducing growth arrest or apoptosis in damaged cells. However, under certain stressful conditions, p53 activity can result in massive apoptosis in sensitive tissues, leading to severe pathological consequences for the organism. One such situation is anticancer therapy that is often associated with general genotoxic stress, leading to p53-dependent apoptosis in the epithelia of the digestive tract and in the hematopoietic system. A chemical inhibitor of p53, capable of suppressing p53-mediated apoptosis, was shown to protect mice from lethal doses of gamma-radiation, making pharmacological suppression of p53 a perspective therapeutic approach to reduce the side-effects of cancer treatment. There are other situations, besides anti-cancer therapy, when humans are exposed to stressful conditions known to involve p53 activation, which, in extreme cases, could result in the development of life-threatening diseases. Here we review the experimental evidence on the role of p53 in tissue injuries associated with hypoxia (heart and brain ischemias) and hyperthermia (fever and burns), comparing these pathologies with the consequences of genotoxic stress of cancer treatment. The accumulated information points to the involvement of p53 in the generation of the pathological outcome of the above stresses, making them potential targets for the therapeutic application of p53 inhibitors.

Animals↗
PubMed2001

p53 Involvement in the control of murine hair follicle regression.

p53 is a transcription factor mediating a variety of biological responses including apoptotic cell death. p53 was recently shown to control apoptosis in the hair follicle induced by ionizing radiation and chemotherapy, but its role in the apoptosis-driven physiological hair follicle regression (catagen) remains to be elucidated. Here, we show that p53 protein is strongly expressed and co-localized with apoptotic markers in the regressing hair follicle compartments during catagen. In contrast to wild-type mice, p53 knockout mice show significant retardation of catagen accompanied by significant decrease in the number of apoptotic cells in the hair matrix. Furthermore, p53 null hair follicles are characterized by alterations in the expression of markers that are encoded by p53 target genes and are implicated in the control of catagen (Bax, Bcl-2, insulin-like growth factor binding protein-3). These data suggest that p53 is involved in the control of apoptosis in the hair follicle during physiological regression and imply that p53 antagonists may be useful for the management of hair growth disorders characterized by premature entry into catagen, such as androgenetic alopecia, alopecia areata, and telogen effluvium.

Animals↗
PubMed2000

p53 is essential for chemotherapy-induced hair loss.

Anticancer drugs stimulate apoptosis in the hair follicles (HF) and cause hair loss, the most common side effect of chemotherapy. In a mouse model for chemotherapy-induced hair loss, we demonstrate that p53 is essential for this process: in contrast to wild-type mice, p53-deficient mice show neither hair loss nor apoptosis in the HF keratinocytes that maintained active proliferation after cyclophosphamide treatment. HF in p53 mutants are characterized by down-regulation of Fas and insulin-like growth factor-binding protein 3 and by increased expression of Bcl-2. These observations indicate that local pharmacological inhibition of p53 may be useful to prevent chemotherapy-associated hair loss.

Alopecia↗
PubMed2000

Different impact of p53 and p21 on the radiation response of mouse tissues.

Mammalian tissues differ dramatically in their sensitivity to genotoxic stress, although the mechanisms determining these differences remain largely unknown. To analyse the role of p53 and p21 in determination of tissue specificity to DNA damage in vivo, we compared the effects of gamma radiation on DNA synthesis on whole-body sections of wild type, p53-deficient and p21-deficient mice. A dramatic reduction in 14C-thymidine incorporation after gamma irradiation was observed in the majority of rapidly proliferating tissues of wild type and p21-/- but not in p53-/- mice, confirming the key role of p53 in determination of tissue response to genotoxic stress in vivo and suggesting that p53-mediated inhibition of DNA synthesis does not depend on p21. Rapid radiation induced p53-dependent apoptosis was mapped to the areas of high levels of p53 mRNA in radiation sensitive tissues analysed (white pulp in the spleen and bases of crypts in small intestine), indicating that p53 regulation at the mRNA level is a determinant of cellular sensitivity to genotoxic stress. High p53 mRNA expression is inherited as a recessive trait in cell-cell hybrids suggesting the involvement of a negative control mechanism in the regulation of p53 gene expression.

3T3 Cells↗
PubMed2000

Suppression of p53: a new approach to overcome side effects of antitumor therapy.

The p53 protein is traditionally believed to be a tumor suppressor. Activation of p53-dependent apoptosis in response to damage to cell DNA provides for the elimination of possible tumor cell precursors. However, in some cases the activity of p53 can be dangerous for the organism. Thus, p53-dependent apoptosis induced in normal tissues during chemo- and radiotherapy can cause severe side effects of antitumor therapy and, therefore, limits its efficiency. This review analyzes experimental data on the role of p53 in the primary and late tissue response to DNA-damaging exposures. Comparison of normal and p53-deficient mice indicated that the apoptosis in radiosensitive tissues during the first hours after irradiation is really caused by the activity of p53 which, in turn, is determined by a high level of expression of mRNA of p53. We supposed that a temporary suppression of p53 can decrease the damage to sensitive tissues and accelerate their recovery after the antitumor radio- and chemotherapy. To test this hypothesis, we have isolated a chemical inhibitor of p53 and determined its activity in vitro and in vivo. This compound, called pifithrin-alpha, protects wild-type mice against lethal doses of radiation, has no effect on p53-deficient animals, and does not induce visible tumors. These results show that the suppression of p53 is a promising approach in the prevention of side effects of antitumor therapy.

Animals↗
PubMed1999

A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy.

Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Because these effects are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to prevent damage of normal tissues during treatment of p53-deficient tumors. To test this possibility, a small molecule was isolated for its ability to reversibly block p53-dependent transcriptional activation and apoptosis. This compound, pifithrin-alpha, protected mice from the lethal genotoxic stress associated with anticancer treatment without promoting the formation of tumors. Thus, inhibitors of p53 may be useful drugs for reducing the side effects of cancer therapy and other types of stress associated with p53 induction.

Animals↗
PubMed1998

Stress-induced secretion of growth inhibitors: a novel tumor suppressor function of p53.

p53 tumor suppressor gene controls cell response to a variety of stresses inducing growth arrest or apoptosis in damaged cells. It largely determines the sensitivity of tumor and normal cells to radiation and chemotherapy, and, therefore, defines both the efficacy and limitations of anti-cancer treatment. To determine molecular mechanisms of p53-dependent stress response in normal tissues we identified and compared the spectra of radiation-responsive genes in cells of different origin and p53 status using a cDNA array hybridization technique. The majority of genes identified were p53-dependent and cell type specific. Several of the new p53 responders encode known secreted growth inhibitory factors. This suggests that p53, in addition to its intrinsic antiproliferation activity, can cause 'bystander effect' by inducing export of growth suppressive stimuli from damaged cells to neighboring cells. Consistently, a p53-dependent accumulation of factors, which causes growth inhibitory effects in a variety of cell lines, was found after gamma irradiation in the media from established and primary cell cultures and in the urine of irradiated mice. Moreover, p53-dependent factors released by normal human fibroblasts potentiated the cytotoxic effect of a chemotherapeutic drug on co-cultivated tumor cells. This suggests a previously unknown role for normal cells in chemo- and radiation therapy of cancer.

3T3 Cells↗
PubMed1998

Could p53 be a target for therapeutic suppression?

The function of p53 has been traditionally viewed in the context of its tumor suppressor activity. In fact, the p53-dependent growth arrest and apoptosis, occurring in response to a variety of stimuli, act to protect the organism from cancer by eliminating potential tumor precursors. However, the same functions of p53 could determine severe damage of normal tissues as a consequence of genotoxic stress associated with anti-tumor therapy. This makes p53 a potential target for therapeutic suppression with the purpose of rescuing normal tissues from the side effects of cancer treatment. We analyze the accumulated information regarding the role of p53 in acute and long-term consequences of genotoxic stress in vivo. Comparison of p53 wild type and p53-deficient mice indicates that p53, in fact, determines massive apoptosis occurring shortly after gamma irradiation in radiosensitive tissues. Sites of apoptosis match the tissue-specific pattern of p53 mRNA expression indicating that p53 regulation at mRNA level is a determinant of acute radiosensitivity of tissues. In the hematopoietic system, radiation-induced death of both differentiating and stem cells strongly depends on p53, suggesting that p53 suppression would decrease damage and promote faster recovery of hematopoiesis after anti-cancer therapy. However, p53 does not effect the recovery of radiosensitive epithelia since their stem cells, in contrast to differentiating cells, die in a p53-independent manner. The validity and potential complications of therapeutic suppression of p53 in cancer treatment and under other stressful conditions are discussed in relation to the p53 functions in normal development.

Animals↗
PubMed1997

Intracellular localization of p53 tumor suppressor protein in gamma-irradiated cells is cell cycle regulated and determined by the nucleus.

DNA damage leads to the stabilization of p53 protein and its translocation to the nucleus, resulting in activation or suppression of p53-responsive genes. However, a significant proportion of cell nuclei remain negative for p53 and p53-inducible cyclin-dependent kinase inhibitor p21waf1 after a single dose of gamma-irradiation. Quantitation of DNA content in p53-positive and -negative nuclei 4-6 h after 10 Gy of gamma-irradiation of human breast carcinoma MCF7 cells, fibrosarcoma HT1080 cells, and diploid skin fibroblasts showed that p53 and p21waf1 nuclear accumulation occurs predominantly in the G1 phase and at the beginning of the S phase of the cell cycle. The majority of the nuclei in late S phase and in G2-M phase remained p53- and p21waf1-negative. This suggests that there is a cell cycle window during which p53 can accumulate in the nucleus and activate expression of p21waf1. To determine whether cell cycle-dependent distribution of p53 is caused by cytoplasmic modifications of p53 protein or by properties of the nucleus, p53 localization was analyzed in multinucleated cells obtained by polyethylene glycol-mediated cell fusion. Dramatic differences in p53 accumulation were found among the nuclei in individual multinucleated cells. Distribution of p53-positive and -negative nuclei among the phases of the cell cycle was similar to that observed in a regular cell population. These results suggest that the observed differences in p53 accumulation in the nuclei of irradiated cells are determined by cell cycle-dependent nuclear functions. In contrast to p53, p21waf1 was equally distributed among the nuclei of multinucleated cells regardless of the stage of the cell cycle, indicating that the observed phenomenon is specific for p53.

Breast Neoplasms↗
PubMed1997

Transgenic mice with p53-responsive lacZ: p53 activity varies dramatically during normal development and determines radiation and drug sensitivity in vivo.

To analyze the involvement of p53-dependent transcriptional activation in normal development and in response to DNA damage in vivo, we created transgenic mice with a lacZ reporter gene under the control of a p53-responsive promoter. Five independent strains showed similar patterns of transgene expression. In untreated animals, lacZ expression was limited to the developing nervous system of embryos and newborn mice and was strongly decreased in the adult brain. gamma-irradiation or adriamycin treatment induced lacZ expression in the majority of cells of early embryos and in the spleen, thymus and small intestine in adult mice. Transgene expression was p53 dependent and coincided with the sites of strong p53 accumulation. The lacZ-expressing tissues and early embryos, unlike other adult tissues and late embryos, are characterized by high levels of p53 mRNA expression and respond to DNA damage by massive apoptotic cell death. Analysis of p53-null mice showed that this apoptosis is p53 dependent. These data suggest that p53 activity, monitored by the reporter lacZ transgene, is the determinant of radiation and drug sensitivity in vivo and indicate the importance of tissue and stage specificity of p53 regulation at the level of mRNA expression.

3T3 Cells↗
PubMed1992

ART-CH, a new chicken retroviruslike element.

A 3' region of a previously unknown retroviruslike element named ART-CH (avian retrotransposon from chicken genome) was obtained in the course of polymerase chain reaction-mediated cloning of avian leukosis virus long terminal repeats (LTRs) from DNAs of infected chicken cells. About 50 copies of ART-CH are present in the genome of chickens of different breeds. ART-CH is not found in DNA of quails, ducks, turkeys, or several other birds tested. The ART-CH element is about 3 kb in size, including 388 bp LTRs. The major class of ART-CH-specific RNA, also 3 kb in size, is detected in various organs of chickens. An ART-CH polypurine tract, a tRNA(Trp)-binding site, regions around the TATA box and polyadenylation signal, and the beginning of the putative gag gene strongly resemble the corresponding regions of avian leukosis viruses and EAV, the two described classes of chicken retroviruses. An open reading frame capable of encoding a polypeptide with a putative transmembrane domain is located upstream of the right ART-CH LTR. This sequence, as well as the U3 and U5 regions of the ART-CH LTR, has no obvious similarities with the corresponding parts of other known vertebrate retroviruses and retrotransposons. A short sequence upstream of the right LTR of ART-CH is very similar to sequences which flank the 3' ends of the oncogenes v-src, v-myc, v-fps, and v-crk in four different recombinant avian retroviruses and which are absent from the genomes of other studied avian retroviruses. Thus, ART-CH is a new endogenous chicken provirus that may participate in the formation of recombinant oncogenic retroviruses.

Amino Acid Sequence↗
PubMed1987

[Endogenous MMTV in the normal mammary gland and in dimethylanthracene-induced mammary cancer in BALB/c mice].

Immunization of DMBA-treated mice by the glycoprotein fraction from mammary glands of mice BALB/c did not decrease the frequencies of induction of mammary tumors. This is in contrast to the results obtained during immunization by the formaldehyde treated preparation of Mouse Mammary Tumor Virus (MMTV). EcoRI and HindIII cleaved DNA from the DMBA-induced mammary tumors did not contain the additional virus specific fragments. In mammary tumors the expression of p27 MMTV was registered in contrast to normal mammary glands and mammary epithelium cultures in which the proteins of MMTV are not expressed even after induction.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

[Possible participation of endogenous MMTV virus in chemical carcinogenesis of mouse mammary glands].

A study was made of the effect of immunization with formalinized MMTV on mammary tumor incidence in BALB/c mice exposed to dimethylbenzanthracene. In mice immunized with MMTV, the incidence of mammary tumours was significantly lower and the latent period longer as compared with the control group immunized with MULV. The indirect fixed immunofluorescence technique has shown that tumour cells in both groups express gp52 and p27 antigens. The possible involvement of endogenous MMTV into chemical carcinogenesis in murine mammary glands is discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

[Inactivating effect of o-methylhydroxylamine on phage lambda and its mutants].

The kinetics of inactivation of lambda+, lambda C160, lambda Nsus7, lambda Gsus9, lambda Tsus6 phages under the effect of O-methylhydroxylamine was studied. Inactivation curves of all the phages under study were found to be of a complex character and early in the reaction (up to 4 hours) to deviate from exponential dependence of the inactivation rate upon the time of incubation with the mutagen. All the phages under study showed differences in the inactivation rates early in the reaction. Constants of the inactivation rate in the linear part of the curve vary from 30 hours-1 for lambda+ to 0.14 hours-1 for lambda C160. The possible causes of the complicated pattern of inactivation courves of lambda phage and its mutants are discussed.

Coliphages↗
PubMedDate not supplied

[Study on the effect of a biostimulant on the growth and toxigenic function of Clostridium tetani strain Copenhagen-471].

Bakstim, a new biostimulating preparation obtained from the organs of the immune system of animals, was developed. The impact of Bakstim on the growth and toxigenic function of C. tetani production strain Copenhagen-471 was evaluated. The addition of the preparation to Gluzman commercial medium for obtaining tetanus toxoid led to an increase in the yield of bacterial biomass from 1.9 to 4-fold and an increase in the toxoid production from 2 to 2.8-fold. The optimum concentration of this biostimulant ensuring the maximum yield of tetanus toxin from the production culture was determined (1,000 mg/l). Bakstim will supposedly be used as additive to nutrient media for the production of tetanus toxoid.

Bacterial Proteins↗
PubMedDate not supplied

[Detection of antigens immunologically related to the envelope antigens of mouse mammary gland cancer virus antigens in human breast cancer tissue].

A highly sensitive method of electroimmunodiffusion in acetate cellulose films developed by G.I. Abelev on the principle of isotachophoresis was used for the detection in human mammary gland carcinoma (HMGC) of an antigen related to envelope antigens of mouse mammary gland cancer (MMGC) virus. In 4 out of 10 HMGC cases, fractions of proteins with molecular weight about 50,000 d previously isolated in PAAG with sodium dodecyl sulphate were found to contain an antigen reacting with the antiserum to p52 MMGCV precipitation band which proved immunological identity of both antigens.

Adenocarcinoma↗
PubMedDate not supplied

[Detection of MMTV gp52 in C3H and C3Hf strain mice].

Immunofluorescence in paraffine sections demonstrated the difference in expression of the membrane glycoprotein of mouse mammary tumor virus (gp52) in two mouse sublines: C3H and C3Hf. In the C3Hf the glycoprotein becomes detectable in the mammary gland in the second part of pregnancy while in C3H line mature females before pregnancy. No viral glycoprotein could be found in the spleen, liver, kidneys and other organs in males and females of the two sublines or in C3H embryos.

Animals↗