RESUMO
We studied the effect of dipeptide gamma-d-Glu-d-Trp (thymodepressin) on migration of CD34+ hemopoietic precursors and their direct adhesion to fibronectin in tumor-bearing mice on days 8, 11, 15, and 17 of tumor growth and on expression of CXCR-4 (CD184+) to SDF-1 and integrin beta1 (CD29+) by bone marrow cells. In tumor-bearing mice treated with gamma-d-Glu-d-Trp, the percent of CD34+ hemopoietic precursors in the peripheral blood considerably decreased throughout the observation period; the content of CD34+ hemopoietic precursors in the tumor tissue was 2-3-fold below the control against the background of increased content of CD34+ cells in the bone marrow. In animals treated with the peptide, the content of cells expressing CXCR-4 in the peripheral blood, bone marrow, and tumor tissue significantly decreased, while the percent of cells expressing integrin beta1 receptor (CD29+) in the bone marrow increased 2-fold, which was paralleled by an almost 2-fold increase in the percent of cells binding to fibronectin. We hypothesized that dipeptide gamma-d-Glu-d-Trp suppressed mobilization/migration of CD34+ hemopoietic precursor cells from the bone marrow to the peripheral blood of tumor-bearing mice.
Assuntos
Antígenos CD34/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Neoplasias , Peptídeos/farmacologia , Animais , Células da Medula Óssea/fisiologia , Movimento Celular/fisiologia , Feminino , Células-Tronco Hematopoéticas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Neoplasias/patologia , Neoplasias/fisiopatologiaRESUMO
The influence of Glu-Trp (EW) synthetic dipeptide isomers on hemopoietic progenitor cells and certain immune response reactions is determined by their optical and chemical properties. Thus, the all L-amino acid containing dipeptides L-Glu-L-Trp and L-gammaGlu-L-Trp have no effect on proliferation of committed and pluripotent CFU-S in intact bone marrow. The optical isomers of the Glu residue are an essential determinant of the EW dipeptide biological activity. The inversion of the amino acid optical form imparts suppressor properties: D-Glu-D-Trp,D--gammaGlu-D-Trp, D-Glu-L-Trp and D-gammaGlu-L-Trp inhibit proliferation of hemopoietic progenitors in intact bone marrow. The type of the peptide bond between L-Glu and Trp is another important factor for the biological activity of the L-Glu-containing peptides. Unlike L-Glu-D-Trp with alpha-peptide bond, the dipeptide L-gammaGlu-D-Trp with gamma-peptide bond stimulates CFU-S-8 proliferation in intact bone marrow. The diverse effects of the EW optical isomers on hemopoietic progenitors underlie the radioprotective properties of the D-Glu-containing dipeptides and the radiotherapeutic ones of the L-Glu dipeptides. In animals, pre-irradiation injection of D-Glu-D-Trp, D-gammaGlu-D-Trp, D-Glu-L-Trp, D-gammaGlu-L-Trp, or post-irradiation injection of L-Glu-L-Trp, L-gammaGlu-L-Trp promoted regeneration of the hemopoietic progenitor population.
Assuntos
Dipeptídeos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Animais , Células da Medula Óssea/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , EstereoisomerismoRESUMO
We studied the effect of thymodepressin on migration and adhesion of mouse hemopoietic CD34+ cells under normal conditions and under the effect of granulocytic CSF. It was found that the peptide reduced the absolute number of CD34+ hemopoietic cells in the peripheral blood, increased the percent of cells bound to fibronectin and expressing receptor for integrin beta1 (CD29+) in the bone marrow of mice under normal conditions and after stimulation with granulocytic CSF, and reduced the relative number of cells carrying CXCR4 receptor for stromal factor-1 (CD184+) in the bone marrow (CD34+CD184+) and blood (CD184+) of mice stimulated with granulocytic CSF. The results suggest that thymodepressin can inhibit migration of CD34+ cells from bone marrow into peripheral blood under conditions of normal and granulocytic CSF-stimulated hemopoiesis.
Assuntos
Antígenos CD34/metabolismo , Células da Medula Óssea/fisiologia , Movimento Celular/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Hematopoese/efeitos dos fármacos , Peptídeos/farmacologia , Animais , Antígenos CD34/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
We studied the effects of optical (dd-, ll-, dl-, and ld-dipeptides with alpha-bond, EW) structural isomers and cyclic (dd-, ll-, dl-, and ld-dipeptides with gamma-bond, iEW) analogs of Glu-Trp synthetic dipeptide on the population of normal hemopoietic stem cells. Dipeptides containing lGlu (lGlu-lTrp, lGlu-dTrp) injected to mice were inert towards committed bone marrow CFU-S; dGlu-containing dipeptides (dGlu-dTrp, dGlu-lTrp) inhibited the growth of CFU-S-8; and LiGlu-dTrp stimulated these cells. Inhibitory or stimulatory effects of optical and chemical isomers of Glu-Trp dipeptide are determined by optical orientation and nature of peptide bond of Glu residue. The effects of cyclic and mixed peptides towards colony formation are similar to those of the corresponding linear dipeptides.
Assuntos
Dipeptídeos/química , Dipeptídeos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Animais , Ensaio de Unidades Formadoras de Colônias , Feminino , Células-Tronco Hematopoéticas/citologia , Isomerismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , EstereoisomerismoRESUMO
Studies of cooperative effects of D- or L-isomers of iEW dipeptide and neuraminidase on the number of splenic CFU, comparison of the peptide effects on CD34+ cells and splenic CFU, and evaluation of the effects of iEW D- or L-isomers on parameters of T-cell activation showed that interactions of L-(iEW) and D-(iEW) with CD34+ surface receptors are realized through the same mechanism, while their different biological effects on hemopoietic precursor cells in vivo can be explained by their different influence on T-component of the microenvironment.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Dipeptídeos/farmacologia , Células-Tronco/efeitos dos fármacos , Animais , Antígenos CD34/análise , Complexo CD3/análise , Feminino , Camundongos , Camundongos Endogâmicos CBA , Neuraminidase/farmacologia , EstereoisomerismoRESUMO
Was studied the influence of the Thymodepressin (dipeptide D-iEW--a new Russian immuno- and haemodepressant), on the hyperthermic sensitivity of haemopoietic precursors (CFU-S) and tumor model cells (EL-4 and Rauscher leukaemia). It was determined, that the injection of the Thymodepressin to donor mice, or the incubation with the preparation of the marrowy cells of normal mice provides the increasing of the CFU-S resistance to the following heating (43 degrees C). On the contrary, Thymodepressin-treated tumor cells became even more heat-sensitive. The data show that Thymodepressin can be useful for protection the haemopoietic precursors not only from radiation and chemotherapy, as it was shown earlier, but also from the hyperthermy.
Assuntos
Células-Tronco Hematopoéticas/efeitos dos fármacos , Temperatura Alta , Peptídeos/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Feminino , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/terapia , Substâncias Protetoras/farmacologiaRESUMO
In experiments on mice F1 total exposed to gamma-irradiation at the 5.0 Gy, showed that a intraperitoneal injection neogen at the dose 10 micrograms/kg oue time at the day and night during the 8 days after irradiation results in recovery of the number blood platelets and time issue of blood from standard wound to normal level on the week by compare with irradiated control animals.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Lesões Experimentais por Radiação/tratamento farmacológico , Trombopoese , Adjuvantes Imunológicos/administração & dosagem , Animais , Radioisótopos de Cobalto , Interpretação Estatística de Dados , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Contagem de Plaquetas , Doses de Radiação , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/imunologia , Lesões Experimentais por Radiação/fisiopatologia , Trombopoese/efeitos dos fármacos , Trombopoese/efeitos da radiação , Trombopoetina/fisiologia , Fatores de TempoRESUMO
The effect of the synthetic peptide IEW (Neogen) with immunomodulating properties on postradiation recovery of haemopoiesis was investigated. We have shown that Neogen is a potential stimulator of haemopoiesis. The administration of Neogen after irradiation shortened duration of period of the recovery of the compartment of CFU-S-8 and the amount of bone marrow cells. The comparision of the effects of Neogen and GM-CSF (Leucomax) and G-CSF (Granocyte 34) have shown that the targets for these agents are probably different: polypotent CFU-S-for Neogen, and CFU-GM-for GM-CFS. Based on the results, we suggested the mechanism of Neogen effects on heamopoiesis.
Assuntos
Adjuvantes Imunológicos/farmacologia , Medula Óssea/efeitos da radiação , Hematopoese/efeitos dos fármacos , Hematopoese/efeitos da radiação , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/efeitos da radiação , Radioisótopos de Cobalto , Ensaio de Unidades Formadoras de Colônias , Interpretação Estatística de Dados , Feminino , Hematopoese/imunologia , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Doses de Radiação , Radiação Ionizante , Fatores de TempoRESUMO
We studied the possibility of using a new synthetic heme-inhibiting peptide thymodepressin for improving the efficiency of transplantations of syngeneic and allogeneic bone marrow. Thymodepressin was injected to recipients 3 times (48, 24, and 2 h) before irradiation and transplantation of bone marrow suspension. The yield of 9- and 12-day colonies increased, the number of proliferating CFU-S-12 and pre-CFU-S in recipient bone marrow increased in comparison with the control. In case of an allogeneic donor-recipient combination, the number of 9-day splenic colonies in thymodepressin-treated animals increased 5-fold compared to the control. We hypothesized that thymodepressin therapy and irradiation form an adaptive response of the recipient hemopoietic microenvironment in the bone marrow, which provides conditions for optimal functioning of donor hemopoietic precursors.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/efeitos da radiação , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/química , Imunossupressores/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Fatores de TempoRESUMO
It was studied on mice how prior whole body hyperthemia affects a colony-forming ability of bone marrow after gamma-irradiation. It was found that heating of the animals (42 degrees C, 10 min) 18-22 h before their total irradiation (4 Gy) increases 2-fold the level of CFUs8 and CFUs12 determined in the spleen exotest. The induced radioresistance correlated with accumulation of heat shock proteins, HSP70 and HSP25, in tissues of preheated mice. Injection of quercetin (a selective inhibitor of the heat shock protein synthesis) 0.5 h before the heating fully abolished both the subsequent heat shock protein accumulation and the rise in CFUs populations as compared with control. It is suggested that heat shock proteins, whose expression increases in response to hyperthermia, can play a role of endogenous radioprotectors. Possible mechanisms of their protective action under irradiation are discussed.
Assuntos
Proteínas de Choque Térmico , Células-Tronco Hematopoéticas/efeitos da radiação , Animais , Feminino , Proteínas de Choque Térmico HSP27 , Proteínas de Choque Térmico HSP70/fisiologia , Hematopoese/fisiologia , Hematopoese/efeitos da radiação , Células-Tronco Hematopoéticas/fisiologia , Hipertermia Induzida , Camundongos , Camundongos Endogâmicos CBA , Chaperonas Moleculares , Proteínas de Neoplasias/fisiologia , RatosRESUMO
Myelosuppression is a toxicity-related limitation for aranoza dosage. The drug proved effective in the treatment of uterine sarcoma, cancer of the head and neck, breast, Hodgkin's disease and lymphosarcoma during stage II of clinical studies. Complete regression was reported in the treatment of melanoma (ca. 12%). Good results of chemoimmunotherapy should be expected in untreated patients as well as intraarterial infusions for local lesions of the extremities. Clinical trials of aranoza used in combined modalities of therapy in various sites continue.
Assuntos
Antineoplásicos/uso terapêutico , Glicosídeos/uso terapêutico , Interferon-alfa/uso terapêutico , Melanoma/tratamento farmacológico , Metilnitrosoureia/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Quimioterapia Combinada , Glicosídeos/administração & dosagem , Glicosídeos/efeitos adversos , Humanos , Infusões Intra-Arteriais , Interferon-alfa/administração & dosagem , Metilnitrosoureia/administração & dosagem , Metilnitrosoureia/efeitos adversos , Metilnitrosoureia/análogos & derivados , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de TempoRESUMO
Hematologic thrombopenia and leukopenia formation limits use of nitrullin as a toxic hazard. The drug showed moderate effect in treating inoperable non-small cell cancer of the lung and satisfactory end results. The treatment had marked symptomatic effect in patients with this cancer and, as a consequence, improved the quality of life. Nutrullin had immuno-modulating effect. Its application alone or in combination with VPN showed good results in the management of small-cell cancer of the lung.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Citrulina/análogos & derivados , Citrulina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Nitrosoureia/uso terapêutico , Adenocarcinoma/mortalidade , Adulto , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Citrulina/efeitos adversos , Humanos , Neoplasias Pulmonares/mortalidade , Metástase Linfática , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Nitrosoureia/efeitos adversos , Fatores de TempoRESUMO
Synthetic polypeptide D-(iEW) (Thymodepressin) was shown to reduce the bone marrow CFU-S in the S-phase of cell cycle. Apparently, due to this property the agent being administered 2 days before the irradiation with 4 Gy causes a prominent restoration of the CFU-S population afterwards. The 3-5 times higher value of this parameter as compared to the control (irradiation only) is likely to be connected to the increased "survival" of the Thymodepressin-protected CFU-S after the treatment with ionizing irradiation.
Assuntos
Células da Medula Óssea/efeitos da radiação , Células-Tronco Hematopoéticas/efeitos da radiação , Peptídeos/farmacologia , Protetores contra Radiação/farmacologia , Baço/efeitos da radiação , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Feminino , Raios gama , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Baço/citologia , Baço/efeitos dos fármacos , Fatores de TempoRESUMO
Dipeptides of the EW-sequence, consisting of D-amino acids, were shown to inhibit spleen colony formation both after in vitro treatment of bone marrow and after the peptide injection to the donor 2-48 h prior to bone marrow taking. The inhibiting effect of D-(EW) peptides can be eliminated by injection of thymic cells to the recipient. L-(EW) peptides have no influence on colony forming activity of intact bone marrow cells but stimulate regeneration of colony formation by irradiated (1 Gy) bone marrow. Unlike L-(EW), the D-(EW) peptides suppress the development of hemopoietic stem cells into the S-phase. Supposedly, D-(EW) represent a new generation of immunoactive peptides possessing of inhibiting activity.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antiarrítmicos/farmacologia , Dipeptídeos , Peptídeos/farmacologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , EstereoisomerismoRESUMO
Efasol and potassium tetrachloropalladate being injected into mice prior to irradiation with a dose of 150 sGy increase the colony forming activity of animals bone marrow cells transplanted in lethally irradiated recipient mice. The palladium presence in such compounds is supposed to be a reason of radioprotection. Upon the combined application of potassium tetrachloropalladate and irradiation of mice with an adaptive dose of 5 sGy a potentiation of individual effect of each separate agent to increase CFUs resistance against the consequent irradiation was observed.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/efeitos da radiação , Paládio/farmacologia , Protetores contra Radiação/farmacologia , Adaptação Biológica , Animais , Transplante de Medula Óssea , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Doses de Radiação , Fatores de TempoRESUMO
Thymohexine treatment of intact CFU-S was shown not to change their capacity to form colonies both in vivo and in vitro. Thymohexine, similarly to thymus cells, increased colony yield from rabbit antimouse brain antiserum (RAMBS)-treated bone marrow. Combined treatment with thymohexine and thymocytes did not restore colony formation by RAMB serum-treated bone marrow. Thymohexine halved the harmful effect of low doses of ionizing radiation on CFU-S, and, moreover, treatment with the peptide after 4 Gy-irradiation led to more intensive restoration of CFU-S population as compared to control.
Assuntos
Adjuvantes Imunológicos/farmacologia , Oligopeptídeos/farmacologia , Peptídeos/síntese química , Peptídeos/farmacologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/efeitos da radiação , Timo/química , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Peptídeos/análise , Quimera por RadiaçãoRESUMO
Radiotherapeutic activity of histone fractions H1 and H2A/H2B were studied. It was demonstrated that both fractions are able to reduce the damaging effect of ionizing radiation on spleen colony forming unit (CFU-S) population. Histone preparations stimulated colony-forming activity of bone marrow cells exposed to dose of 0.5-3.0 Gy both in the case of incubation with preparations and intravenous or intraperitoneal administration into recipients of irradiated cells. The effect of histones and accessory thymocytes on CFU-S population is compared.
Assuntos
Células-Tronco Hematopoéticas/efeitos da radiação , Histonas/farmacologia , Lesões Experimentais por Radiação/patologia , Animais , Divisão Celular/efeitos da radiação , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Feminino , Hematopoese Extramedular/efeitos da radiação , Células-Tronco Hematopoéticas/patologia , Camundongos , Tolerância a Radiação , Baço/patologia , Baço/efeitos da radiaçãoRESUMO
The radiotherapeutic effect of thymogen (Glu-Trp) and thymohexin (Arg-Lys-Asp-Val-Tyr-Arg) synthetic peptide immunomodulators was investigated. Both thymogen and thymohexin were demonstrated to be able to reduce the damaging effect of ionizing radiation (1 Gy) on CFU-S by half. The treatment by these preparations after irradiation at dose of 4 Gy leads to more intensive restoration of CFU-S population as compared with control.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Dipeptídeos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Oligopeptídeos/uso terapêutico , Peptídeos/uso terapêutico , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Adjuvantes Imunológicos/farmacologia , Sequência de Aminoácidos , Animais , Feminino , Células-Tronco Hematopoéticas/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Dados de Sequência Molecular , Oligopeptídeos/farmacologia , Peptídeos/farmacologia , Lesões Experimentais por Radiação/etiologia , Protetores contra Radiação/farmacologiaRESUMO
The data concerning the reasons of CFU-S radioresistance increase after low dose irradiation of mice were obtained; the reparation processes in CFU-S adapted by low dose irradiation were shown to be more active than in intact ones. Colony formation increase was demonstrated to be more pronounced in adapted animals when they had been injected by 50 mcg of synthetic polyribonucleotide PolyI-PolyC two days before irradiation in challenge dose. The thymogen immunomodulator administration to adapted and intact donor animals leads to the increase of colony yield in equal extent.
Assuntos
Adaptação Fisiológica/efeitos da radiação , Dipeptídeos , Células-Tronco Hematopoéticas/efeitos da radiação , Lesões Experimentais por Radiação/fisiopatologia , Adaptação Fisiológica/efeitos dos fármacos , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Animais , Células-Tronco Hematopoéticas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Poli I-C/farmacologia , Poli I-C/uso terapêutico , Doses de Radiação , Lesões Experimentais por Radiação/prevenção & controle , Tolerância a RadiaçãoRESUMO
Whether accessory T cells can be replaced by the synthetic immunomodulators thymogen (Glu-Trp) and thymohexin (Arg-Lys-Asp-Val-Tyr-Arg) was studied. The latter immunomodulator was found to show a 3-fold increase in splenic colony formation after incubation of bone marrow cells with rabbit antimouse brain serum (RAMBS). The former preparation failed to show the same action. Its effect was close to that of thymocytes. When the recipients exposed to lethal irradiation were administered the RAMBS-treated bone marrow cells and one of the peptides, it was shown that in concomitant administration, thymohexin and thymocytes lost their ability to restore colony formation by RAMBS-treated bone marrow. Thymogen did not suppress the stimulating activity of thymocytes. It is suggested that the differences observed between the tested peptides in their ability to recover colony formation were determined by their structure.