On the question of differences in the number of endogenous haemopoietic tissue colonies in the spleens of irradiated hairless and haired mice.
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Biomedical subjects
Publications and source records attributed to A Vacek.
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Protection from undesirable effects of radiotherapy or chemotherapy, primarily from myelosuppression, remains still a crucial problem to be studied. Attention has been therefore paid to various immunomodulatory agents that through the monocyte/macrophage system induced production of cytokines, which can induce and operate restoration of haemopoiesis and thus act radioprotectively. Some synthetic analogues of MDP free of undesirable side-effects, were synthesized in the Czech Republic. Lipophilic beta-D-GlcNstearoyl-(1- > 4)-norMurNAc-L-Abu-D-isoGln (DDD-St) was designed to be easily entrapped into liposomes and this liposomal DDD-St protected efficiently mice against irradiation, when administered i.p., i.v. or s.c. 24 h prior to lethal irradiation (survival rate in the range of 30-80% compared with 0% in control). Especially the subcutaneous application of liposomal DDD-St was very efficient. The parameters characteristic of recovery of haemopoiesis in bone marrow on day 10 after 6.5 Gy irradiation were significantly improved in comparison with the controls. Very high radioprotective effect of s.c. administered liposomal DDD-St can be explained (together with induction of haemopoiesis) by an effective and long-lasting activation of nonspecific immunity, which is able to withhold an onset of septicemia in early days after irradiation. In conclusion, the liposomal DDD-St should be therapeutically beneficial in moderating the haemopoietic damage, which is an undesirable effect of radiotherapy or chemotherapy.
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The effect gained by activation of haemopoietic cell populations by a single injection of dextran sulphate (DS) on the protective effect of cystamine and mexamine administered in small doses was monitored in mice. On irradiation 24 hours after the injection of DS the number of endogenous spleen colonies increased following the administration of mexamine and cystamine, the number of haemopoietic stem cells surviving in the femur after irradiation increased, and recovery of the cellularity of irradiated bone marrow was accelerated. Both substances administered 24 hours after the injection of DS significantly reduced the lethal effects of gamma rays. The maximum values of the dose reduction factor, for combined radiation protection, reached 1.48 as regards decreased lethal effects and 1.6 as regards equieffective E-MSC exposure.
The effect of pretreatment of mice with a single injection of dextran sulphate (DS) on the protective capacity of moderate hypoxia was analysed. Dextran sulphate activated haemopoietic stem cell populations, and irradiation under hypoxia one day after DS injection increased the number of haemopoietic stem cells surviving in the bone marrow of the femur, their recovery after irradiation, and the number of endogenous spleen colonies. A moderate hypoxia (15% O2 and 12% O2) significantly reduced the lethal effect of gamma rays in mice after DS injection and increased the value of LD 50/30.
Injection of dextran sulphate before irradiation was shown to protect jejunal epithelium stem cells (D0 increased from 1.13 to 1.82 Gy). The protective effect of a combination of dextran sulphate and gas hypoxic mixture (10% O2) did not exceed that of the administration of the gas hypoxic mixture (10% O2) alone.
A single administration of dextransulfate (40 mg/kg, 1-3 days before irradiation), or a double injection of heparin (250 units/kg, 24 hr and 15 min before irradiation) potentiated a weak radioprotective effect of gas hypoxic mixture (GHM-10) on animals exposed to absolutely lethal doses.
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In experiments on (CBA X C57Bl)F1 mice irradiated with doses of 8-12 Gy a study was made of the effect of a mixture of polyI-polyC (2.5 mg/kg, 2 days before irradiation) and mexamine (30 mg/kg, 5 min before irradiation) on the survival rate of animals and the times of their death. It was shown that polyI-polyC potentiates the protective effect of mexamine not increasing its toxicity. The protective agents used in a combination decrease the "intestinal" death of irradiated animals while used separately fail to produce this effect.
The fraction of the survived intestinal crypts associated with patches of Peyer is higher to those non-patch-associated crypts of mice for three inbred strains. The difference in the survival between associated and non-patch-associated crypts increases with dose of gamma-irradiation. This difference for old mice is less than for young mice. Pre-irradiation (5 Gy) of mice one week before the conditioned gamma-irradiation cannot modify the difference in the survival between associated and non-patch-associated crypts. Radioprotection of mice by hypoxic gas mixture (10% O2) cannot modify this difference. Pre-treatment of mice by dextran-sulfate alone or in combination with hypoxic gas mixture decreased the survival of intestinal crypts associated with patches of Peyer to the level of non-path-associated crypts. The difference in the survival between two subpopulation of intestinal stem cells is less after neutron irradiation than after gamma-irradiation.