The effects of parenteral lipid emulsions on cancer and normal human colon epithelial cells in vitro.

Differences in lipid metabolism of tumor and normal tissues suggest a distinct response to available lipid compounds. In this study, the in vitro effects of five types of commercial parenteral lipid emulsions were investigated on human cell lines derived from normal fetal colon (FHC) or colon adenocarcinoma (HT-29). Changes of the cellular lipid fatty acid content, cell oxidative response, and the cell growth and death rates were evaluated after 48 h.

Lipoxygenase inhibitors induce arrest of tumor cells in S-phase of the cell cycle.

Inhibitors of the lipoxygenase pathway of arachidonic acid metabolism represent a potential anti-tumor drugs. These compounds have been found to inhibit the growth and induce the apoptosis of various tumor cells both in vitro and in vivo. In this study, the effects of the lipoxygenase inhibitors esculetin and nordihydroguaiaretic acid (NDGA) on the progression of the cell cycle were investigated in eight mammalian cell lines of different origin.

Drugs elevating extracellular adenosine enhance cell cycling of hematopoietic progenitor cells as inferred from the cytotoxic effects of 5-fluorouracil.

Objective: Our previous studies showed that the combined administration of drugs elevating extracellular adenosine, i.e., dipyridamole and adenosine monophosphate (AMP), enhanced hematopoiesis in normal mice and increased hematopoietic recovery in irradiated mice.

Inhibition of the cytochrome P-450 modulates all-trans-retinoic acid-induced differentiation and apoptosis of HL-60 cells.

We studied the effects of inhibition of cytochrome P-450 by proadifen (SKF525A) on the processes induced in myeloid leukemia HL-60 cells by all-trans-retinoic acid (ATRA). The parameters reflecting cell proliferation, differentiation, and apoptosis were detected by flow cytometry as the principal method at selected time intervals (24-96 hours). Changes in the expression of Bcl-2 protein were detected by Western blotting.

Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine act additively to enhance the hemopoietic spleen colony formation in irradiated mice.

The effects of combined administration of two drugs elevating extracellular adenosine, namely dipyridamole (DP) and adenosine monophosphate (AMP), and granulocyte colony-stimulating factor (G-CSF) on hemopoietic stem cells in vivo were investigated. The experiments were performed on mice using the endogenous spleen colony formation in gamma-irradiated animals as an endpoint. The results have shown that DP and AMP act additively with G-CSF to enhance spleen colony formation and thus the erythroid repopulation of the spleen.

Pretreatment with granulocyte colony-stimulating factor reduces myelopoiesis in irradiated mice.

The purpose of this study was to investigate effects of the treatment prior to irradiation with granulocyte colony-stimulating factor (G-CSF) on hematopoiesis in B10CBAF1 mice exposed to a sublethal dose of 6.5 Gy of 60Co gamma radiation. G-CSF was administered in a 4-day regimen (3 microg/day); irradiation followed 3 h after the last injection of G-CSF.

Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine synergize to enhance haematopoietic reconstitution in irradiated mice.

The activation of adenosine receptors has recently been demonstrated to stimulate haematopoiesis. In the present study, we investigated the ability of drugs elevating extracellular adenosine to influence curative effects of granulocyte colony-stimulating factor (G-CSF) in mice exposed to a sublethal dose of 4 Gy of 60Co radiation. Elevation of extracellular adenosine in mice was induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug.

Enhancement of haemopoietic spleen colony formation by drugs elevating extracellular adenosine: effects of repeated in vivo treatment.

The potential role of adenosine receptor signalling in the amplification of haemopoietic stem cells in vivo was investigated. Elevation of extracellular adenosine in mice was induced by the joint administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate, an adenosine prodrug. The response of haemopoietic stem cells to the drug treatment was measured by endogenous spleen colony-forming assay in sublethally gamma-irradiated animals.

Synergistic effect of granulocyte colony-stimulating factor and drugs elevating extracellular adenosine on neutrophil production in mice.

Experimental evidence suggests that the activation of purinoceptors by extracellular adenosine can modulate proliferation and/or differentiation of hematopoietic cells. The present study was undertaken to investigate the potential interactions of this system of intercellular signaling with the effects of granulocyte colony-stimulating factor (G-CSF) on granulopoiesis in vivo. Elevation of extracellular adenosine in normal mice was induced by the joined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug.

Radioprotection of mouse hemopoiesis by dipyridamole and adenosine monophosphate in fractionated treatment.

The purpose of the studies reported here was to investigate the ability of the combined administration of dipyridamole and adenosine monophosphate, drugs known to elevate extracellular adenosine, to protect mice undergoing treatment with fractionated irradiation (five doses of 2 or 3 Gy each) given at 24-h intervals. Based on observations of hemopoietic recovery (endogenous hemopoietic spleen colony formation, marrow granulocyte-macrophage colony-forming cells, peripheral blood cells) after the completion of fractionated irradiation and on survival studies, it was demonstrated that the repeated administration of the drugs 60 min before each of the radiation fractions mitigates the hemopoietic injury and enhances the survival of mice irradiated with an additional "top-up" dose. It could be deduced that the single protective actions of the drugs retain their efficacy in repeated treatment and enhance the sparing effect of dose fractionation on hemopoiesis.

Effects of postirradiation carboxymethylglucan administration in mice.

The hemopoiesis-enhancing ability of a soluble glucan derivative, i.e. carboxymethylglucan (CMG), was investigated in gamma-irradiated mice.

Radioprotective efficacy of dipyridamole and AMP combination in fractionated radiation regimen, and its dependence on the time of administration of the drugs prior to irradiation.

We have recently demonstrated that the combined administration of dipyridamole and adenosine monophospate to mice induces radioprotective effects in terms of postirradiation haemopoietic recovery in animals irradiated with a single dose. The aim of the present experiments was to investigate the radioprotective ability of the drug combination under conditions of fractionated radiation treatment. It has been shown that administration of drugs either 15 or 60 min before each of the five daily 3-Gy doses of gamma-radiation enhances haemopoietic recovery and survival of mice exposed to an additional "top-up" dose of 3.

Effects of drugs inhibiting prostaglandin or leukotriene biosynthesis on postirradiation haematopoiesis in mouse.

Two non-steroidal anti-inflammatory drugs, i.e. indomethacin (INDO), an inhibitor of prostaglandin production, and esculetin (ESCUL), an inhibitor of leukotriene production, were tested for their ability to modify haematopoiesis in three experimental systems: (a) in vitro clonal proliferation of marrow GM-CFC from the irradiated mouse was found to be augmented by addition of INDO at a low concentration, and inhibited by ESCUL in a dose-dependent manner; (b) in the lethally irradiated and bone marrow-transplanted mice treated with the drugs in the postirradiation period, stimulatory effects of INDO on CFU-S and GM-CFC populations and an inhibitory effect of ESCUL on GM-CFC were observed; and (c) when the drugs were administered i.

Elevation of extracellular adenosine induces radioprotective effects in mice.

The radioprotective effectiveness of the elevation of extracellular adenosine induced in mice by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate, a soluble adenosine pro-drug, was evaluated. Based on survival studies, endogenous hemopoietic spleen colony formation, and the postirradiation behavior of bone marrow granulocyte-macrophage colony-forming cells (GM-CFC), it was demonstrated that the combined administration of dipyridamole and AMP protects mice when given either 15 or 60 min before irradiation. It could be deduced that the radioprotective action is induced by at least two independent mechanisms: (1) protection by hypoxia as a result of the effect of the treatment on the cardiovascular system, and (2) and enhanced regeneration of the hemopoietic stem cells due to either enhanced postirradiation repair or an increased proliferation of the hemopoietic stem cells.

The effect of nordihydroguaiaretic acid, an inhibitor of prostaglandin and leukotriene biosynthesis, on hematopoiesis of gamma-irradiated mice.

The effects of the inhibition of the cyclooxygenase and lipoxygenase metabolic pathways of arachidonic acid on the postirradiation recovery of hematopoietic functions in mice were investigated. Nordihydroguaiaretic acid (NDGA), an inhibitor of prostaglandin (PG) and leukotriene (LT) production, was given to animals in single doses (0.015 to 0.

Noradrenaline reduces cardiovascular effects of the combined dipyridamole and AMP administration but preserves radioprotective effects of these drugs on hematopoiesis in mice.

Recent results of the authors have demonstrated that the elevation of extracellular adenosine induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), a soluble adenosine prodrug, mediates radioprotective effects in mice. Furthermore, it has been shown that this action is induced by at least two mechanisms: (1) protection by hypoxia as a result of the effects of treatment on the cardiovascular system (bradycardia, vasodilation), and (2) an enhanced regeneration of the radiation-perturbed hematopoiesis. Here, it was ascertained that the joint use of an optimal dose of noradrenaline given with dipyridamole and AMP combination eliminates the hypothermic and hypoxic effects of the treatment, but preserves the radioprotective action of dipyridamole and AMP combination in terms of hematopoietic recovery and partially also survival enhancing effects of the drugs in gamma-irradiated mice.

Enhancement of hematopoietic recovery in gamma-irradiated mice by the joint use of diclofenac, an inhibitor of prostaglandin production, and glucan, a macrophage activator.

The effects of diclofenac (inhibitor of prostaglandin production) and carboxymethylglucan (immunomodulator and an agent stimulating hematopoiesis), when given to mice 1 day before gamma-irradiation, were studied. Both of the agents were administered either alone or in combination. The investigations included the assessment of post-irradiation hematopoietic recovery in terms of bone marrow and spleen cellularity and endogenous spleen colony formation, as well as the determination of the survival of lethally irradiated mice.

Effect of dipyridamole and adenosine monophosphate on cell proliferation in the hemopoietic tissue of normal and gamma-irradiated mice.

Combined treatment with dipyridamole and adenosine monophosphate enhances cell proliferation in the hemopoietic tissue of normal and gamma-irradiated mice. This effect can be explained by the elevation of extracellular adenosine, and the receptor-mediated activation of the cell adenylate cyclase system.

Enhancement of hypoxia radioprotection and decrease of hypoxia toxicity caused by adenosine monophosphate.

It was shown in experiments on mice that the radioprotective effects of adenosine monophosphate (AMP) or of a combination of Mg aspartate and AMP join with those induced by hypobaric hypoxia. The hypotensive effects of these drugs lead probably to hypoxia in radiosensitive tissues which acts additively with hypoxia elicited by way of respiration. Furthermore, Mg aspartate and AMP decrease the toxicity of high degrees of hypobaric hypoxia.

Possibilities of the combined use of non-steroidal anti-inflammatory drugs and sulfhydryl compounds in radioprotection.

The combined preirradiation administration of indomethacin and cystamine was found to enhance synergistically the recovery of hemopoiesis in sublethally gamma-irradiated mice. This effect can be explained by a common operation of two mechanisms of radioprotection, i.e.

Combined radioprotection by preirradiation peroral cystamine and postirradiation glucan administration.

The possibilities of combined radioprotection, using preirradiation peroral cystamine and postirradiation intraperitoneal glucan administration in sublethally and lethally whole-body gamma-irradiated mice were investigated. The results demonstrated at least additive radioprotective effects of both agents, manifested in the enhancement of postirradiation haemopoietic recovery and increased survival of irradiated mice. The effects appear to depend on the sequential cell protection mediated by cystamine and enhanced haemopoietic repopulation induced by glucan.

Radioprotective effect of inosine and its enhancement by magnesium and global hypoxia.

The slight radioprotective action of inosine, when injected intraperitoneally to mice shortly before gamma-irradiation, can be enhanced by the administration of magnesium aspartate. This effect can be explained by the additivity of the vasodilatory actions of both agents. Inosine increases the radioprotective effectiveness of hypobaric hypoxia (10% O2), probably due to the additivity of the hypoxic effects in radiosensitive tissues.

Therapeutic effects of the joint administration of magnesium aspartate and adenosine monophosphate in gamma irradiated mice.

The joint administration of magnesium aspartate and adenosine monophosphate, injected on days 1 to 4 post radiation, has been found to exert stimulatory effects on the recovery of hemopoietic functions in sublethally gamma irradiated mice. These therapeutical effects were enhanced in animals protected by peroral administration of cystamine. The treatment scheme used did not modify survival of lethally irradiated mice.

Enhancement of haemopoietic recovery in sublethally gamma-irradiated mice by the joint use of indomethacin and cystamine.

The effects of indomethacin and cystamine, administered prior to gamma-irradiation of mice, were investigated. Synergistic enhancement of haemopoietic recovery was observed under the conditions of a joint use of both drugs. The reason for this synergistic action is probably a joint operation of two mechanisms, i.

Effect of indomethacin, diclofenac sodium and sodium salicylate on peripheral blood cell counts in sublethally gamma-irradiated mice.

Treatment with indomethacin and diclofenac sodium was found to increase granulocyte counts in the blood of sublethally gamma-irradiated mice. Treatment with sodium salicylate was ineffective in this respect, administration of sodium salicylate together with indomethacin even decreased the indomethacin-induced effects. The results suggest that the hemopoiesis-stimulating effects of non-steroidal anti-inflammatory drugs cannot be correlated with the anti-inflammatory activity but rather with the side effects of these compounds, including the action on gastro-intestinal prostanoid production.