Flow cytometric analysis of pentakis(aziridino)thiatriazadiphosphorine oxide (SOAz)-induced changes in cell cycle progression of HeLa and HL-60 cells.

The treatment of HeLa and HL-60 cells with various concentrations of pentakis(arizidino)thiatriazadiphosphorine oxide results in inhibition of growth and modification of cell cycle distribution. These phenomena were observed at 10(-4) M and 5 X 10(-5) M for HeLa cells and 10(-5) M and 5 X 10(-6) M for HL-60 cells. The estimation of DNA content by flow cytometry showed an important shift in the distribution of cycling cells with a striking arrest in G2 for both cell lines with a concomitant late S-phase accumulation for HeLa cells. Incubation of cells in drug-free medium 3 days after treatment did not show any change in DNA distribution, suggesting the irreversibility of drug action.

Role of iron in tumor cell protection from the pro-apoptotic effect of nitric oxide.

F2The host defense against tumor cells is in part based upon the production of nitric oxide (NO) by activated macrophages. However, carcinogenesis may involve mechanisms that protect tumor cells from NO-mediated apoptosis. In the present study, we have assessed the effects of exogenous NO on the proliferation and survival of human liver (AKN-1), lung (A549), skin (HaCat), and pancreatic (Capan-2) tumor cell lines, compared with normal skin-derived epithelial cell cultures. Except to the HaCat cell line, all of the other human epithelioid cells were sensitive to the antiproliferation effect of S-nitroso-N-acetyl-penicillamine or Deta NONOate, whereas tumor cells had low if any response to sodium nitroprusside. Growth inhibition with exogenous NO correlated with increased apoptosis, but was not mediated by cyclic GMP, peroxynitrite generation, or poly(ADP-ribose) polymerase modulation, all of which involved in NO-mediated growth inhibition of normal skin-derived epithelial cell cultures. The simultaneous addition of iron-containing compounds protected tumor cells from NO-mediated growth inhibition and apoptosis. Intracellular iron quantification indicated that, as deferoxamine, exogenous NO significantly decreased intracellular ferric iron levels in tumor cells. Together, the current study reveals that intracellular iron elevation rescues tumor cells from NO-mediated iron depletion and subsequent growth inhibition and apoptosis.

Pharmacological and physicochemical properties of a new anthracycline with potent antileukemic activity.

The antiproliferative effect of F860191, a new anthracycline with high antitumor activity in L1210 leukemia-inoculated mice, was investigated in vitro on different leukemia cell lines. Comparison of the IC50 value of F860191 with that of daunorubicin and doxorubicin disclosed a superior activity for this drug against the three leukemia cell lines tested. Studies on the mechanism of the antiproliferative activity showed that F860191 induced a G2 + M arrest in the cycle of treated cells. Physicochemical properties of this drug suggested that the high cytotoxic effect of F860191 could be related to its capacity to induce free radicals and to generate DNA breaks through its interaction with topoisomerase II.

A new anthracycline with potent anti-leukemic activity overcomes P-glycoprotein multidrug resistance.

In this study, we assessed the ability of a new anthracycline, moflomycin, to circumvent multidrug resistance. Moflomycin showed superior anti-proliferative activity compared to daunorubicin and doxorubicin on two resistant cell lines: leukemic HL-60 cell line resistant to daunorubicin (HL-60/DR) and breast cancerous cell line resistant to doxorubicin (MCF-7/AR). The effect of moflomycin on cell proliferation was correlated with an increased uptake and a decreased cellular efflux. The data obtained in the presence of the P-gp inhibitor, verapamil, confirmed the absence of interaction between P-gp and moflomycin. Our results indicate that moflomycin exhibits an important reduction in cross-resistance with daunorubicin and doxorubicin resulting from its ability to circumvent P-gp.

Enhanced topoisomerase II-induced DNA breaks and free radical production by a new anthracycline with potent antileukemic activity.

In a previous study we reported that a new anthracycline derivative (moflomycin) exhibited a higher antileukemic activity compared to other anthracyclines, such as daunorubicin and doxorubicin. To explain the superior antileukemic effect of moflomycin and to disclose a possible structure-activity relationship, we investigated the three main mechanisms by which anthracyclines are though to exert their antitumor effect: DNA binding, free radical production and topoisomerase II inhibition. The DNA interaction was assessed both by DNA binding and DNA unwinding assays, free radical generation was studied by electron spin resonance, and topoisomerase II interaction by analysis of the stimulation of enzyme-induced DNA breaks. The results showed a higher free radical production and a greater stimulation of topoisomerase II-mediated DNA cleavage by moflomycin than doxorubicin, associated with a lower DNA affinity. The different biochemical characteristics of moflomycin, particularly its interaction with topoisomerase II, are related to the structural modifications performed on the chromophore. These properties, associated with a higher stability of the molecule induced by the presence of an iodine atom on the sugar moiety, are probably responsible for the higher antileukemic activity of this compound.

Investigation of the effects of 50 Hz magnetic fields on purified human hematopoietic progenitors.

Epidemiological reports suggest a possible association between exposure to extremely low frequency electromagnetic fields (ELF-EMFs) and the frequency of leukemia in men working in the field of electricity or in children living near power lines. At present, there is no experimental evidence for such an association. In this study we investigated the effects of 50 Hz EMFs (sinusoidal EMF of 10 microT or 1 mT) on human purified hematopoietic progenitor cells which are the first targets of a leukemogenic process. The results failed to reveal any significant changes in cell proliferation, cell kinetics, ultrastructure or clonogenic potential of these progenitors which could be related to a leukemogenic effect.

Can 50 Hz magnetic fields alter iron metabolism and induce anaemia?

UNLABELLED: PURPOSE. Some changes in tissue iron concentration have been reported in animals exposed to electromagnetic fields. In other studies, variations in the haemoglobin level were occasionally observed. In the present experiment, the effects of exposing a rat to a 50 Hz magnetic field (MF) were therefore investigated for the possible induction of anaemia due to changes in iron metabolism. MATERIALS AND METHODS: Male Brown Norway rats (n=225) were exposed to a sinusoidal 50 Hz MF of 500 microT for 15 weeks. Haematological parameters, differential bone marrow cell counts and sideroblasts were investigated. Blood parameters of iron metabolism were measured. Iron concentration and total iron content were also determined in the spleen and liver, to assess iron storage in these organs. RESULTS: Significant differences between the exposed and control rat were only detected for iron storage in the spleen, and for the percentage of bone marrow cells of the red cell lineage. CONCLUSION: The changes observed were not associated with anaemia during the 15 weeks of MF exposure. However, the decrease in bone marrow cells of the red cell lineage and the changes in iron storage detected at the end of the experiment did not allow the possibility to be ruled out that exposure to 50 Hz MFs may induced delayed biological effects.

Absence of the effects of 50 Hz magnetic fields on the progression of acute myeloid leukaemia in rats.

PURPOSE: As the most recent epidemiological studies provide no definite conclusions about the effects of 50/60 Hz magnetic fields (MFs) on the incidence of leukaemia in humans, animal models in a well-controlled environment are useful for evaluating the possibility of an association between MFs and leukaemia. The present study was designed to determine whether 50 Hz magnetic fields can alter the progression of leukaemia. MATERIALS AND METHODS: A well-characterized model of transplantable acute myeloid leukaemia in rats was used for the first time. This model is closely related to human acute myeloid leukaemia, the type most frequently reported in epidemiological studies of adults. After leukaemic cell implantation, rats were exposed to a sinusoidal 50 Hz MF of 100 microT for 18 h a day, 7 days a week, throughout leukaemia progression. The parameters investigated were: survival time, body weight, haematologic parameters, infiltration of blood, bone marrow, spleen and liver by leukaemic cells. RESULTS: The results showed no significant changes (p > 0.05) in leukaemic MF-exposed versus unexposed rats for any of the parameters involved in leukaemia progression. CONCLUSION: These data do not support the hypothesis that 50 Hz magnetic fields influence leukaemia progression in humans.

A new anthracycline with potent antileukemic activity exhibits reduced mutagenicity.

The mutagenicity of a new anthracycline (moflomycin) with potent antileukemic activity was studied by the Ames test in four strains of Salmonella typhimurium (TA97a, TA98, TA100 and TA102), and compared to the mutagenicity of doxorubicin, widely used as antineoplastic agent. Unlike doxorubicin, moflomycin displayed no mutagenic activity in strains TA98 and TA100. Low mutagenicity was only observed in TA102 strain and was not enhanced after metabolic activation. This result indicates that moflomycin induce mutagenicity by reverting base-pair substitution. The structural changes in the sugar moiety may be involved in the reduced mutagenicity of moflomycin. The low mutagenicity of moflomycin shown in this study enhances the potential advantage of this new derivative which displays a high antileukemic activity.

A study of the social and clinical characteristics of in-patients at a psychiatric unit in northern Nigeria.

In a study of the social and clinical characteristics of inpatients at the Jos University Teaching Hospital Psychiatric unit in Northern Nigeria, 387 patients made up from 421 consecutive admissions into the unit over a 9-month period, were studied. The patients were followed up at the out-patient clinic after discharge for a period of at least 3 months. Functional psychoses (66%) and especially schizophrenia (35%) predominated. About 14% of the cohort had depressive psychosis. There was a statistically significant (p < 0.001) excess of females with depressive illness. The mean duration of hospitalization was 15 days and at discharge, the majority of the patients (79%) were improved. Three months after discharge, 46% of the patients had defaulted from follow-up. The most important factor associated with default was patients' residence of 100 kilometres or more from the hospital. Of those still attending the out-patient clinic 15% had relapsed.

[Comparison of the effects of ketorolac and aspirin on hemostasis in the rabbit]. / Comparaison des effets du kétorolac et de l'aspirine sur l'hémostase chez le lapin.

OBJECTIVE: Comparison of ketorolac with aspirin and placebo for the antithrombotic activity using the Folts' model of experimental arterial thrombosis and the perioperative blood loss. STUDY DESIGN: Experimental randomized blinded study anaesthetized, tracheotomized and mechanically ventilated. Carotid blood flow variations were detected by a probe directly inserted around the artery and monitored by an electromagnetic flowmeter. A segment of the exposed carotid artery was de-endothelialized by gently squeezing the artery with a needle holder forceps, and an external constrictor was placed around it (stenosis 60%), to induce cyclic flow reductions (CFR). During 20 min, CFR rate was assessed. Animals were then randomized in 3 groups of 9: ketorolac (K) 1 mg.kg-1, aspirin (A) 10 mg.kg-1 or saline (S), injected intravenously (peripheral ear vein). After drug administration, CFR rate was assessed over 20 min, to determine the potential antithrombotic activity of the drug (curative phase). Thereafter, the opposite carotid artery was injured and stenosed and the occurrence of CFR was assessed over 20 min (preventive phase). The amount of blood loss of a xipho-pubic laparotomy with a spleen section was also measured 30 min after drug administration. RESULTS: In all untreated animals, CFRs developed with a mean rate of 4 cycles/20 min. Aspirin completely abolished CFR during the curative phase in all rabbits, except in one. No effect was observed during this phase with ketorolac or saline. During the preventive phase, a partial inhibition of CFRs was induced by ketorolac and aspirin. Peri-operative bleeding was not increased significantly by ketorolac or aspirin. Postinjection bleeding-time did not differ between the three groups. CONCLUSIONS: Ketorolac (1mg.kg-1) has not a strong antithrombotic activity. Ketorolac and aspirin do not increase peri-operative blood loss, and therefore do not seem to strongly interfere with haemostasis in the rabbit.