Heme enzyme patterns in genetically and chemically induced mouse liver tumors

Chemically induced rat hepatocyte nodules and hepatomas have repeatedly been shown to be deficient in Phase I drug-metabolizing enzymes. Some of these reduced activities are attributable to a diminution of the heme-containing terminal electron acceptor, cytochrome P-450. We recently demonstrated that spontaneous mouse liver tumors exhibit the same deficiency. Therefore, chemically induced and spontaneous liver tumors share common metabolic alterations which are likely to represent intrinsic characteristics of the tumorigenic process and are independent of its etiology. To determine whether the cytochrome P-450 deficit was the result of an altered heme metabolism, we quantitated four heme-containing proteins in normal mouse liver, spontaneous mouse liver tumors, and those induced by a single injection of diethylnitrosamine: cytochrome P-450; cytochrome b5; tryptophan 2,3-dioxygenase (EC 1.13.11.11); and catalase (EC 1.11.1.6). The amounts of these components in spontaneous tumors relative to normal liver were 0.35, 0.68, 0.76, and 0.51, respectively. Similar values were obtained with chemically induced tumors. The enzymes delta-aminolevulinic acid synthase (EC 2.3.1.37), the rate-limiting enzyme in the heme synthetic pathway, and heme oxygenase (EC 1.14.99.3), a degradative enzyme, were also quantitated. The amounts of these enzymes in spontaneous tumor relative to liver were 0.49 and 1.51, respectively. Again, similar values were observed for the chemically induced tumors. Alteration of the latter two enzyme activities may be sufficient for the altered hemoprotein patterns seen in mouse liver tumors. Further, this pattern of metabolic alteration is common to both chemically induced and spontaneous tumors. Thus, tumor resistance to cytotoxic agents activated by the monooxygenase system is not necessarily induced by exposure to these agents, nor as a result of selection.     

Heme enzyme patterns in rat liver nodules and tumors

Chemically induced rat hepatocyte nodules and carcinomas have a reduced capacity to oxidize drugs. The reduction in monoxygenase activity results largely from the partial loss of cytochrome P-450, a heme-containing terminal electron acceptor. To determine whether the cytochrome P-450 deficit was indicative of an altered heme metabolism, we quantitated four heme-containing proteins in normal rat liver and in rat liver nodules and cancers induced by 2-acetylaminofluorene or diethyl-nitrosamine: cytochrome P-450; cytochrome bs; catalase (EC 1.11.1.6); and tryptophan 2,3-dioxygenase (EC 1.13.11.11). The amounts of these components in nodules were 45%, 88%, 50%, and 59% of normal liver, respectively; in 2-acetylaminofluorene-induced cancers, 65%, 74%, 64%, and 65%, respectively; and in diethylnitrosamine-induced cancers, 40%, 69%, 56%, and 52%. delta-Aminolevulinic acid synthase (EC 2.3.1.37), the rate-limiting enzyme in the heme synthetic pathway, and heme oxygenase (EC 1.14.99.3), a degradative enzyme, were also quantitated. The amounts of these enzymes in nodules were 95% and 138% of normal liver, respectively, whereas in 2-acetylaminofluorene-induced cancers, they were 47% and 233%, and in diethylnitrosamine-induced cancers, they were 50% and 175%. These data indicate that four nonmitochondrial liver hemoproteins were diminished to about the same extent in hepatic nodules and cancers. Nodules and cancers also demonstrated an increased capacity for heme degradation, while cancers also demonstrated a decreased capacity for heme synthesis. Thus, the resistance of nodules and tumors to P-450-activated cytotoxic agents may ultimately result from a disturbance in heme metabolism.     

Mitochondria in hematopoiesis and hematological diseases

Mitochondria are involved in hematopoietic cell homeostasis through multiple ways such as oxidative phosphorylation, various metabolic processes and the release of cytochrome c in the cytosol to trigger caspase activation and cell death. In erythroid cells, the mitochondrial steps in heme synthesis, iron (Fe) metabolism and Fe-sulfur (Fe-S) cluster biogenesis are of particular importance. Mutations in the specific delta-aminolevulinic acid synthase (ALAS) 2 isoform that catalyses the first and rate-limiting step in heme synthesis pathway in the mitochondrial matrix, lead to ineffective erythropoiesis that characterizes X-linked sideroblastic anemia (XLSA), the most common inherited sideroblastic anemia. Mutations in the adenosine triphosphate-binding cassette protein ABCB7, identified in XLSA with ataxia (XLSA-A), disrupt the maturation of cytosolic (Fe-S) clusters, leading to mitochondrial Fe accumulation. In addition, large deletions in mitochondrial DNA, whose integrity depends on a specific DNA polymerase, are the hallmark of Pearson's syndrome, a rare congenital disorder with sideroblastic anemia. In acquired myelodysplastic syndromes at early stage, exacerbation of physiological pathways involving caspases and the mitochondria in erythroid differentiation leads to abnormal activation of a mitochondria-mediated apoptotic cell death pathway. In contrast, oncogenesis-associated changes at the mitochondrial level can alter the apoptotic response of transformed hematopoietic cells to chemotherapeutic agents. Recent findings in mitochondria metabolism and functions open new perspectives in treating hematopoietic cell diseases, for example various compounds currently developed to trigger tumor cell death by directly targeting the mitochondria could prove efficient as either cytotoxic drugs or chemosensitizing agents in treating hematological malignancies.     

Comparative effect of heme analogues on hematopoiesis in lymphoproliferative disorders

Anemia is a common characteristic of lymphoproliferative disorders (LPD) and the impairment of blood formation in these disorders is not fully understood. Heme synthesis and the heme degradative enzyme heme oxygenase are critical to hematopoietic differentiation and disturbances may contribute to anemic states. Tin protoporphyrin (SnPP) is a potent inhibitor of heme oxygenase, and has proven to be a useful clinical agent. Bone marrow cells from seven patients with LPD were studied for their in vitro hemopoietic response to growth factors and SnPP. Heme oxygenase mRNA levels were determined by Northern blot analysis of bone marrow samples. Quantitation of hematopoiesis in cultures with erythropoietin or GM-CSF revealed adequate CFU-E, BFU-E and CFU-GM growth by LPD bone marrow. Inclusion of 10 μM SnPP in cultures was found to significantly enhance CFU-E/BFU-E growth by LPD marrows, whereas Zinc protoporphyrin had a marked inhibitory effect. Little or no effect by SnPP was seen on CFU-GM. In contrast, normal bone marrow cultures failed to show an enhanced response to 10 μM SnPP. Analysis of heme oxygenase mRNA levels revealed that LPD marrows had elevated expression of heme oxygenase mRNA as contrasted with normals. Furthermore, measurements revealed that heme oxygenase activity was markedly suppressed by SnPP in the LPD bone marrow cultures. Results lend further support to the importance of heme oxygenase in the differentiation process. Although LPD bone marrow cells may respond to erythropoietin in vitro, in stressed conditions where heme oxygenase is elevated, suppression of heme oxygenase may potentiate the erythropoietic response in this disease.     

Comparative Effect of Heme Analogues on Hematopoiesis in Lymphoproliferative Disorders

Anemia is a common characteristic of lymphoproliferative disorders (LPD) and the impairment of blood formation in these disorders is not fully understood. Heme synthesis and the heme degradative enzyme heme oxygenase are critical to hematopoietic differentiation and disturbances may contribute to anemic states. Tin protoporphyrin (SnPP) is a potent inhibitor of heme oxygenase, and has proven to be a useful clinical agent. Bone marrow cells from seven patients with LPD were studied for their in vitro hemopoietic response to growth factors and SnPP. Heme oxygenase mRNA levels were determined by Northern blot analysis of bone marrow samples. Quantitation of hematopoiesis in cultures with erythropoietin or GM-CSF revealed adequate CFU-E, BFU-E and CFU-GM growth by LPD bone marrow. Inclusion of 10 μM SnPP in cultures was found to significantly enhance CFU-E/BFU-E growth by LPD marrows, whereas Zinc protoporphyrin had a marked inhibitory effect. Little or no effect by SnPP was seen on CFU-GM. In contrast, normal bone marrow cultures failed to show an enhanced response to 10 μM SnPP. Analysis of heme oxygenase mRNA levels revealed that LPD marrows had elevated expression of heme oxygenase mRNA as contrasted with normals. Furthermore, measurements revealed that heme oxygenase activity was markedly suppressed by SnPP in the LPD bone marrow cultures. Results lend further support to the importance of heme oxygenase in the differentiation process. Although LPD bone marrow cells may respond to erythropoietin in vitro, in stressed conditions where heme oxygenase is elevated, suppression of heme oxygenase may potentiate the erythropoietic response in this disease.     

Endogenous glutathione levels modulate both constitutive and UVA radiation/hydrogen peroxide inducible expression of the human heme oxygenase gene.

Induction of the expression of the mammalian heme oxygenase gene appears to be a general response to oxidant stress. In view of the role of glutathione in protecting cells against solar UVA radiation and other forms of oxidant stress, we have investigated the relationship between intracellular glutathione levels and the inducibility of the human heme oxygenase gene after treatment of populations of cultured skin fibroblasts with either UVA radiation or hydrogen peroxide. We observe a clear relationship between cellular glutathione status and both the constitutive and oxidant-inducible accumulation of heme oxygenase mRNA. Glutathione depletion may lead to enhanced gene expression either as a result of the potentiated accumulation of active oxygen intermediates or as a result of the direct influence of glutathione on a critical target involved in signal transduction.     

Effects of Cr(VI) on the expression of the oxidative stress genes in human lung cells

Intracellular metabolism of chromium(VI) [Cr(VI)] may lead to oxidative stress and this may account for the ability of Cr(VI) to act as a complete carcinogen. Therefore, we examined the effects of Cr(VI) treatment on the expression of oxidative stress genes in normal human lung LL 24 cells and human lung adenocarcinoma A549 cells. RT-PCR and northern blot analyses were used to determine the steady-state mRNA levels of catalase, glutathione S-transferase, glutathione reductase, Cu/Zn- and Mn-superoxide dismutases, glutathione peroxidase, NAD(P)H:quinone oxidoreductase, heme oxygenase and interleukin 8 in control cells and cells treated with 5-200 microM of Cr(VI). We found that only expression of the heme oxygenase gene is strongly elevated under the treatment with Cr(VI), and only in normal human lung LL 24 cells. Our data showed that even in the absence of Cr(VI) treatment, the level of heme oxygenase gene expression is much higher in A549 cells than in LL 24 cells. As glutathione is believed to play a protective role in cells against different forms of oxidative stress, we studied the correlation between intracellular glutathione levels and the inducibility of the heme oxygenase gene after treatment of cells with Cr(VI). Our results demonstrate that glutathione levels are increased by 35 % of control values in LL 24 cells treated with Cr(VI). The data obtained indicate that heme oxygenase, known to be a stress- inducible gene, may be involved in cellular pathways critical to the carcinogenic activity of Cr(VI) in normal human lung cells. Intracellular glutathione levels and reactive oxygen species do not appear to be primarily responsible for the stress response, induced by Cr(VI) in the studied human cells.      

Changes in host liver fatty acid synthase in tumour-bearing mice

The effect of the tumour-bearing state, with or without induced weight loss on host liver fatty acid synthase and acetyl coenzyme A content has been studied in NMRI mice bearing either the cachexia-inducing colon adenocarcinoma (MAC16) or the related tumour (MAC13), which does not produce weight loss. The specific activity of fatty acid synthase was increased in the host liver of animals bearing either tumour and the hepatic content of acetyl CoA was decreased. Animals bearing the MAC16 tumour fed a diet in which 80% of the calories were supplied as medium chain triglycerides (MCT) had depressed fatty acid synthase and increased acetyl CoA levels, similar to those found in non-tumour-bearing controls.     

BCNU-induced quantitative and qualitative changes in hepatic cytochrome P-450 can be correlated with cholestasis

Summary Male Sprague-Dawley rats were given single i.p. injections of 1,3-bis(2-chloroethyl)-1-Nitrosourea (BCNU) to investigate changes in hepatic microsomal cytochrome P-450 content and metabolic activity. On day 14 after treatment (20 mg/kg), cytochrome P-450 content had decreased by approximately 25% and ethylmorphineN-demethylase activity (nmol product/nmol P-450/min) had decreased by 36%. In contrast, ethylmorphineO-deethylase and 7-ethoxycoumarinO-deethylase activities were not significantly decreased by BCNU treatment. Hepatic delta-aminolevulinic acid synthetase activity was only 60% of control values, and microsomal heme oxygenase activity was slightly but not statistically elevated. Cytochrome P-450 content in control and BCNU-treated rats increased in a similar manner after phenobarbital or -naphthoflavone induction. Electrophoretic analysis of cytochrome P-450 proteins isolated from hepatic endoplasmic reticular membranes of treated and control rats suggested that alterations in these proteins occurred in BCNU-treated rats. These changes in cytochrome P-450 content and activity are very similar to those reported in isolated systems exposed to bile acids or in rats with experimentally produced cholestasis. BCNU has been shown to produce cholestasis, which precedes its effects on microsomal mixed-function oxygenase activity. Thus, the delayed effects of BCNU on microsomal drug metabolism are probably secondary to its interference with bile formation.Abbreviations ALA delta aminolevulinic acid - BCNU 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine) - BHCNU 1,3-b9s(trans-4-hydroxycyclohexyl)-1-nitrosourea - CCNU 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (lomustine) - EM ethylmorphine - EMND ethylmorphineN-demethylase - EMOD ethylmorphineO-deethylase - ECOD ethoxycoumarinO-deethylase - BAPH benzo[a]pyrene hydroxylase - MFO hepatic microsomal mixedfunction oxygenases Supported in part by NIH BRS grant RR07079 and by gifts from the Mayer and Chiles Foundations of Portland, Oregon     

The identification of heme oxygenase as a major hypoxic stress protein in Chinese hamster ovary cells.

Chronic hypoxia increases the expression of a set of stress proteins (oxygen regulated proteins or ORPs) which is implicated in the development of drug resistance and radiation sensitivity in tumour cells. Five major ORPs have been documented, and two, ORP 80 and ORP 100, are considered to be identical to the glucose regulated stress proteins GRP78 and GRP94, respectively. We report here that ORP 33 is a form of the heme catabolic enzyme, heme oxygenase, using evidence obtained from northern blotting, two-dimensional polyacrylamide gel electrophoresis and western analysis. Heme oxygenase is believed to be an important component of the cellular response to oxidative stress. The significance of heme oxygenase as a hypoxia-induced stress protein is discussed.     

A possible effect of heme on the fate of DNA ligase activity extracted from differentiating mouse erythroleukemia cells

When mouse erythroleukemia (MEL) cells were induced to differentiate by growth in the presence of dimethyl sulfoxide, hexamethylene bisacetamide (HMBA), or hemin, the apparent activity of DNA ligase extractable from inducer-treated cells decreased 70 to 80% when compared to untreated cells. Earlier work had indicated that these changes did not occur in a differentiation-resistant MEL cell variant and suggested that the decrease in the level of DNA ligase activity might be related to the differentiation process. Since the MEL cells accumulate high levels of both hemoglobin-bound and non-hemoglobin-bound heme, the effect of both hemoglobin and hemin on DNA ligase activity of MEL cell extracts was tested. When cell-free extracts containing DNA ligase activity were preincubated with hemin at concentrations up to 150 microM, an 80% or greater inhibition of the DNA ligase activity resulted. The ATP-dependent DNA ligase from bacteriophage T4 was also inhibited by hemin, but the NAD-dependent DNA ligase from Escherichia coli was not sensitive to this treatment. Preincubation of these same extracts with hemoglobin at levels comparable to those present in differentiating cells did not result in inhibition of any of the ATP-dependent DNA ligases tested. Culturing the cells with dimethyl sulfoxide in the presence of imidazole resulted in a marked decrease in globin chain accumulation but did not reverse the dimethyl sulfoxide-related decrease in DNA ligase activity. These data suggest the possibility that heme or its metabolites, but not globin or hemoglobin, could serve to modify the process of DNA replication and/or repair in differentiating MEL cells via inhibition of DNA ligase activity. These data are consistent with the findings of Lo et al. (S.C. Lo, R. Aft, and G.C. Mueller, Cancer Res., 41: 864-870, 1981) which correlated the onset of differentiation-related terminal cell division in MEL cells with the levels of nonhemoglobin heme present in these cells.     

Protein synthesis in liver tissue under the influence of a methylcholanthrene-induced sarcoma in mice.

Amino acids are incorporated at increased rates into hepatic proteins in tumor-bearing humans and animals. In this study, we hoped to elucidate whether this is an expression of increased hepatic protein synthesis or altered isotope dilution in the precursor pool(s). Liver tissue from sarcoma-bearing mice (MCG 101) showed increased specific activities of arginine and leucine in hepatic proteins after i.p. injection of these precursors. The specific radioactivity of leucine in the free amino acid incorporation rate into proteins was also found in incubated liver slices and in a cell-free system of incubated free and membrane-attached polysomes. The increased amino acid incorporation was the net result of increased as well as decreased relative turnover of various hepatic proteins. The hepatic content of RNA was increased, but hepatic DNA and protein content was unchanged in tumor-influenced livers. Increased amino acid incorporation into hepatic proteins in tumor-bearing animals and also probably in cancer patients is due to a net increased hepatic protein synthesis, probably not confined to acute-phase reactants only.     

Effects of melatonin administration on cytokine production in patients with advanced solid tumors

There is growing evidence that the pineal gland has antineoplastic properties, which include the action of melatonin (MLT) on the immune system through the release of cytokines by activated T-cells and monocytes. Despite these intriguing preliminary findings, only few studies have been undertaken to date on MLT's action in cancer patients. The present study was carried out on 23 patients (15 males and 8 females, range 48-71 years), with advanced solid tumors, who received MLT (10 mg/day orally for a month) after conventional therapy. Blood was assayed for tumor necrosis factor alpha (TNF-alpha), Interleukin-2 (IL-2) and human interferon gamma (IFN-gamma). Blood samples were taken immediately before the start of MLT administration and 30 days after therapy. Plasma was collected in EDTA tubes on ice, centrifuged immediately at 4-degrees-C and stored frozen at -80-degrees-C until assayed. Cytokines were quantified by immunoradiometric assays. Circulating levels of TNF-alpha, IL-2 and IFN-gamma increased by 28%, 51% and 41% respectively after MLT administration. These increments were statistically significant (paired Student's t-test, p<0.01). These findings are consistent with the hypothesis that MLT modulates immune functions in cancer patients by activating the cytokine system.     

Induction of IW32 erythroleukemia cell differentiation by p53 is dependent on protein tyrosine phosphatase.

The biological activity of p53 in IW32 erythroleukemia cells was investigated. IW32 cells had no detectable levels of p53 mRNA and protein expression. By transfecting a temperature-sensitive mutant p53 cDNA, tsp53val135, into the cells, we have established several clones stably expressing the mutant p53 allele. At permissive temperature, these p53 transfectants were arrested in G1 phase and underwent apoptosis. Moreover, differentiation along the erythroid pathway was observed as evidenced by increased benzidine staining and mRNA expression of beta-globin and the erythroid-specific delta-aminolevulinic acid synthase (ALAS-E). Treatment of cells with protein tyrosine phosphatase inhibitor vanadate blocked the p53-induced differentiation, but not that of cell death or growth arrest. Increased protein tyrosine phosphatase activity as well as mRNA levels of PTPbeta2 and PTPepsilon could be observed by wildtype p53 overexpression. These results indicate that p53 induced multiple phenotypic consequences through separate signal pathways in IW32 erythroleukemia cells, and protein tyrosine phosphatase is required for the induced differentiation.     

Studies on the role of iron in the alterations observed in hexachlorobenzene-induced porphyria

This study was designed to determine whether iron contents are altered in hexachlorobenzene (HCB)-induced porphyria, and whether there is any relation between these alterations and the effects of the drug on several enzymes of the haem pathway. To this end, the effect of HCB administration on total, non-haem and haem iron levels was studied. Further, the effects of the addition of: both heated and non-heated HCB-porphyric liver preparations, iron as sulfate, ferritin and haemin and alpha alpha'-bipyridyl and 8-hydroxyquinoline were studied on the following enzymes: delta-aminolaevulinic acid synthase, delta-aminolaevulinic acid dehydratase, porphobilinogenase and porphyrinogen carboxy-lyase. Total and non-haem iron levels increased significantly as a result of HCB intoxication, but there was a non-significant decrease in haem iron content. The increased iron levels did not appear to be directly involved in the increased activities of delta-aminolaevulinic acid synthase and delta-aminolaevulinic acid dehydratase observed in HCB-induced porphyria, since it was not possible to detect any activation in heating and crossed assays nor by the addition of inorganic iron, protein-iron or haemin. Results from heating and crossed assays suggested the existence of an activator for porphobilinogenase and an inhibitor for porphyrinogen carboxy-lyase, while results obtained with chelating agents suggested that iron could partly account for the activation of porphobilinogenase. Iron was not directly involved with the decreased activity of porphyrinogen carboxy-lyase, since neither iron chelators nor different types of iron produced physiologically significant effects.     

Altered expression of acute-phase reactants in mouse liver tumors

We studied the expression of eight liver acute-phase genes in spontaneous and diethylnitrosamine-induced mouse liver tumors (MLTs) under basal and induced conditions. Primary spontaneous and chemically induced MLTs were used for RNA isolation and histopathologic analysis. In the noninduced state, all MLTs showed similar levels of mRNA for albumin, serum amyloid A, alpha 1-acid glycoprotein, haptoglobin, and alpha-, beta-, and gamma-fibrinogens compared with control or background livers. The mRNA for the alpha 1-major acute-phase protein, however, was consistently elevated in both spontaneous and diethylnitrosamine-induced MLTs. The expression of these acute-phase reactants in 11 MLTs was examined following exposure of the mice to turpentine. The relative expression of these mRNAs in these MLTs varied widely compared with mRNA expression in controls. Though all MLTs expressed the same three species of fibrinogen mRNAs as did the controls, no MLT demonstrated downregulation of albumin mRNA levels, and only 1 of 11 MLTs showed a marginal increase in serum amyloid A mRNA levels. Synthesis of mRNA for alpha 1-acid glycoprotein and haptoglobin was intermediate. The study of the response of MLTs to specific acute-phase stimuli may make possible a better understanding of the basis for coordinated expression of acute-phase reactants and of the variable phenotypes associated with cancers.     

Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin

Serum melatonin (MLT) levels have been reported to diminish significantly by the 5th and 6th decades of life as the incidence of breast cancer increases. Given MLT’s anti-cancer activity, we hypothesize that age-related decline in pineal MLT production leads to enhanced breast cancer development and growth as women age. In this study, we sought to determine whether the growth of tissue-isolated mammary tumors in young, adult, and old female Buffalo rats relates to the age-related changes in MLT and its MT1 receptor. Significant decreases in the peak nighttime serum MLT levels were observed in old as compared to adult and young rats. Significantly diminished nighttime and early morning levels of MT1-melatonin receptors were observed in uteri from old rats compared to adult and young rats. Growth rates in transplanted, tissue-isolated, carcinogen-induced mammary tumors are significantly increased in old rats as compared to adult or young rats. The growth-suppressive actions of exogenous MLT are diminished in old rats compared to adult and young rats. This decrease in tumor response correlates with reduced expression of the MT1 receptor in old as compared to young and adult rats. Thus, enhanced mammary tumor growth is associated with old age and diminished levels of MLT and MT1 receptor during old age, resulting in reduced sensitivity to exogenous MLT. Finally, our studies demonstrate that the tissue-isolated tumor model is viable model system in which to study the role of aging on breast cancer growth.     

Growth and fatty acid metabolism of human breast cancer (MCF-7) xenografts in nude rats: impact of constant light-induced nocturnal melatonin suppression

The nocturnal melatonin (MLT) surge is a relevant oncostatic signal for a variety of experimental malignancies. Population studies support the hypothesis that exposure to light at night may represent a new risk factor for breast cancer possibly through the suppression of pineal MLT production and/or circadian disruption. We tested the ability of constant light exposure to suppress MLT production in female nude rats and stimulate the growth of tissue-isolated MCF-7 human breast cancer xenografts via increased tumor linoleic acid (LA) metabolism. Rats maintained on an alternating light/dark cycle (L:D group) exhibited a robust circadian MLT rhythm that was abolished following constant light exposure. During the exposure of animals bearing tissue-isolated human MCF-7 breast cancer xenografts to constant light, the rate of tumor growth markedly increased relative to the L:D group. Tumor LA uptake and its metabolism to the mitogen 13-hydroxyoctadecadienoic acid (13-HODE) were also substantially higher under constant light conditions. This is the first biological evidence for a potential link between constant light exposure and increased human breast oncogenesis involving MLT suppression and stimulation of tumor LA metabolism.     

Heme arginate treatment for myelodysplastic syndromes

Heme arginate was given to 26 patients with a myelodysplastic syndrome (MDS) as infusions of 2-3 mg/kg body weight weekly for 8-12 weeks. Most of the patients first received a loading dose on four consecutive days. Six of the patients showed improvement in cytopenias during the therapy. In three of the responders severely depressed blood cell counts recovered to normal or close to normal. So far the maximum duration of a response after the cessation of the treatment is 25 months, and the two ongoing responses have lasted for 11 and 12 months, respectively. In two responders of the eight patients with more than 15% ring sideroblasts the number of ring sideroblasts decreased during the treatment but remained unchanged in six non-responders. The responders were characterized by a low or low normal heme synthase activity which increased during the treatment, whereas the non-responders showed a higher mean heme synthase activity which decreased during the treatment. In general, the responders had significantly fewer defects in heme synthetic enzyme activities than the non-responders. FAB type, karyotype or growth pattern in in vitro cultures of hematopoietic progenitors did not predict the response. Apart from one case of mild venous irritation, no other adverse effects were seen. The present study shows that heme arginate induces beneficial effects on cytopenia in some MDS patients and has very few side-effects.