Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The susceptibility of the face region of the chick embryo to the teratogenic action of intraamniotically injected hydrocortisone contrasts with the resistance of the limbs to its action while at the same time their dysmorphogenesis may be induced by other agents. Since glucocorticoid receptors were shown to mediate face teratogenesis, their development was investigated in freshly dissected limb buds of 3-, 3.5-, and 4-day-old chick embryos in comparison with the face region. The specific binding of 3H-dexamethasone to molybdate-stabilized glucocorticoid receptors was estimated by the dextran-coated charcoal method and complemented by cytologic analysis of mitotic activity in control and hydrocortisone-treated embryos. The glucocorticoid receptors were found in both organ anlagen already on day 3 when their concentration in femtomoles per microgram DNA was significantly higher in the face region. Accordingly, on day 3 intraamniotic hydrocortisone inhibited the mitotic activity in the face without affecting the developing limbs. On days 3.5 and 4 the concentration of glucocorticoid receptors was similar in both organ anlagen. Administration of hydrocortisone on day 4 induced mitotic depression in the face as well as in the limbs. However, the degree of inhibition appeared to be dependent upon the actual mitotic rate. In the face region where the mitotic activity culminated at that time, the inhibition was much deeper and longer-lasting than in the developing limbs characterized by continuous decrease of proliferation rate in controls. These findings are consistent with a view that glucocorticoid receptors are a prerequisite, but not the only factor in receptor-mediated teratogenesis.
Teratog Carcinog Mutagen 1986
PMID:Glucocorticoid receptor-mediated teratogenesis and cell proliferation in the limbs and face of the chick embryo. 287 9

In previous structure-activity studies, we have demonstrated that attachment of a glucose molecule to the chloroethylnitrosourea cytotoxic group produces a compound with reduced murine bone marrow toxicity and retention of full antitumor activity. To further define this protective role conferred by the glucose moiety in bone marrow cells, we have replaced the nitrosourea cytotoxic group with another class of alkylating agent, a bifunctional nitrogen mustard. In a detailed structure-activity analysis, we have now characterized four analogues, with the mustard cytotoxic group positioned at carbon 2 [1,3,4,6-tetra-O-acetyl-2-(di-2-chloroethyl)amino-2-deoxy-D-glucopyranos e (TGM)], carbon 6, or carbon 1 (D- and L-isomers) of the aminoglucose molecule. On a molar basis, TGM was most toxic to normal BALB/c X DBA/2 F1 mice, with a 10% lethal dose (LD10) of 3.8 mumol/kg. The D- and L-isomers of 2,3,4,6-tetra-O-acetyl-N,N-bis(2-chloroethyl)glucopyranosylamine (C-1) were the least toxic, with an LD10 of 73 mumol/kg for both. Optimal antitumor activity against the murine P388 leukemia (single i.p. administration of the LD10) did not differ significantly among the four analogues, with increased life span ranging from 83-86%. P388 antitumor activity for nitrogen mustard (HN2) was significantly less, 60% increased life span (P = 0.01), while p-di(2-chloroethyl)amino-L-phenylalanine produced an increased life span of greater than 101%. An LD10 of 6-bis-(2-chloroethyl) amino-6-deoxy-D-glucose (C-6) or TGM produced significantly less depression of WBC counts than did an equitoxic dose of the C-1 isomers, HN2, or p-di(2-chloroethyl)amino-L-phenylalanine. The mean nadir WBC count for C-6 equaled 86% of control, and for TGM, 80% of control. Consistent with this sparing effect on the peripheral WBC, C-6 and TGM produced significantly less in vivo murine bone marrow DNA synthesis depression, 77 and 64% of control, respectively, as compared to the depression nadir produced by HN2 (27% of control), the D-isomer of C-1 (17%), the L-isomer of C-1 (18%), and p-di(2-chloroethyl)amino-L-phenylalanine (2%). These structure-activity studies demonstrate that conjugation of the mustard cytotoxic group to carbon 6 or carbon 2 of glucose produces an analogue that retains P388 antitumor activity significantly greater than that of HN2, with a concomitant reduction in murine bone marrow toxicity.
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PMID:Antitumor activity and bone marrow toxicity of aminoglucose mustard anticancer agents in mice. 293 28

The human carcinogen and nitrogen mustard chlornaphazine (CN) has been confirmed to be mutagenic to Salmonella and, unexpectedly, the more so when evaluated in the presence of liver S9 mix. It also has been established as clastogenic to Chinese hamster lung cells exposed in vitro to dose levels greater than 2.5 micrograms/ml. Chlornaphazine subdued mice at doses of 5 g/kg, but only the occasional death occurred during the 4 days following oral administration of this dose in corn oil. Consequently, a median lethal dose level was not established. Nonetheless, dose levels of 500 mg/kg or greater gave a clear positive response in both the mouse and the rat bone marrow micronucleus assay. Although depression of erythropoeisis was observed in mice, a clastogenic response still was observed in the bone marrow 24 hr after dosing. The positive response in the rat was greater than that observed in the mouse. The present data provide a further instance of an established human carcinogen being readily detected by standard in vitro and in vivo mutagenicity assays.
Environ Mol Mutagen 1988
PMID:Mutagenicity to bacteria, cultured cells, and rodents of the human carcinogen chlornaphazine. 305 19

Groups of male B6C3F1 mice (N = 12) were exposed to ambient air or to gaseous 1,3-butadiene (BD) at 6.25, 62.5, and 625 ppm for 10 exposure days (6 hr + T90/day). Exposure to BD induced in bone marrow: 1) a significant increase in the frequency of chromosomal aberrations (CA); 2) a significant elevation in the frequency of sister chromatid exchanges (SCE); 3) a significant lengthening of the average generation time (AGT); 4) a significant depression in the mitotic index (MI); and, as measured in the peripheral blood, 5) a significant increase in the proportion of circulating polychromatic erythrocytes (%PCE), and 6) a significant increase in the level of micronucleated PCE (MN-PCE) and micronucleated normochromatic erythrocytes (MN-NCE). The most sensitive indicator of genotoxic damage was the frequency of SCE (significant at 6.25 ppm), followed by MN-PCE levels (significant at 62.5 ppm), and then by CA and MN-NCE frequencies (significant at 625 ppm). The most sensitive measure of cytotoxic damage was AGT (significant at 62.5 ppm), followed by %PCE (significant at 625 ppm), and then by MI (significant by trend test only). Because each cytogenetic endpoint was evaluated in every animal, a correlation analysis was conducted to evaluate the degree of concordance among the various indicators of genotoxic and cytotoxic damage. The extent of concordance ranged from a very good correlation between the induction of MN-PCE and the induction of SCE (correlation coefficient r = 0.9562) to the lack of a significant correlation between the depression in the MI and any other endpoint (r less than 0.37).
Environ Mutagen 1987
PMID:Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F1 mice by multiple exposures to gaseous 1,3-butadiene. 356 68

The ability of inhaled methyl isocyanate (MIC) to induce genotoxic and cytotoxic damage in vivo was evaluated by assessing the induction of chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs) in bone marrow metaphase cells, the induction of micronuclei in polychromatic erythrocytes (MN-PCEs), and the inhibition of bone marrow cellular proliferation and erythropoiesis. B6C3F1 mice were exposed to MIC by two exposure regiments: in two experiments, male mice only were exposed to 3, 10, and 30 ppm for 2 hr; in four experiments, male and female mice were exposed to 1 and 3 ppm (in one experiment, to 6 ppm, also), 6 hr per day for 4 consecutive days. The various cytogenetic endpoints were analyzed in bone marrow and peripheral blood (4-day exposure regimen only) samples taken from bromodeoxyuridine tablet-implanted animals killed 11 to 22 hr after cessation of the exposure to MIC. Exposure to MIC for 2 hr induced a significant delay in cellular proliferation but did not induce a significant increase in CAs, SCEs (evaluated at 3 and 10 ppm, only) or in bone marrow MN-PCEs. Also, this exposure regimen did not inhibit the rate of erythropoiesis. Following exposure to MIC for 4 days, a weak but significant increase in CAs and SCEs was observed in male (in one experiment) and in female (in two experiments) mice. The induction was especially apparent in the single experiment in which mice were exposed to 6 ppm MIC. At this concentration, a significant increase in MN-PCEs in peripheral blood was observed in male but not female mice. Delay in bone marrow cell proliferation was observed in male mice beginning at 3 ppm and in female mice at 6 ppm. The 4-day exposure regimen resulted also in a depressed rate of erythropoiesis, with male mice appearing to exhibit greater depression than female mice. The results demonstrate that exposure to MIC by inhalation results in bone marrow damage, indicating the systemic genotoxic/cytotoxic activity of MIC and/or reactive metabolites.
Environ Mutagen 1987
PMID:Methyl isocyanate: an evaluation of in vivo cytogenetic activity. 380 24

Chick embryos were mutagenized in ovo in order to study developmentally related alterations in immune functions in survivors of this prenatal toxicant insult. In this experimental system, a single exposure of 6-day chick embryos to 0.1 microgram aflatoxin-B1 (AF-B1) in 10 microliters of acetone was employed, and the control embryos received 10 microliters of solvent alone. This dosage of AF-B1 administered to 6-day embryos was found to increase the incidence of sister chromatid exchanges in blood cells approximately fivefold above the baseline observed in solvent controls. A second sham control, where no solvent was administered, was included in some experiments. The cell cycle times in blood increased slightly during the initial exposure to AF-B1. However, a majority of the AF-B1 and acetone exposed embryos survived and hatched without incident. Losses occurred mainly in the latter part of embryogenesis. After hatching, no significant differences were observed in body weight between different treatment groups up to 26 weeks of age and no change in primary humoral immunity was detected. In contrast, two parameters of cell-mediated immunity, graft vs host (GvH), and cutaneous basophil hypersensitivity (CBH) reactions were both depressed as a result of exposure to AF-B1. The AF-B1 treatment group was significantly reduced in the GvH reaction compared with sham-treated controls. In the CBH assay, AF-B1-exposed chicks showed reduced immunity compared with acetone controls. These results suggest that long-term selective immune depression can occur following embryonic exposure to AF-B1.
Environ Mutagen 1985
PMID:Embryonic exposure to aflatoxin-B1: mutagenicity and influence on development and immunity. 393 Feb 39

Nitrogen mustard (N-mustard) inhibits the ouabain-sensitive and the furosemide-sensitive Rb uptake of Ehrlich ascites tumor cells, whereas the transport, which is resistant to both inhibitors, is not affected by the alkylating agent. At N-mustard concentrations below 10 microM, the reduction in Rb uptake is predominantly due to an interference with the furosemide-sensitive system. The dose response curve for the inhibition by N-mustard of the furosemide-sensitive Rb uptake closely parallels the dose response curve for the anti-tumor activity of the alkylating drug. This is in contrast to the behaviour of the ouabain-sensitive Rb transport. The inhibition of the furosemide-sensitive Rb uptake is expressed much less in cells which are resistant to N-mustard. The recovery of the furosemide-sensitive transport system after a single exposure to N-mustard is relatively slow and characterized by an initial 4 h lag period, whereas the repair of DNA-interstrand cross-links starts immediately after removal of the drug. At mM concentrations furosemide blocks the multiplication of Ehrlich ascites tumor cells. However, lower concentrations of furosemide which cause a 50% reduction in the furosemide-sensitive Rb uptake do not interfere with cell proliferation. This is in contrast to the behaviour of N-mustard which exerts a clear-cut depression of cell growth at concentrations leading to a 50% inhibition of the furosemide-sensitive Rb transport. It is concluded, therefore, that the inhibition of the furosemide-sensitive system alone is not sufficient to explain the anti-tumor activity of the alkylating agent. The effect is discussed as part of a more extended N-mustard-induced membrane alteration which may be important for the growth inhibitory effect of the alkylating agent.
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PMID:Nitrogen mustard interference with potassium transport systems in Ehrlich ascites tumor cells. 401 67

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces fetal asymmetric limb malformations with exposure of pregnant mice to 50 mg/kg on day 11 of gestation. Hindlimbs were more frequently malformed than forelimbs, and a fourfold greater incidence of postaxial ectrodactyly was found in left forelimbs than in right forelimbs, and a two fold excess in left hindlimbs compared to right hindlimbs. The level of cell death and mitotic index were measured in forelimbs and hindlimbs from treated and control embryos at 1, 4, 18, 24, 48, and 72 hr after exposure to ascertain if these parameters could be correlated with the differential teratogenic susceptibility of the limbs. An increase in necrotic index was first detected in treated limbs at 4 hr, increased at 18 hr, peaked at 24 hr, and began declining at 48 hr to reach the control baseline at 72 hr. At 24 hr, the correlation between the level of cell death and susceptibility of malformation was the strongest, with the left hindlimb having a necrotic index of 58%, the right hindlimb 47%, the left forelimb 30% and the right forelimb 12%. In both forelimbs and hindlimbs, MNNG treatment initially depressed mitotic activity followed by an elevation at 48 hr relative to controls. The magnitude of the depression, extent of the elevation, and overall pattern of mitotic activity could not be uniformly related to limb defects. These results indicate that the amount of cell death in limb buds at 24 hr after MNNG exposure may predict target organ susceptibility. Depressions in mitotic activity and alterations in the pattern of mitosis were also observed which were not as clearly correlated with the incidence of malformations as was the amount of cell death.
Teratog Carcinog Mutagen 1983
PMID:Contribution of mesenchymal cell death and mitotic alteration to asymmetric limb malformations induced by MNNG. 613 67

Between October, 1978 and June, 1979, nine patients with biopsy-proven cutaneous T-Cell lymphoma were treated with combined total-skin electron beam radiation (TSEB) and topical chemotherapy. TSEB was administered using 3.8 MeV electron and dual exposure technique. All patients received skin dose of 400 rad once weekly to a total dose of 2000 to 2400 rad followed by topical chemotherapy with mechlorethamine hydrochloride (HN2) two to four weeks after completion of radiation. A complete response followed TSEB in seven of nine patients, but a relapse of disease activity has subsequently occurred within the first year for all the patients despite adjunct therapy, except for one patient who remains disease free for more than 21 months. Generalized severe erythema developed during or shortly after completion of radiation in six of nine patients, with blistering at the overlapping treatment fields and body folds in four patients. In addition four patients developed diffuse permanent telangiectasia of skin and one patient developed linear sclerosis, telangiectasis and painful ischemic ulceration on the fingertips two years after completion of electron beam therapy. Most patients had evidence of mild depression of lymphocyte responsiveness to Phytohemagglutinin after TSEB. Our conclusion is that the short-term benefits and convenience of this particular technique do not justify the acute and chronic toxicity encountered.
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PMID:Combined moderate dose electron beam radiotherapy and topical chemotherapy for cutaneous T-Cell lymphoma. 640 98

Three main aspects involved in the chemical induction of anaphase-telophase aberrations in the first mitosis after treatment were analyzed: 1) the relationship between the frequency of anaphase-telophase aberrations and the time of fixation after treatment; 2) the dose-response relationships; and 3) the proliferative rate of cells exposed to chemicals which interact with DNA by different mechanisms. Experiments were carried out using Chinese hamster ovary (CHO) cells. The compounds examined were adriamycin (ADR) and mitomycin C (MMC). The frequency of cells with chromatin bridges or with lagging chromosomes as well as the mitotic index was determined in each experiment. The results obtained showed that 1) chromatin bridges and lagging chromosomes are apparently induced during the S period of the previous interphase; 2) the increase in the cytotoxicity index (inferred from the mitotic index) and the frequency of cells with chromatin bridges and lagging chromosomes were proportional to the treatment lapse and to the dose employed; and 3) the effect of ADR on cell growth differs from the effect of MMC. While ADR decreased the mitotic activity of cells in logarithmic growth phase, MMC induced mitotic delay. In accordance with these results, the occurrence of chromatin bridges in anaphase-telophase could be explained by the induction of chromosome stickiness and, to a lesser extent, by the induction of exchange-type aberrations. On the other hand, lagging chromosomes seem to be the result of chromatid or chromosome breaks because the lagging chromosomes observed were primarily, if not all, fragments and not whole chromosomes. Our evaluation of the anaphase-telophase test indicates that it is very sensitive method for the detection of chemical clastogens, but other factors, such as mitotic depression, must be taken into account to avoid false-negative results.
Environ Mutagen 1984
PMID:Anaphase-telophase analysis of chromosomal damage induced by chemicals. 642 71


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