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)

Two murine lymphomas, L5MF-22 of B10.129(5M) (H-2b) origin and P388 of DBA/2 (H-2d) origin, were inoculated into lethally irradiated hybrid (C57BL/6 x DBA/2)F1 (B6D2F1) mice (H-2b/H-2d). Marked localized graft resistance was found in the spleen and occasionally in the liver of recipient mice as a result of a non-T-dependent hybrid resistance (HR). Significant reduction of HR of B6D2F1 mice could be obtained when viable lymphoma cells were inoculated along with inactivated cells of the same tumor or of genetically related leukemias. These results suggest that in vivo competition for HR effectors can take place in mouse spleen and liver leading to a depression of the localized resistance.
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PMID:Inhibition of hybrid resistance to lymphomas by inactivated tumor cells in lethally irradiated mice. 617 39

Doses of N-(phosphonacetyl)-L-aspartic acid (PALA) lower than those required for therapeutic activity against the spontaneous murine breast tumor (BALB/c X DBA/8 F1) were found to produce significant depression in uridine triphosphate pools in the tumor. Using such low, nontherapeutic, but biochemically active doses of PALA in combination with 5-fluorouracil (FUra(, it was possible to maintain the dose of FUra at its full maximum tolerated single agent dose. In comparison with the maximum tolerated dose of FUra alone, the combination of FUra plus low-dose PALA produced a significant increase in the level of tumor FUra-containing RNA, only a slight increase in intestinal FUra-containing RNA, and no increase in bone marrow FUra-containing RNA. These biochemical results correlated with the therapeutic findings of significantly increased antitumor activity without an increase in host toxicity. A review of currently reported PALA plus FUra clinical protocols reveals that the experimental parameters which have produced successful therapeutic results in the laboratory (i.e., a low-PALA:high-FUra dosage ratio) have not yet been translated into clinical trial. Final judgment on the clinical efficacy of PALA:FUra combinations must await the results of proposed low-PALA:high-FUra clinical trials.
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PMID:Therapeutic utility of utilizing low doses of N-(phosphonacetyl)-L-aspartic acid in combination with 5-fluorouracil: a murine study with clinical relevance. 618 48

We analyzed the effects of a polycythemic substrain of Friend leukemia virus, i.e. the FLV-P virus, on splenic NK activity of DBA/2 susceptible mice. One day after virus injection a significant increase of NK activity was found, which persisted until day 10. On the other hand, 14-21 days after virus injection a marked and significant depression of activity was measured. This depression was associated with the appearance of suppressor cells able to inhibit the lytic activity of untreated splenocytes when mixed in vitro in the 4 h 51Cr-release assay. The suppressor cell population was insensitive to treatment with anti-Thy 1.2 plus complement, was adherent to Sephadex G-10 and nylon, but did not adhere to plastic, suggesting it is neither a T-cell nor a typical macrophage. The possible relevance of NK activity modulation in relation to the induction of leukemia is discussed.
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PMID:Modulation of natural killer (nk) cell activity during FLV-P virus infection of mice. 621 62

The effects of pretreatment with 3-methylcholanthrene (MC) and beta-naphthoflavone (beta NF) on the hepatic microsome-mediated mutagenesis of aflatoxin B1 (AFB1) and benzo[a]pyrene, and on the metabolism of aflatoxins B1 and B2, were investigated in inbred mouse strains. The inbred strains of mice studied included Ah nonresponsive strains (DBA/2Ha, AKR/Sn and RF/J), which were also nonresponsive to the induction of the metabolism of AFB1 to AFM1 (AFB1-4-hydroxylase activity), and Ah responsive strains (C57BL/6Ha, ICR/Ha, C3H/St, A/St, Balb/cCr, C57e/Ha and CBA/Pi), which were also responsive to the induction of AFB1-4-hydroxylase activity. The hepatic microsome-mediated enzyme activities studied included: mutagenic activation of AFB1 and benzo[a]pyrene in the Ames Salmonella typhimurium TA-98 system; metabolism of AFB1 and AFB2 to AFM1 and AFM2, respectively; and benzo[a]pyrene metabolism measured as the formation of fluorescent phenolic metabolites, i.e. aryl hydrocarbon hydroxylase (AHH) activity. Time-course and dose-response studies in C57BL/6Ha mice revealed that the metabolism of aflatoxin B1/B2 to aflatoxin M1/M2 (AFB1/B2-4-hydroxylase activity) was induced by both MC and beta NF. In the nonresponsive strains studied, pretreatment with MC or beta NF produced essentially little alteration of AFB1-4-hydroxylase activity or AHH activity or the mutagenic activation of AFB1 and benzo[a]pyrene. On the other hand, AFB1-4-hydroxylase activity in the responsive strains was induced 4- to 10-fold by MC (60 mg/kg) and 2.5- to 7-fold by beta NF (150 mg/kg). Also in the responsive strains, induction of AFB1-4-hydroxylase activity was strongly associated with (a) the depression of the mutagenic activation of AFB1, and (b) with the induction of both AHH and the mutagenic activation of benzo[a]pyrene. In summary, the results described in this report suggest that: (a) induction of AFB1-4-hydroxylase activity by MC (or beta NF) is associated with the depression of AFB1 mutagenesis and with the induction of benzo[a]pyrene mutagenesis; and (b) induction by MC (or beta NF) of AHH activity, AFB1-4-hydroxylase activity and AFB2-4-hydroxylase activity is controlled by either the same or closely linked genetic factors.
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PMID:Genetic expression of aflatoxin metabolism. Effects of 3-methylcholanthrene and beta-naphthoflavone on hepatic microsomal metabolism and mutagenic activation of aflatoxins. 631 70

The present findings demonstrate that a total i.v. transfer of 100 X 10(6) C57BL/6 (B6) parental spleen cells into untreated (C57BL/6 X DBA/2)F1 hybrids (B6D2F1) resulted in acute runting, which was associated with a significantly elevated graft-vs.-host (GVH) index over a one-month period following GVH induction. Furthermore, this B6-induced acute GVH disease was associated with a marked depression of natural killer (NK) cell activity (spleen and peripheral blood) (with or without addition of mouse fibroblast interferon), which correlated with lymphoid cell hypocellularity, prominent splenic extramedullary hematopoiesis (EMH), and parallel depressions of both concanavalin A- and lipopolysaccharide-induced mitogenesis. Significantly increased killing by antibody-dependent cellular cytotoxicity of antibody-coated chicken red blood cells, as well as increased T cell killing of the NK-insensitive cell line P815 (as compared to the significantly decreased killing of the NK-sensitive cell line YAC-1) was also observed in the spleens of this 100 X 10(6) B6-injected F1 group. In marked contrast to this 100 X 10(6) B6-injected acute GVH group, untreated mice injected i.v. with the same or greater numbers of parental DBA/2 spleen cells (100 X 10(6)-150 X 10(6) DBA/2 spleen cells) exhibited a milder and more chronic form of GVH disease, which was not associated with a significant decrease of NK activity. It was of considerable interest that a total i.v. transfer of 50 X 10(6) B6 spleen cells (i.e. one-half of that required to produce acute GVH, markedly depressed NK, and prominent splenic EMH) into B6D2F1 hybrids also resulted in a more chronic form of GVH disease, but was associated with significantly increased levels of NK activity at two weeks post GVH induction.
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PMID:Natural killer activity in (C57BL/6 X DBA/2)F1 hybrids undergoing acute and chronic graft-vs.-host reaction. 664 88

The behavioral and neurochemical effects of acute and chronic ethanol administration were studied in BALB/c, C57B1/6 and DBA/2 mice. The rates of dopamine synthesis and release in the striatum were estimated by measuring the accumulation of DOPA and DOPAC, respectively, after inhibition of aromatic amino acid decarboxylase with NSD-1024. Biphasic behavioral effects were found in BALB/c and DBA/2 mice, but not in C57B1/6 mice, with low doses of ethanol producing activation and high doses, depression. Biphasic effects were also found in the dopamine response to acute doses of ethanol. The BALB/c and DBA/2 mice showed larger suppressions of DA release in the lower dose ranges of ethanol, and smaller increases at the higher doses than did the C57B1/6 mice. Ethanol stimulated dopamine synthesis in a monophasic, dose-dependent manner, and C57B1/6 mice were less sensitive to this effect of ethanol compared to the other tested strains of mice. Chronic ethanol feeding produced behavioral tolerance to the high-dose depressant effects of ethanol, but not to the low-dose activating effects. Similarly, tolerance developed in the dopaminergic responses to a higher challenge dose of ethanol (3.5 g/kg). These findings demonstrate that genetically determined differences exist in the sensitivity of the dopaminergic systems of mice to ethanol, and suggest that central dopamine neurons may be important in the behavioral effects of ethanol.
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PMID:Neurochemical correlates of tolerance and strain differences in the neurochemical effects of ethanol. 668 1

The influences of genotype and sex on spontaneous motor activity in a Y-maze after nicotine administration and on nicotine concentrations in liver and brain were assessed in three inbred mouse strains. The rank order of liver nicotine elimination rates in these strains was found to be C57 > C3H = DBA for females and DBA > C3H = C57 for males. Within the C57 and C3H strains, females eliminated nicotine significantly faster than males, while DBA females and males eliminated nicotine at similar rates. The rank order of motor depression at early time points after nicotine administration was found to be DBA = C57 > C3H for both males and females. Females of all three strains demonstrated less sensitivity to nicotine's depressant effects than males. There did not appear to be any consistent association between rate of liver nicotine elimination or brain nicotine level and motor depression as measured in the Y-maze. Although variability in liver nicotine elimination and in brain nicotine content may account for some of the observed behavioral effects, these data suggest that strain and sex differences in tissue sensitivity to nicotine are of primary importance.
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PMID:The influence of genotype and sex on behavioral sensitivity to nicotine in mice. 677 24

Moderate body deuteration combined with a cytostatic drug [methotrexate (MTX)] significantly increases the survival time of young adult DBA/2 mice bearing transplantable P815. L5178Y, or L1210 tumors. Neoplastic cells were grown in vitro from tumor stock and injected i.p. into mice from two groups, one drinking tap water, and other drinking 30% heavy water in tap water. One-half of the animals in each of these two groups was given a single injection of MTX (4 mg/kg body weight) on 3 consecutive days per week. At death, extension of primary and metastatic tumors was examined and was found to be macro- and microscopically comparable in the corresponding groups. The mean survival time of untreated mice drinking tap water was about 2 weeks following injection of the fast-growing P815, L5178Y, or L1210 (V) tumors and approximately 5 weeks after injection of cells from a slower-growing L1210 subline. Body deuteration alone roughly doubled the survival time solely of mice bearing this L1210 subline. Treatment with MTX approximately doubled the mean survival time of hosts bearing one of the fast-growing tumors. Combined treatment with heavy water and MTX increased the mean survival time of the mice in all groups by 15 to 125% as compared to control values. The reasons for this effect are unknown. However, heavy water has been shown to exert antimitotic activity and to depress the incorporation of radioactive precursors into DNA of proliferating mammalian cells. The depression of antibody formation following antigenic stimulation and the reduction in numbers of nonneoplastic lymphoid cells of mice following moderate body deuteration may have contributed to the enhancement of MTX activity in addition to other effects of deuterium.
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PMID:Survival of tumor-bearing mice exposed to heavy water or heavy water plus methotrexate. 680 Jun 46

The effects of the PCBs mixture, Aroclor 1254, as modifiers of monooxygenases were studied in rabbits and mice. From data presented, it is not possible to generalize the biological effects of PCBs observed with rats, namely, that they are potent, nonspecific inducers of monooxygenase activities. This environmental pollutant enhanced microsomal drug-metabolizing enzymes in livers of rabbits and C57Bl/6J and DBA/2J mice. In rabbit lung, it inhibited, and in rabbit kidney, it enhanced the metabolism of ethylmorphine. Further, at dosages used, PCBs were poor inducers of aryl (benzo(a)pyrene) hydroxylase activity in livers of C57BL/6J and DBA/2J mice; they enhanced aryl hydrocarbon hydroxylase activity in rabbit kidney but caused a significant depression of its activity in rabbit lung. These studies demonstrate that the biologic impact of the widely distributed environmental pollutant, PCBs, may differ in different species and emphasize the need to carry out toxicological studies in more than one species of animals. The differential effects observed on various organs may also be important determinants of organ-targeted chemical toxicity.
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PMID:Polychlorinated biphenyls (PCBs) inducible monooxygenases in rabbits and mice: species and organ specificities. 680 95

We examined the ability of uridine to increase the therapeutic index of 5-fluorouracil (FUra) against C57BL/6 X DBA/2 F1 mice bearing a Day 1 B16 melanoma or L1210 leukemia. FUra (400, 600, or 800 mg/kg, i.p.) followed in 24 hr by a 5-day s.c. infusion with uridine (5 g/kg/day, s.c.) was compared with the maximum tolerated dose of FUra (200 mg/kg, i.p.) plus a 5-day infusion with 0.9% NaCl solution. High-dose FUra plus delayed infusion with uridine was more effective than FUra (200 mg/kg) in inhibiting the growth of the B16 melanoma. High-dose FUra plus uridine rescue was, however, no more effective than FUra (200 mg/kg) in increasing the survival times of mice bearing the L1210 leukemia. To see if uridine rescue from FUra toxicity correlated with effects against a sensitive normal tissue, bone marrow nucleated cellularity of normal, non-tumor-bearing mice was monitored after drug treatment. In mice treated with FUra (200 mg/kg) followed in 24 hr by a 5-day infusion with either uridine (5 g/kg/day) or 0.9% NaCl solution, there was not as great a decrease in cellularity at the nadir with uridine, and, in addition, uridine accelerated recovery as compared to 0.9% NaCl solution. Furthermore, uridine (5 g/kg/day), but not thymidine (dThd) (5 g/kg/day) or 2'-deoxyuridine (dUrd) (5 g/kg/day), had a sparing effect on the depression in bone marrow nucleated cellularity seen at the nadir on Day 4 after Fura (200 mg/kg). The specificity of uridine to rescue mice from the lethal toxicity of the related fluorinated pyrimidines, 5-fluorouridine and 5-fluoro-2'-deoxyuridine, was also examined. Mice were treated with 5-fluorouridine (250 mg/kg, i.p.) followed in 24 hr by a 5-day infusion with uridine (1, 5, or 10 g/kg/day), dThd (1, 5, or 10 g/kg/day), or dUrd (1 or 5 g/kg/day). Uridine (1, 5, or 10 g/kg/day) rescued mice from the lethal toxicity of 5-fluorouridine, whereas dThd or dUrd was ineffective. Similarly, a 5-day infusion with uridine, but not dThd or dUrd, rescued mice from the lethal toxicity of 5-fluoro-2'-deoxyuridine (1800 mg/kg, i.p.).
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PMID:Use of uridine rescue to enhance the antitumor selectivity of 5-fluorouracil. 685 Jun 28


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