Histamine as a selective protector against cellular damage produced by ionizing radiation

MEDINA VANINA; CRICCO GRACIELA; MOHAMAD NORA; CROCI MAXIMO; NUÑEZ MARIEL; MARTIN GABRIELA; COCCA CLAUDIA; BERGOC ROSA; RIVERA ELENA

28 de abril- 2 de Mayo ,2004, Bergish-Gladbach, Alemania

Congreso; European Hiastamine Research XXXIII Annual Meeting.; 2004

Histamine As A selective protector against cellular damage produced by ionizing radiation    V. Medina, G. Cricco, N. Mohamad, M. Croci , M. Núñez, G. Martín, C. Cocca, R. M. Bergoc, E.S. Rivera (1) Radioisotopes Laboratory, School of Pharmacy and Biochemistry, Buenos Aires University, Junin 956, 1113 Buenos Aires, ARGENTINA. (2) Immunooncology Institute, 3200 Cordoba Av., 1187 Buenos Aires, ARGENTINA.    The present work investigated the capacity of HA to modulate the oxidative damaged produced by ionizing radiation.    In order to study the effect of histamine (HA) on radiosensitivity of transformed cells, MDA-231 (human breast carcinoma cells) were irradiated in vitro with doses ranging from 0 to10 Gy employing a 137Cs source of 189 TBq (Dose rate: 7.7 Gy/min). HA from 0.1 to 10 mM was added to cultures 20 hs before irradiation. The survival curves were adjusted using the Lineal-quadratic model. The levels of the free radicals superoxide (O2·-) and hydrogen peroxide (H2O2) were determined by flow citometry employing the specific fluorescence dyes dichloride fluorescein diacetato and dihydroethidium. In addition the activity of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (Gpx) were determined in MDA cells treated with HA 10 mM and/or irradiated with 2Gy.    HA treatment produced a significant dose dependent decrease in cell survival (p<0.001 Two WayANOVA) clearly showing that it enhances radiosensitivity of transformed cells.  The survival fraction at 2Gy was 0.24 for control conditions compared to 0.11 for HA-treated cells. This effect of HA on radiosensitivity was correlated with a significant increase in H2O2 and in O2·- levels. 0.001 Two WayANOVA) clearly showing that it enhances radiosensitivity of transformed cells.  The survival fraction at 2Gy was 0.24 for control conditions compared to 0.11 for HA-treated cells. This effect of HA on radiosensitivity was correlated with a significant increase in H2O2 and in O2·- levels. 0.001 Two WayANOVA) clearly showing that it enhances radiosensitivity of transformed cells.  The survival fraction at 2Gy was 0.24 for control conditions compared to 0.11 for HA-treated cells. This effect of HA on radiosensitivity was correlated with a significant increase in H2O2 and in O2·- levels. 0.001 Two WayANOVA) clearly showing that it enhances radiosensitivity of transformed cells.  The survival fraction at 2Gy was 0.24 for control conditions compared to 0.11 for HA-treated cells. This effect of HA on radiosensitivity was correlated with a significant increase in H2O2 and in O2·- levels.  To study the possible protective effect of histamine on small-intestine and bone marrow, thirty mice were separated into Control irradiated and irradiated receiving HA (HA-group). All animals received a single dose of 10 Gy on whole-body. HA-group received a daily sc injection (0.1 mg/kg) starting 20 hs before irradiation. Mice were sacrificed 5 days after irradiation.     Intestinal mucosae of 10 Gy irradiated HA-treated mice showed mild mucosal atrophy with conservation of villous projections and absence of edema, cellular preservation of nuclear and cytoplasmic characters. The number of crypts was 35 % higher than irradiated control animals. Similarly, bone marrow of HA group showed mild hipocellularity. The present data indicate that histamine can enhance radiosentivity of malignant cells and in addition protects normal tissues from high doses of ionizing radiation. This selective effect is exerted in part by the modulation of antioxidant enzymes. Topic: 1. Radiation effects Experimental studies Interestingly, in a model of Knockout mice completely depleted of endogenous histamine, it was observed a significant delay in bone marrow repopulation after whole body irradiation. These results are in agreement with the hypothesis that histamine has a role in the regulation of hematopoiesis as well as an inhibitory effect on apoptosis. The parameters a, b and the ratio a/b were calculated with the GraphPad Prism software and the values obtained were: 0.75(0.35-1.16)Gy-1, 0.05(-0.19-0.20)Gy-2 and 6.45(2.2-13.1)Gy respectively. The role of histamine on growth of normal and cancer cell has been extensively investigated in the last years and it has been clearly established that the treatment with histamine produces a significant growth inhibition of different cell lines derived from human neoplasias.