14116 Background: We have previously reported that O-LM inhibits malignant cell proliferation and increases survival in rodent tumor models (Int J Cancer S13:183, 2002). Molecular and immunological basis of O-LM action were reported (J Clin Oncol 24:18S, 2006). As O- LM selectively protects normal tissues from high doses of ionizing radiation (Proc Int Cancer Congress,1495–9, 1998), we here investigated O- LM protective action upon radiation effects on immune cells. Methods: Balb/c mice (n=15 each group) were employed: control (C); 2Gy whole body irradiated (IR); treated with O-LM (Zn, Se, Mn 4μg/ml each; L. Muta 4 ng/ml; 0.1 ml/day, sc) for 15 days and 2Gy irradiated (O-LM+IR). Mice were sacrificed at day 3, 7 or 15 post-irradiation (PI). Proliferation was evaluated in lymphocytes by [3H]- Thymidine incorporation after T- or B selective mitogen stimulation. In cell-free supernatants (SN) from mitogen-stimulated cultures cytokines involved in lymphocyte regulation and/or inflammation were determined by ELISA. Results: Irradiation induced a decrease in T lymphocyte proliferation at 3 and 7 days PI (% of decrease in IR: 47.6±9.0, p<0.05; 42.0±7.2, p<0.02 respectively). Pretreatment with O-LM recovered proliferation to basal values (day 3 PI 93.4±10.2%; day 7 PI 130.9±15.3%, O-LM+IR vs. C; p=NS). No modifications were observed in B cells. At day 3 PI, a marked decrease in IFN? levels was obtained in SN of IR mice that was reverted by O-LM treatment (pg/ml: IR 1653±419; C 10884±2783, p<0.02; O-LM+IR 16924±4284, p<0.05 vs C). Also, at day 7 PI, an important increase in TNFa was observed in IR mice, that were reverted by O-LM (pg/ml: IR: 300.7±62.3 vs O-LM+IR: 28.7±2.3, p<0.02). No differences were found in IL-2 levels. Conclusions: The therapeutic action of O-LM is based on its ability of targeting simultaneously multiple pathways involved in cancer development. Present data demonstrate that O-LM protects animals from irradiation by recovering the immune function, improving T lymphocyte activity and modulating the production of key cytokines as IFN? and TNFa. The reported effect may represent a potential benefit for cancer patients undergoing radiotherapy. No significant financial relationships to disclose.
Action of Varespladib (LY-315920), a Phospholipase A2 Inhibitor, on the Enzymatic, Coagulant and Haemorrhagic Activities of Lachesis muta rhombeata (South-American Bushmaster) Venom
