Endogenous Nitric Oxide Synthesis Inhibitor Asymmetrical Dimethyl-L-Arginine (ADMA) and Neoplasms in Children

Abstract

Abstract Background: Neoplasms in children are uncommon diseases however they have broad impact on the society. Despite novel therapeutic strategies for children suffering from leukemia or solid tumor, the mortality rate of the disease is still high. The endogenous nitric oxide synthesis inhibitor asymmetrical dimethyl-L-arginine (ADMA) is considered to be a strong cardirovascular risk factor and may lead to new therapeutic strategies. Our previous findings indicate that elevated plasma level of ADMA is correlated with worse prognosis in adult patients with NHL. There are no data available pointing at metabolites of NO-pathway nor clinical evidence as prognostic factor of oncological treatment in children. Aim: To investigate the relation between elevated plasma level of NO-pathway metabolites and well established markers of clinical stage of the disease. Material and method: 12 children with acute leukemias (ALL, AML), 13 with solid tumor (PNET, osteosarcoma, Wilms’ tumor, RMS) during hemato-oncological treatment were recruited to a pilot study and N=15 healthy children to a control group. Plasma concentrations of ADMA, SDMA, L-Arg was determined. Relationship to clinical stage of the disease, biochemical and blood markers was tested. Results Table 1: Differences in mean plasma concentrations of arginine, ADMA and SDMA in pts with leukemia vs pts with solid tumor vs control group Control:N=15 Mean ±SD Median ±SEM Leukemia;N=12 Mean±SD Median ±SEM Solid tumour; N=13 Mean±SD Median ±SEM P L-Arg 68,58±24,29 60,19±6,27 31,28±8,63 30,82±2,49 49,59±10,81 49,18±3,00 0,0000 ADMA 0,62±0,10 0,61±0,02 1,17±1,10 0,53±0,32 0,98±1,10 0,46±0,31 NS SDMA 0,44±0,18 0,39±0,04 1,18±1,10 0,80±0,32 1,56±1,02 1,09±0,28 0,0024 ARG/ADMA 112,8±46,28 107,4±11,94 67,40±54,31 69,48±15,68 228,82±451,44 117,35±125,21 NS Table 2:Significant correlations in group of pts with solid tumor and in patients with leukemia LEUKEMIA; N=12 R p ADMA & Ca 0,78 0,008 SDMA & Ca 0,75 0,011 SDMA & CRP −0,78 0,021 Arg/ADMA & K −0,72 0,019 Arg/ADMA & Ca −0,64 0,043 Arg& MONOCYTE 0,65 0,043 ADMA & TOT.BILIRUB. −0,92 0,000 ADMA & TOT.PROTEIN 0,75 0,032 SDMA & EOSINOPHILE 0,73 0,025 SDMA & TOT.BILIRUB −0,82 0,007 Arg/ADMA & TOT.BILIRUB. 0,81 0,009 SOLID TUMOR; N=15 R p Arg &RBC 0,70 0,016 Arg & Hb 0,64 0,035 Arg & LYMPHOCYTE 0,81 0,003 Arg & EOSINOPHILE 0,76 0,011 ADMA &MONOCYTE −0,78 0,008 ADMA & TOT.PROTEIN 0,62 0,040 ADMA & Hb 0,64 0,035 Arg/ADMA &MONOCYTE 0,82 0,004 Arg/ADMA & BASOPHILE 0,65 0,043 Conclusions:A lower plasma level of L-Arg was found both in pts with leukemia and solid tumors. Higher plasma concentration of SDMA was found in patients with leukemia and solid tumor compared to the control group. Further studies are necessary to clarify the significance of these findings.