The effects of anticancer drugs on levels of nitric oxide and adrenomedullin

Nephrotoxicity is one of the most important complications of anticancer treatment. Ifosfamide, platinum and methotrexate (MTX) affect renal tubular epithelial cells. Nitric oxide (NO) serves many functions within the kidney. Adrenomedullin (AM) is a potent vasodilator peptide, and may function as a circulating hormone and an autocrine/paracrine mediator involved in the regulation of the cardiovascular system, blood pressure, and renal function. It also has a renoprotective effect and inhibits the generation of reactive oxygen metabolites. To our knowledge, no studies have investigated the effects of anticancer drugs on levels of AM and NO. We investigated the effects of these drugs on the levels of AM and total nitrite, a stable product of NO, and their relations to renal functions. The study was performed in 18 patients (13 males, 5 females) who received chemotherapeutic regimens including high-dose MTX or ifosfamide and platinum. Total nitrite was quantitated by means of the Griess reaction, while AM level was measured by high performance liquid chromatography (HPLC). Plasma total nitrite level (micromol/L) was decreased after chemotherapy (78.73 +/- 47.28 vs. 46.69 +/- 13.89, p: 0.002). A statistically significant difference was found between fractional excretion (FE) of total nitric oxide (FE(NO)) before and after chemotherapy (25.89 +/- 23.11 vs. 51.74 +/- 40.01, p: 0.008). The differences in plasma AM levels (pmol/ml) before (25.07 +/- 4.98) and after (30.20 +/- 1.39) chemotherapy were also statistically significant (p: 0.005). FE(AM) after chemotherapy (1.41 +/- 1.01) was found to be higher than before chemotherapy (0.64 +/- 0.43) (p: 0.000). Our results indicate that some chemotherapeutic agents (high-dose MTX, ifosfamide, and cisplatinium) may cause renal tubular damage. FE(AM) and FE(NO) may also be used for the detection of subclinical acute tubular nephrotoxicity. However, further detailed researches will be necessary to establish the certain role of NO and AM in toxicities of chemotherapeutic agents.