Nitric Oxide and Asymmetric Dimethlyarginine Levels in Malignancy Associated Thrombosis and Their Modulaiton by Anticoagulants.

Abstract

Nitric oxide (NO) represents one of the major endothelial derived vasoactive mediators. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase which inhibits NO production at Pathophysiologic levels. While the association of ADMA in cardiovascular diseases is known, no information on the ADMA levels is available in cancer patients. To test the hypothesis that endothelial dysfunction in cancer patients may result in increased ADMA levels, plasma samples were analyzed from an open label, multidose, active comparator designed study in which all patients (n=110) were initially treated with low molecular weight heparin, enoxaparin (E) at 1–1.5 mg/kg sc for 5 days. These patients were further subdivided. One group continued to receive E whereas the other group received warfarin (W) for up to 12 weeks. Baseline blood samples (BL), 5 days post E (IPE) and 4–6 week samples from the E and W were analyzed for ADMA and NO levels (Cardiovasics, Palo Alto, CA; R&D Systems, Minneapolis, MN, respectively). In comparison to the aged matched controls both the ADMA and NO levels were markedly elevated in cancer patients. The E treated group showed a marked decrease in the ADMA levels which persisted throughout the treatment period. However in the W converted group the ADMA levels rebounded to an increased level indicating that E differentially regulated ADMA in these patients. The down regulation pattern of NO was similar for both enoxaparin and warfarin. These results suggest that patients with cancer and thrombosis exhibit simultaneous up regulation of ADMA and NO. While enoxaparin and warfarin show a differential regulation of ADMA both result in down regulation of NO. The fact that E regulates ADMA is highly suggestive of its regulatory role in iNOX which may be involved in the inflammatory response in cancer patients. Furthermore, these studies underscore the anti-inflammatory mechanisms by which low molecular weight heparins such as E, mediate their therapeutic effects in cancer asscoiated thrombosis.GroupNitric Oxide (uM)ADMA (uM)Aged matched controls18±51.51±0.52BL63±185.34±1.5IPE22±92.81±0.94–6 weeks enoxaparin20±82.45±0.94–6 weeks warfarin25±83.67±1.1