Papa-NONOate

Bovine pulmonary artery endothehal cells exposed to NO generated by spermine-NONOate and papa-NONOate and to the same fluxes of ONOO" generated by SIN-1 resulted in ceUular injury and death (Gow et al. 1998). Loss of ceUular viability was evident after 18 h postexposure. Events preceding cell death included depolarisation of the mitochondrial membrane, evident as early as 6 h postexposure, loss of ceUular redox activity at 16 h, and DNA fragmentation detected by in situ staining at 18 h after exposure. "NO did not affect the cellular viabihty. 

Chinese hamster V79 lung fibroblast cells pretreated with bolus NO or NO delivered from NONOate NO donors were markedly sensitised to subsequent cisplatin treatment, whereas S-nitrosothiol NO donors exerted little effect (Wink et al. 1997). The enhancement in cisplatin cytotoxicity from pre-treatment with DEA/NO and PAPA/ NO persisted for 180 and 240 min, respectively thereafter cytotoxicity returned to a level consistent with cisplatin treatment alone. 

Early studies examined the cytotoxicity of a range of NONOates (MAMA-NO, PAPA-NO and DETA-NO) against acute nonlymphocytic leukaemia cells (Shami et al. 1998) and chronic lymphocytic leukaemia (B-CCL) cells and compared the ICso of each with their NO release kinetics (Adams et al. 2001). The most cytotoxic (ICso 274 xM) was DETA-NO with a release half-time of 20 h whereas MAMA-NO with a release half-time of 1 min was the least toxic (IC50 1.6 mM). A linear relationship was established between IC50 and the log of the release half-time. 

Wink et al. (1997) NO gas or NONOate/ cisplatin Hamster lung hbroblasts (V79) Clonogenic survival 50-fold reduction in cell survival in NO saturated medium >1000-fold reduction in 1 mM DEA-NO or PAPA-NO ... 

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