ABSTRACT
Nitric oxide [NO] could be pro or anti-apoptotic depending on cell type and caspase-3 activity. We aimed at studying the effect of antimetabolite chemotherapy on the enzymatic activity of nitric oxide synthase [NOS], caspase-3 and iron regulatory protein-1 [IRP-1] in 20 newly diagnosed acute myeloid leukemia [AML] patients and 10 hepatitis C virus infected hepatocellular carcinoma [HCC] patients since they have varied sensitivity to NO. AML patients received 7+3 regimen [combination of cytosine arabinoside [ara-C] and doxorubicin [DOX] and HCC patients received 5-fluorouracil [5-FU] 500 mg/m2 for 5 days every 3 weeks. All patients were followed up for 6 months to assess their response to therapy. The effect of adding S-nitroso-N-acetyl-penicillamine [SNAP], an NO donor, to chemotherapy on malignant cell survival of mononuclear cells [MNC] from AML patients [NO sensitive] and hepatocytes [NO resistant] from HCC patients was studied in vitro. Ten AML patients in remission and 10 patients having chronic hepatitis C [CHC] of matched age and sex served as controls for AML and HCC patients respectively. Results showed a significant decrease in plasma NOS activity in AML than HCC cases. Also, the MNC and hepatocytes were significantly different in cell aconitase activity, iron content and caspase-3 activity. Significantly higher NOS activity at diagnosis in chemosensitive AML patients compared to chemoresistant patients was also shown. Better chemotherapy response has been associated with significant decline in plasma NOS. MNC aconitase activity and iron content and rise of cellular caspase-3 activity compared to their levels at diagnosis. The HCC cells had significantly higher cellular iron content than chronic hepatitis-C infected cells. The former cells were resistant to 5-FU in vivo and in vitro. In vitro 6-h incubation of MNC with ara-C/ DOX/SNAP -combination was associated with lower percent cell surival, higher caspase-3 activity than cells incubated with ara-C or SNAP/ara-C. Conversely, HCC was insignificantly affected by incubation with 5-FU alone or with SNAP. The cytosolic aconitase activity was significantly inhibited in MNC and HCC following incubation with SNAP alone or with chemotherapy compared to corresponding cells in medium. A decline in intracellular iron was a feature that accompanied sensitivity to chemotherapy in AML cells in vivo and in vitro. This denotes that the interplay between NO level, caspase-3 activity and IRP-1 level largely determines antimetabolite chemosensitivity in different cells. NO donor may have a role in increasing chemosensitivity in AML while its value appears limited in HCC
ABSTRACT
The effect of varying concentrations of the histamine H2-receptor antagonists; nizatidine, ranitidine and famotidine on neuromuscular transmission was examined using isolated toad rectus abdominis muscle. Also, the possible interaction between the H2- receptor antagonists and the non-depolarizing neuromuscular blocker D-tubocurarine was investigated. Isolated total toad rectus abdominis muscle preparations were exposed to increasing concentrations of acetylcholine [Ach] to obtain full concentration- response curves, then the effects of two concentrations of nizatidine, ranitidine and famotidine, on the contractile effect of Ach was examined. Also, the effect of D-tubocurarine on the contractile effects of Ach in the absence and in the presence of chosen concentrations of the H2-receptor antagonists was examined. Nizatidine and ranitidine at low concentrations augmented and at higher ones inhibited the Ach-induced contractions of the toad rectus abdominis, while famotidine at the two concentrations used lack a significant effect on the contractile effect of Ach. In addition, nizatidine and ranitidine at a low concentration antagonized the D-tubocurarine blocking activity on the Ach induced contractions, but at high concentration they augmented D-tubocurarine's effect. In contrast famotidine did not alter the inhibitory effects of D-tubocurarine on Ach-induced contractile response
Conclusion: The present study suggests that nizatidine and ranitidine probably possess either anticholinesterase-like effect or neuromuscular blocking effect, depending on their concentration. Confirming this, low concentrations of these H2 antagonists antagonized the neuromuscular blocking activity of D-tubocurarine while their high concentrations potentiated the effect of D-tubocurarine. In contrast famotidine did not alter the contractile effect of Ach or the D-tubocurarine neuromuscular blocking activity. This would suggest that nizatidine and ranitidine should be used with caution for premedication purpose, anticipating clinically relevant drug interactions with neuromuscular blockers while famotidine, could be considered safer in premedication. Yet, further clinical studies are needed