We have shown previously that metastatic prostate and breast cancer cells express functional voltage-gated Na+ channels (VGSCs) which potentiate a variety of cellular behaviours involved in the metastatic cascade (e.g. Grimes et al.,1995; Fraser et al.,2002). Small-cell lung cancer (SCLC) has the most aggressive clinical course of any type of pulmonary tumour, and human SCLC cells also have strong VGSC activity (Blandino et al.,1995). However, the role VGSCs in SCLC is not known. We investigated the possible involvement of VGSC activity in proliferation and endocytosis of H510 human SCLC cells. A colorimetric MTT method was used to quantify proliferation. The possible role VGSC activity was tested using tetrodotoxin (TTX) as a specific blocker. Vesicular uptake of horseradish peroxidase (HRP) was used to quantify endocytosis. Results were compiled as the per cent mean (± SEM) of three repeats of drug versus control readings from individual multi-well plates. Data were analysed by Mann-Whitney U test. VGSC expression in human clinical biopsies was studied by immunohistochemical staining using a commercial pan-VGSC antibody. Treatment with TTX (100 nM) for 24 h caused 57 ± 3 % reduction in proliferation. This effect was highly significant (P≤0.01) and was maintained for 48 h. Increasing the TTX concentration to 1 μM produced no further effect. TTX (100 nM) reduced HRP uptake in H510 cells by 81 ± 5 %, nearly to the level of the negative control (endogenous peroxidase activity). Although both types of cell behaviours appeared to be controlled mainly by TTX-sensitive VGSC(s), the possible involvement of TTX-resistant VGSC(s) and /or non-VGSC control, especially in proliferation, could not be ruled out. Immunohistochemical staining showed that there was little or no VGSC protein expressed in normal human lung biopsies. On the other hand, significant upregulation was seen in SCLC. We conclude the following: 1) VGSC activity can potentiate metastatic cell behaviour (proliferation and endocytosis) in human SCLC cells in vitro, as previously shown for metastatic prostate and breast cancer. (2) VGSC expression is upragulated in human SCLC also in vivo. It is possible, therefore, that VGSC expression activity is a novel target for clinical management of SCLC.