Proliferation, apoptosis, and manganese superoxide dismutase in malignant mesothelioma

Proliferation and apoptotic indices of tumour cells may have important prog nostic significance. Manganese superoxide dismutase (MnSOD), an important a nti-oxidant enzyme, has been shown to decrease proliferation of malignant c ells transfected with the MnSOD gene. The aim of the present study was to i nvestigate the indices of cell proliferation and apoptosis and their progno stic significance in human mesothelioma and to assess the effect of MnSOD o n the proliferation and apoptosis of the mesothelioma cells expressing high constitutive MnSOD activity. Tissue sections from 35 subjects with maligna nt pleural mesothelioma were studied for cell proliferation by Ki-67 immuno histochemistry and for apoptosis by the TUNEL assay. In additional experime nts, 2 mesothelioma cell lines expressing either low (M14K) or high (M38K) MnSOD levels were assessed for proliferative and apoptotic responses to epi rubicin. The median proliferation and apoptotic indices of the mesothelioma tissue were 8.2% and 0.75%, respectively. Patients with a high proliferati on (>8%) or apoptotic index (>0.75%) showed a worse prognosis (p < 0.001). MnSOD expression was inversely correlated with cell proliferation (p = 0.02 ). Our cell line experiments indicated that cells expressing high MnSOD lev els were more resistant to apoptosis and showed lower proliferation when ex posed to epirubicin in vitro. These findings show that high proliferation a nd apoptosis are associated with a poor prognosis of mesothelioma and that a high MnSOD level is associated with low proliferation of tumour cells. Fu rthermore, experiments with cultured mesothelioma cells suggest the importa nce of MnSOD in the proliferation and apoptosis caused by drug exposure. (C ) 2000 Wiley-Liss, Inc.