IN-VITRO STUDIES ON SUBTYPES AND REGULATION OF ACTIVE CELL-DEATH

Active cell death (ACD) comprises several subtypes as indicated by mor phology at light- and electron-microscopical level: for example type I ACD or apoptosis, with nuclear condensation, Fragmentation, cytoplasm ic condensation; type II ACD, nuclear pyknosis, cytoplasmic autophagy. Morphologically different types of cell death are considered to refle ct differences in the underlying biochemical and molecular events even tually leading to cell collapse. However, currently no simple biochemi cal or molecular marker for detection of ACD subtypes is available and , therefore, morphological methods are still required to classify ACD. Sometimes, distinction of ACD from necrosis maybe equivocal. Type I A CD occurs in primary hepatocyte cultures treated with TGF-beta 1 and i n colonic adenoma cell cultures treated with the proteinkinase C inhib itor H7 (1[5-iso-quinolylsulfonyl]-2-methylpiperazine). The anti-survi val activity of TGF-beta 1 was confirmed in vivo as TGF-beta 1 strongl y induced apoptosis in normal tissue and in preneoplastic lesions of r at liver. Type II ACD was observed in human mammary carcinoma cells (M CF-7) after treatment with tamoxifen. The anti-survival activity of H7 and of the anti-oestrogens tamoxifen, 4-hydroxy-tamoxifen, ICI 164384 could be dissociated from their anti-proliferative action. In conclus ion, cell culture studies provide a means to select compounds with hig h anti-survival activity for further exploration in preclinical and cl inical testing. (C) 1997 Elsevier Science Ltd.