An electron-microscope study of the mode of cell death induced by cancer-chemotherapeutic agents in populations of proliferating normal and neoplastic cells.

Deletion of scattered single cells by ultrastructurally typical apoptosis was observed to take place continuously in the lining of the small intestinal crypts of normal mice, and in untreated Crocker mouse ascites tumours. Injection of the cancer-chemotherapeutic agents actinomycin D, mitomycin C, cytosine arabinoside and cycloheximide massively enhanced the rate of apoptosis in each situation, the morphology of cell death induced by these drugs being fundamentally different from that of coagulative necrosis, which developed without treatment in the centres of solid nodules that grew after subcutaneous inoculation of the tumour. In the crypt lining, where the predominant cell type affected appeared to be epithelial, the apoptotic bodies were either extruded into the lumen or rapidly phagocytosed and degraded by adjacent viable cells. But bodies in the ascites tumour were rarely ingested by uninvolved cells, presumably because of their wide dispersal in a fluid medium, and the stages in their development were seen more clearly than has been possible in solid tissues, where phagocytosis is ususlly rapid: they eventually underwent a change resembling coagulative necrosis or in-vitro autolysis. Reports suggesting that cancer-chemotherapeutic agents enhance autophagy in solid malignant neoplasms require confirmation, for secondary lysosomes of any sort were found to be uncommon in the treated ascites tumours, and there is little doubt that phagocytosed apoptotic bodies have been mistaken for autophagic vacuoles in the past. The significance of the fact that cancer-chemotherapeutic agents induce a type of cell death that is found in normal tissues is at present unknown.