The nature of cytotoxic drug-induced cell death in murine intestinal crypts.

Tv Anilkumar,T Hunt,Mr Alison,Ce Sarraf

doi:10.1038/bjc.1992.113

Abstract

The nature of cell death in murine small intestinal crypts caused by potentially lethal doses of four classes of cancer chemotherapeutic agents was studied. The drugs used were cytosine arabinoside, vincristine, adriamycin and nitrogen mustard. The compounds readily induced massive cell death in the proliferating compartment of the crypt. In each case, cell death was apparent within an hour, and the incidence of dead cells peaked during the following 4-8 h. By 24 h, little damage was discernible in the crypt systems. Remarkably, dead cells or dead cell fragments were phagocytosed rapidly (within about 1 h) by neighbouring healthy enterocytes. When examined by light microscopy, transmission electron microscopy and scanning electron microscopy, the dead cells showed the characteristic features of having succumbed to an apoptotic mode of cell death without any trace of cell and organelle oedema characteristic of necrosis. The study suggests that cell death by apoptosis operates even when the cells are exposed to severe pathological perturbation and that the phenomenon is not solely a process which operates in response to either physiological stimuli or to mild physical or chemical trauma.

Highlights

It was not considered necessary to kill more than one mouse at each time point, since statistical correlations between dosage and the incidence of cell death have already been described (Ijiri & Potten, 1983; 1987), and the major aim of the present study was to elucidate the manner of death, whether necrosis or apoptosis
Cell death through the apoptotic process is considered as a physiological or near physiological response controlled by extrinsic and intrinsic mechanisms (Wyllie, 1981; Kerr et al, 1987), yet in the present study apoptosis brought about the massive destruction of cells in a renewing system with potentially lethal implications for the host animal
Activation of a non lysosomal endonuclease enzyme is considered as the key event in precipitating apoptosis (Arends et al, 1990), and recent observations indicate that many genes may play a part in regulating the process, some of which have a 'protective' effect in preventing premature apoptosis (Buttyan et al, 1988; Buttyan et al, 1989; Debatin et al, 1990; Hockenbery et al, 1990; Williams et al, 1990; Gregory et al, 1991; Williams, 1991; Yonish-Rouach et al, 1991)

Summary

Objectives

It was not considered necessary to kill more than one mouse at each time point, since statistical correlations between dosage and the incidence of cell death have already been described (Ijiri & Potten, 1983; 1987), and the major aim of the present study was to elucidate the manner of death, whether necrosis or apoptosis

Methods

Results

Discussion

Conclusion