Apoptosis induced by anticancer drugs

Abstract

Most of the cytotoxic anticancer drugs in current use have been shown to induce apoptosis in susceptible cells. The fact that disparate agents, which interact with different targets, induce cell death with some common features (endonucleolytic cleavage of DNA, changes in chromatin condensation) suggests that cytotoxicity is determined by the ability of the cell to engage this so-called 'programmed' cell death. The mechanism of the coupling of a stimulus (drug-target interaction) to a response (cell death) is not known, but modulation of this coupling may affect the outcome of drug treatment. This review surveys the recent evidence which supports the idea that the drug-target interaction per se is not the sole determinant of cellular sensitivity of cytotoxic drugs. Studies of the signals which might engage apoptosis, the genes which modulate it and the biochemical process of drug-induced apoptosis itself are described, where possible, for glucocorticoids, topoisomerase inhibitors, alkylating agents, antimetabolites and antihormones. It is suggested that identification of the gene products which couple the stimulus to the response, and so determine intrinsic cellular sensitivity (and resistance), will be important targets for new types of drugs. These might then allow responses to occur in the major cancers of man, which are chemoresistant.

Oncogenic transformation potentiates apoptosis, S-phase arrest and stress-kinase activation by etoposide

“…This apoptosis development can occur in a p53-dependent (Hermeking and Eick, 1994;Teodoro et al, 1995;Lowe et al, 1994) and in a p53-independent way (Teodoro et al, 1995), and is inhibited by bcl-2 (Bissonnette et al, 1992;Fanidi et al, 1992). Since most cancer drugs can induce apoptosis (Fisher, 1994;Thompson, 1995;Hickman, 1992;Kerr et al, 1994), these results might indicate that oncogenes might function to decrease the threshold for apoptosis in tumor cells (Fisher, 1994). This idea would suggest that one or a set of genes altered during tumor formation would increase the likelihood of apoptosis following drug treatment.…”

Survivin expression in ovarian cancer and its correlation with clinico-pathological, surgical and apoptosis-related parameters

“…A more in depth investigation of the complex physiology of divergent survivin variants is needed in order to clarify the biological and the clinical role of differentially located survivin isoforms. (Hoskins et al, 2000), it is conceivable that the assessment of biochemical factors more strictly related to tumour cell biology and intrinsic aggressiveness could help identifying high-risk patients and facilitating management of this disease.Apoptosis (programmed cell death) has been proposed to play a role not only in cancer onset and progression but also in sustaining decreased tumour cell sensitivity to chemotherapy (Hickman, 1992;Thompson, 1995), which still represents one of the main prognostic indicators in this neoplasia (Hoskins et al, 2000). In this context, the analysis of the molecules possibly involved in the modulation of apoptosis seems to be particularly attractive.…”

“…Apoptosis (programmed cell death) has been proposed to play a role not only in cancer onset and progression but also in sustaining decreased tumour cell sensitivity to chemotherapy (Hickman, 1992;Thompson, 1995), which still represents one of the main prognostic indicators in this neoplasia (Hoskins et al, 2000). In this context, the analysis of the molecules possibly involved in the modulation of apoptosis seems to be particularly attractive.…”

A virus-directed enzyme prodrug therapy (VDEPT) strategy for lung cancer using a CYP2B6/NADPH-cytochrome P450 reductase fusion protein

“…The electrophilic mustard exhibits DNA crosslinking activity that eventually leads to apoptotic cell death. 11,12 In conventional chemotherapy, the active metabolites have to travel to the often distal tumor site to exert their cytotoxic effect. Therefore, high doses of CPA are used (up to 7 g/m 2 ) 8 to ensure that the levels of cytotoxic metabolites are sufficient at the tumor sites.…”