Cell killing mechanisms

Enediynes hold substantial promise as anti cancer drugs because of their potency and selectivity Not only do they inhibit cell growth they have a greater tendency to kill cancer cells than they do normal cells The mechanism by which enediynes act involves novel chemistry unique to the C C—C=C—C C unit which leads to a species that cleaves DNA and halts tumor growth... 

Host cells are killed by cytotoxic T-ceUs or natural kiUer cells by the processes of necrosis or apoptosis. Necrosis leads to release of cell contents that can sufficiently disturb the tissue to initiate a local inflammatory response. However, the cell killed by apoptosis is then phagocytosed, which does not cause local disturbance, so that inflammation does not occur (Chapter 20). Apoptosis is achieved by two mechanisms release of toxic granules by the cytotoxic cells or by the binding of the cytotoxic ceU to the host ceU, via its death receptor protein (see below). 

In rat liver tissue, p-cresol was 5- to 10-fold more toxic than the o- or -isomers as determined by the degree of cell killing. Furthermore, the toxicity ofp-cresol was dependent on the formation of a reactive intermediate, and it was suggested that the mechanism of toxicity for p-cresol may differ from that of the o- and 7 -isomers. 

Drugs that act by different mechanisms may have additive or synergistic therapeutic effects. Tumors may contain heterogeneous clones of cells that differ in their susceptibility to drugs. Combination therapy will thus increase log cell kill and diminish the probability of emergence of resistant clones of tumor cells. 

Cladribine (Leustatin) is a synthetic purine nucleoside that is converted to an active cytotoxic metabolite by the enzyme deoxycytidine kinase. Like the other purine antimetabolites, it is relatively selective for both normal and malignant lymphoid cells and kills resting as well as dividing cells by mechanisms that are not completely understood. 

Initially these hypotheses directed almost all attention to platinum-DNA interactions in the studies concerning the working mechanism of cis-Pt. However, it cannot be excluded that other cis-Pt-induced processes at the cellular level might attribute to the ultimate cell killing. In this respect the natural immune response should be mentioned. It appears, however, that an ever-increasing amount of research is focused on the interactions of platinum compounds with DNA. 

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