Metabolism of the chloroethylnitrosoureas

Abstract

1. The chemical degradation and metabolism of the 2-chloroethylnitrosoureas (CENUSs) have been critically reviewed with the objective of gaining a better understanding of factors that could aid in the design of new, more effective, anticancer drugs.

2. The CENUs are chemically unstable under normal physiological conditions and can rapidly degrade to give a variety of reactive intermediates capable of carbamoylating proteins and/or alkylating both proteins and DNA.

3. Carbamoylation is thought to make a minimal contribution to the cytotoxic effect of the CENUs, although it may be involved in some of the unwanted side-effects. It would seem desirable, therefore, to design new CENUs with low carbamoylating activity.

4. The main action of the CENUs is by alkylation of DNA via a chloroethyldiazo-hydroxide intermediate. Chloroethylation is important, as opposed to hydroxyethylation, since the former leads to inter-strand DNA cross-linking via an intramolecular rearrangement with the removal of chloride. It is this inter-strand cross-linking which prevents subsequent DNA repair and loss of cytotoxicity.

5. Metabolism usually, although not exclusively, leads to deactivation of the CENUs either by dechlorination or denitrosation of the molecule, generally with the former being the dominant route. These reactions occur very rapidly, and before chemical degradation can take place, and can be an important determinant in the final cytotoxicity. Moreover, both these pathways involve the cytochrome P-450 system and can be induced with phenobarbital.

6. Denitrosation is also thought to involve isozymes of glutathione transferase which, because of the genetic polymorphism, may be an additional determinant in tumour resistance to CENUs, especially as this group of enzymes are also involved in the removal of the alkylating intermediates responsible for the cytotoxicity.