DNA minor groove binding ligands: a new class of anticancer agents

Abstract

This paper gives an overview of the available pharmacological and clinical data of a new class of anticancer drugs which act by binding DNA in the minor groove, comprising cyclopropylpyrrolo-indole (CC-1065) derivatives and Distamycin derivatives. The emphasis of this review is placed on the distinctive mode of action of these drugs. Molecular pharmacology studies indicate that CC-1065 and its derivatives, and the benzoyl mustard derivative of Distamycin, Tallimustine, possess the most striking DNA sequence specificity of alkylation observed to date for an alkylating agent of relatively small molecular weight. The effects on the regulation of gene transcription, the perturbation of the cell cycle, and the mechanism involved in the repair of the DNA lesions induced by these drugs all strongly support the view that minor groove ligands act by a mechanism different from those previously described for other anticancer drugs. The CC-1065 derivatives, Adozelesin and its prodrug, Carzelesin, and Tallimustine were found to be very effective against several murine tumours and human xenografts, and were shown to be active against experimental tumours that were resistant to other antineoplastic agents, including conventional alkylating agents. The clinical studies performed so far do not confirm in humans the remarkable antitumour activity observed in mice. The major reason appears to be a very high susceptibility of human bone marrow to both CC-1065 derivatives and Tallimustine as compared to mouse bone marrow, which makes it impossible to administer these drugs at sufficiently high doses to exert antitumour effects. The search for new minor groove binders, which possess a different DNA sequence specificity of alkylation and which are less cytotoxic for human bone marrow cells, is still in progress. It will be several years before it is possible to draw firm conclusions on the clinical effectiveness of this class of drugs.