Antibody directed enzymes revive anti-cancer prodrugs concept

Abstract

Within a few years of the beginnings of cancer chemotherapy anticancer prodrugs were being synthesised. A series of azo mustards was designed and produced by Ross and Warwick (1955) at the Chester Beatty Research Institute so that under in vivo conditions the azo link would be cleaved by enzymes and agents with powerful alkylating activity would be produced. Other latent compounds followed with a view to activation by enzyme species thought to be present in greater concentration in certain types of cancer than in normal tissues (Connors, 1978; Carl et al., 1980). Unfortunately, a favourable distribution of activating enzymes was not found in human cancers and the prodrugs did not achieve the selective toxicity that was sought. Yet the approach was not fruitless. Cyclophosphamide was developed as an agent that would be activated enzymatically and although this proved to occur mainly in the liver by the cytochrome P-450 system its place in cancer chemotherapy needs no emphasis. More interesting in the present context was the observation of Connors and others (Connors & Melzack, 1971; Cobb et al., 1969) that one of the compounds produced at the Chester Beatty (2,4-dinitro-5-ethyleneminobenzamide), known as CB 1954, had a profound effect on growth of the Walker rat carcinoma, both in vivo and in culture, whilst it had little or no effect on other cancers. This was surprising since it was a mono-functional alkylating agent which should have been relatively inert and the result implied that the Walker carcinoma cells converted CB 1954 to a potent cytotoxic agent. Thus the principle and potential benefits of drug activation at the site of a cancer was established, although the active product was not known. Recently, Roberts et al. (1986) have shown that CB 1954 is converted in Walker carcinoma cells, presumably by enzymatic action, to a difunctional agent resulting in DNA-DNA interstrand links. Whereas enzymes do not appear to be disposed in a consistent and exploitable fashion in human tumours some of their macromolecules viewed as antigenic determinants have shown a more favourable distribution. Even though tumour specific antigens have proved elusive, some antigens have been found to be present in significantly greater concentrations in tumours than in normal tissues of the host. Such antigens when they are expressed on the cell membrane or secreted into tumour extra-cellular fluid lend themselves to the role of targets for antibodies. Monoclonal antibodies armed with drugs, toxins or radioactive isotopes …