Development of the radioimmunoassay in the 1950s and early '60s largely eliminated early problems with human chorionic gonadotropin and permitted the U.K. to offer a national service for gestational trophoblastic disease (GTD) patients. In 1973 a voluntary registration scheme for patients with hydatidiform mole (HM) opened at 3 U.K. locations. The Charing Cross Centre has followed > 35,000 women with HM, and 2,500 have undergone treatment for various forms of GTD. All treated patients are followed indefinitely and the data computerized. Disasters have occurred in 1 country from misinterpretation of erroneous hCG assays. In terms of experience and data collection, the advantages of a specialized service are overwhelming. This society's main thrust should be to ensure that women with GTD in all countries benefit from specialized management.

Antibody-directed enzyme prodrug therapy was conceived as a means of restricting the action of cytotoxic drugs to tumor sites. Since antigenic targets were a central component of the approach, colonic cancer, with its virtually universal expression of carcinoembryonic antigen at the cellular level, presented an obvious starting point. The principle of antibody-directed enzyme prodrug therapy is to use an antibody directed at a tumor-associated antigen to vector an enzyme to tumor sites. The enzyme should be retained at tumor sites after it has cleared from blood and normal tissues. A nontoxic prodrug, a substrate for the enzyme, is then given and, by cleaving an inactivating component from the prodrug, a potent cytotoxic agent is generated. One of the potential advantages of such a system is that a small cytotoxic agent, generated within a tumor site, is much more diffusible than a large antibody molecule. Moreover, failure to express the target antigen by cancer cells does not protect them from the bystander action of the cytotoxic agent. This review will primarily consider the studies of the London group since this is the only group that has so far reported clinical trials and it is only through clinical trials that the requirements of a successful antibody-directed enzyme prodrug therapy system can be identified.

Antibody-directed enzyme prodrug therapy (ADEPT) aims to restrict the cytotoxic action to tumour sites. The obstacles to achieve this were recognised at the outset, but time and experience have given these better definition. The development of fusion proteins has provided the means of making consistent antibody-enzyme constructs on an adequate scale, and glycosylation has provided the means to control the clearance of enzyme from non-tumour sites. Human enzymes have yet to be tested in a clinical setting, and there are pointers indicating that the immunological response to foreign enzymes can be overcome. The relatively small number of purpose-designed prodrugs tested so far leaves this an area ripe for further development. The ongoing iterative process between preclinical and clinical studies is critical to achieving the objective.

Antibody-directed enzyme prodrug therapy has demonstrated feasibility as a treatment for cancer. Numerous prodrug/drug systems have been developed for activation by a variety of enzymes and although many have shown potential in preclinical studies, so far only one system has progressed to the clinic. Clinical studies have identified issues that were not readily apparent in xenograft models, however, these have not been addressed in the development and testing of new prodrugs. The issue of immunogenicity arising from the use of non-human enzymes has also been a major hurdle. The development of recombinant fusion proteins provides reproducible and effective antibody-enzyme products that retain the necessary specificity for prodrug activation. Advances in molecular, structural and systems biology, in combination with bioinformatics, have allowed these molecules to be readily manipulated to provide the desired characteristics.