Cancer drug targeting

Abstract

'Now, if we were to succeed in discovering amongst these (chemoceptors) a receptor which was not represented in the organs of the host, we would have the possibility of constructing an ideal medicament by selecting a haptophore group that fits exclusively this particular receptor of the parasite. A medicament provided with such a haptophore group would be entirely innocuous, because it is not anchored by the organs; it would however strike the parasites with full force and, in this sense, correspond to the invasive substances, the antibodies discovered by Behring, which in the manner of magic bullets, seek out the enemy. Let us hope that it will be possible, chemotherapeutically, to score bull's eyes in this way' (Ehrlich, 1913). Paul Ehrlich's famous vision has been turned into reality in the case of many microbiological infections and this is as much a cause for satisfaction as our failure to achieve it in the case of cancer is a cause for renewed effort. The idea has not been neglected in the cancer field but much talk without fruition is an invitation for boredom to set in. Even Paul Ehrlich probably realised that the analogy was, however evocative, far-fetched because a 'magic bullet' molecule, in the sense of seeking out its target, would require to be equipped with the equivalents of both radar and jet propulsion: a tall order even for today's ingenious molecular engineers. The ballistic terminology lives on, however, in the concepts of targets, carrier vehicles and warheads. So we may ask whether the whole idea is not faintly potty. But before coming to any damning conclusions we should consider what we ask of conventional pharmacological agents. Perhaps our approach to the development of drugs has been coloured by the seemingly exquisite specificity of drugs such as digitalis. When this alkaloid is absorbed it is presumably delivered to all body cells more or less uniformly and it has only a trival effect at therapeutic concentrations on most of them but a profound effect on those of the myocardium. It is, thus, cellular differentiation, that is the phenotypic expression of certain parts of the genome, which confers the specificity associated with digitalis. If the process of malignant transformation Were to confer on cells properties as unique as those of the myocardium and its conducting system, then more effective anticancer drugs might already have been identified. We expect a lot from anticancer drugs. Like digitalis, they must leave the vascular compartment by crossing endothelial cell membranes into extracellular space and gain entry into cells to perform their pharmacological action. This should be negligible in the generality of cells but lethal to those expressing the phenotypic characteristics of cancer, whatever the tissue differentiation of the cancer cell. What is remarkable is that we do have a