|
|
|
|
|
|
|
This is the most scientifically pleasing method of discovering a new anticancer agent. The process is dependent on the ability of biologists to define the nature of the molecular and biochemical changes that initiate and maintain the malignant cell phenotype. Using this knowledge, medicinal chemists and pharmacologists synthesise and screen molecules that may inhibit the phenotype. |
|
|
|
|
|
|
|
|
This so-called designer chemotherapy is in its infancy, but many such compounds are in early clinical stages of development. The developments in this area have been greatly facilitated by the adoption of semiautomated robotic technology to allow rapid activity screening of lead compounds, and hence the development of structure-function models. Examples are inhibition of protein kinase C, tyrosine kinase inhibitors, and various inhibitors of the phospholipase signaling cascade. It remains to be seen whether this will yield more or better drugs than any of the other methods of drug acquisition. |
|
|
|
|
|
|
|
|
III. Animal Toxicology as Applied to Anticancer Drugs |
|
|
|
|
|
|
|
|
In contrast to other areas in medicine, most cytotoxic agents are by their very nature highly toxic substances. The potential for genotoxicity of an agent specifically designed to damage DNA is self-evident. In most clinical situations this is of no consequence, since we are attempting to palliate an incurable and lethal illness. However, in those tumors that are amenable to cure by cytotoxic therapy there is a substantial problem of induction of second malignancies, particularly leukaemia. |
|
|
|
|
|
|
|
|
In high doses most current cytotoxics will be lethal in animal models due to bone marrow suppression, mucositis, cardiac or pulmonary toxicity. At present animal toxicology is only a very rough guide to the types of toxicity one might see in humans. This information is then used to build (what is hoped to be) appropriate screening in patients enrolled within the Phase I trials (e.g., cardiotoxicity in animals will lead to ECG or more intensive cardiac monitoring). |
|
|
|
|
|
|
|
|
The major use of animal toxicology in oncology is to guide a safe starting dose for human Phase I trials. This subject has been extensively reviewed [6]. In the experience of the NCI-USA for the majority of compounds one tenth of the mouse LD10 was a safe starting dose (when expressed on a mg/m2 basis). In Europe it is now common practice to confirm this in rats or another species to avoid undue toxicity at the starting dose. |
|
|
|
|
|
|
|
|
The only other elaboration on this simple theme is the introduction of compound-oriented toxicity testing. In principle, this involves animal testing using a route and schedule that is intended for clinical use rather than the more |
|
|
|
|
|