CANCER NEW DRUG DEVELOPMENT
The first step in the development of new drugs is the identification of suitable compounds for study in human beings. This search at present can take many forms, from a screening of random compounds to the targeted synthesis of drugs to hit pre-specified abnormalities in the cancer cell. The drugs currently used in the clinic come from a range of sources. The initial testing of a candidate drug will involve experiments with cancer cells in the laboratory. These cancer cells come from a variety of sources, ranging from human cancers to artificial tumours generated in laboratory animals. Some of the human cell lines were grown by taking fragments of a surgically removed cancer and placing it in cell culture medium in the laboratory. The process is conceptually attractive – you can test your drug on the ‘real’ cancer.
There are many such cell-lines, possibly the most famous is the HeLa cell line. This was grown from a fragment of cervical cancer taken from a woman called Henrietta Lacks (also sometimes referred to as Helen Lane or Helen Larson in an attempt early on to preserve her privacy), and the cells are very widely used in laboratories around the world. Parenthetically, neither she nor her family gave their consent or permission for this process, resulting in a famous court case in California in 1990 in which it was decided that, in the USA, such a process was lawful. In the UK and other countries, the position is different and informed patient consent for tissue collection is now enforced by legislation. It has been calculated that so many HeLa cells have been cultured that they outnumber many times over the ‘normal’ cells produced by Ms Lacks in her lifetime, giving her a curious form of immortality. The problem with cell lines, however, is that most attempts to grow tumour cells from patients are unsuccessful. Hence the cell lines we have maybe as unrepresentative of typical cancer as HeLa cells are of the person that was Henrietta Lacks. Nonetheless, despite this limitation, human cancer cell lines remain a key component of cancer research and drug testing.
The second form of cell lines used is derived from animal tumours, mostly arising in mice. Many of these tumours are artificially engineered. A good example of this is an engineered cell line used in prostate cancer research. Mice do not get prostate cancer in the way that humans do. However, it is possible to identify genes that are expressed in mouse prostate and to use the promoter regions of those genes to drive the production of proteins that cause cancer. In the case of mice, a gene with the curious name of ‘large-T’ from a cancer-causing virus called SV40 is used. Parenthetically, while many genes have names that are strings of unmemorable letters and numbers (there are 21,000 human genes alone after all – a lot to name), a subset have names varying from the odd (large-T) to the odder (hedgehog, notchless) to downright amusing – a pair of genes involved in cell signalling is called ‘mad’ and ‘Max’!
In order to have mice develop prostate tumours, the hybrid gene containing the prostate-specific gene promoter and the SV40-T gene must be inserted into a fertilized mouse egg. If the insertion is successful, a transgenic mouse results and the growing mice will now express the foreign gene in their prostate glands. As would be predicted, these mice go on to develop multiple prostate tumours. A number of these cancer-prone mice were bred, and the strain is called the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. These mice have proved useful in a number of ways. As the mice reliably develop tumours, they can be used to test cancer- preventing strategies such as dietary interventions. Secondly, the tumours can be used to test drug treatments for effectiveness. Thirdly, tumour cells arising in TRAMP mice have been successfully cultured in the lab and these cell lines can be used for experiments, either alone or re-implanted into adult animals from the same mouse strain – quicker and more reproducible than waiting for the tumours to develop in the TRAMP mice themselves. It is again obvious from the above discussions that such models are only representations of aspects of the human disease, not perfect replications of it. Hence, while useful, drugs must ultimately be tested in humans.