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In this introduction I'll try to set the tone for this meeting and raise some issues that I hope we will address over the next few days. I would like to create an inventory of some of the key issues that we should aim to cover during the discussion sessions. Unusually, this meeting is bringing together two scientific fields: the multidrug resistance field from oncology and the epilepsy field from brain biology. The purpose of this meeting is to see whether there are lessons that can be learned from drug resistance in oncology that may have parallels in drug-resistant epilepsy. This reminds me of a favourite story of mine. An eminent professor once set his class a three hour exam, with 300 questions which they had to answer with either 'true' or 'false'. He handed out the paper and told the students to begin. Immediately, one of the students at the back of the class began flipping a coin and marking his answers down. The professor was offended by this affront to intellectual integrity, but he thought, well, this is a drug transporter exam and we don't know what is going on anyway, so this is as good an approach as any. Towards the end of the exam the professor announced that there were 10 minutes left to go. The person at the back was by now flipping the coin very rapidly. The professor said, 'What are you doing now?'. The student replied, 'I'm checking my answers!' Sometimes in our field we create a consistent set of assumptions and paradigms. It may take someone completely outside the field to look in and realize that there is some fatally flawed assumption. Or perhaps it just requires a naive question to bring to light these mistaken assumptions. This is what I hope will happen in this meeting. In bringing the two groups together, I hope we will lay aside our assumptions and try to use logical reasoning and ask each other questions in an intense but non-personal way, thus challenging each of us to examine our own particular paradigm.
I would like to tell you a bit about where I think the history of drug resistance comes in. This is rooted a long time ago in the treatments of microbial diseases. Erlich, the great German physiologist/chemist, was working in the dye industry. He realized that certain chemicals adhered better to different materials than others. He speculated that such chemistry can also be specific for microorganisms. He said that what was needed was a 'chemotherapia specifica': agents that on the one hand are able to kill certain parasites and on the other hand are not going to cause too much harm to the host organism when applied in effective doses. This is a paradigm that has driven both antibiotic development and also the concept of cancer chemotherapy. Many years later Erlich lamented that drug resistance has followed the development of new drugs 'like a faithful shadow'.
I want to give a brief history of the development of P glycoprotein (Pgp) and the mechanism of drug resistance. Drug resistant clones of cells were derived, and these all turned out to be multidrug resistant (MDR). We identified Pgp as a highly over-expressed protein that was the causative mechanism of resistance by cloning the gene, transfecting it into a naive cell and showing that it caused a similar MDR phenotype. We found where it was localized and we purified and characterized it. We looked for expression in human cancers and normal tissues, and looked for correlation of expression and clinical outcome. We modulated Pgp function using different compounds invitro and in clinical studies. For those of you who don't work on molecular biology or cell genetics, I'll describe an old experiment in which a cell line is taken and treated with a chemotherapeutic drug. The few cells that survive form drug resistant clones. As an example, a clone selected for adriamycin could be about 80 times more resistant to adriamycin than the parental cells. Yet the same cells might be 500 times more resistant to an unrelated drug, vinblastine, which they have never seen before, and 2000 times more resistant to vincristine and 6000 times more resistant to gramicidin. At the same time, another cell line selected by the same drug can have a different phenotype: even though it is 50 times more resistant to adriamycin than the parent cell line, it is 5000 times more resistant to colchicine and only six times more resistant to gramicidin. Both these cell lines are MDR cell lines, and are the result of MDR molecules that are related to each other but are different.
One way in which cancer is a little different from epilepsy is that cancer is a progressive disease in which it is believed that clonal selections occur: the original cells divide and evolve into a preneoplastic lesion and then evolve into a localized tumour. This then metastasizes and becomes resistant to anticancerous agents. There is a continuous selection during which time numerous genomic changes occur. Pgp is expressed in normal tissue, but molecules such as Pgp can be modulated by various factors such as drugs, radiation and growth factors. One of the issues is whether something like Pgp when found in tissue is a cause of the non-response, or whether it is be a side effect of differentiation, for example.
Finally, I would like to say something about more recent profiling studies. We have used a quantitative PCR technique with which we have profiled about 40 ABC transporters. These belong to the Pgp family and MDR family. In the mammary gland these ABC transporters are expressed around mid to low levels. TAPj, which is involved in the transport of antigenic peptides, is at a high level. In this discussion, the organ of interest is the brain. Most of the ABC transporters are expressed at fairly high levels in the brain. MDR1 is high, and MRP1 is very high. The challenge for us is to work out which cell types these transporters are expressed in and what role they play.
Another major challenge is to apply effectively the findings from experimental systems into the clinic. From an oncology perspective, we work on cell lines and experimental tumours, and our experimental system is fairly homogeneous: it can be manipulated with a fairly uniform response. Many mechanisms of resistance have been identified at the molecular level and specific probes have been generated. Then the experimental system can be manipulated to confirm studies of everything above that. The other side of the coin is of course the patient. Patients are non-uniform and the tumour cell (or in epilepsy the brain cell) population involved may be quite heterogeneous. There may be a wide range of responses from the cells themselves or from the patients. Functional assays of the tumour cells correlating with the patient responses are often quite variable. Correlation studies involve getting the right people to do clinical studies, which is logistically often very difficult. These are some of the challenges ahead of us.
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