A new approach to testing whether a particular chemotherapy agent is working well in treating a patient's cancer is being developed by UK scientists. The team led by researchers at the University of Dundee, Scotland, is focusing on the by-products of programmed cell death, or apoptosis, which appears in the blood when an anticancer drug is effectively killing tumor cells.

By designing a mathematical model of the dynamics of formation of these cell death byproducts in blood, Fordyce Davidson and colleagues hope to produce a new diagnostic tool that will provide a quick and easy test of whether a drug is working. Such a test would be more on a par with taking a patient's blood pressure or checking their cholesterol to see whether a drug is working, rather than the current cancer tests, which have to wait crucial months to see whether tumors are shrinking and symptoms subsiding.

All disease processes and all drug effects, leave a "fingerprint" in the complex pattern of proteins in the patient's blood, explains Davidson. This fingerprint can be detected in the blood using sophisticated analytical techniques such as SELDI-TOF (surface-enhanced laser desorption ionization time-of-flight) mass spectrometry.

The dynamics of the interactions between drugs and cancer cells and the release of biomarkers are very complex and a quantitative understanding of these interactions is not available at present. This is precisely where new mathematical models will help. The Dundee team is working closely with pharmaceutical company Cyclacel, Ltd., to develop a new mathematical model of the link between anticancer drugs; such as Cyclacel's experimental anticancer drug, Seliciclib. This cell-death process and the by-product fingerprints in the blood he models of the cell cycle, cell-death chemical pathways, and the by-product biomarkers will have broad implications for developing anticancer agents. Longer-term benefits for drug manufacturers and ultimately cancer patients, particularly those suffering from lymphoid malignancies and lung carcinomas, will emerge from this research.

The team is specifically looking at combining new mathematical models with experimental data to help them understand the BAX-protein-driven apoptotic pathway in mammalian cells, how this is regulated by MCL-1 and surviving in normal cells, and how this regulation mechanism is disrupted in cancerous cells. Cyc202 is one of a new class of transcriptional inhibitors that interferes with the cell-cycle and the BAX-driven apoptotic pathway.

"I anticipate that given the advanced stage of the development of cyc202, that no changes will be made to its formulation [as a result of this work]," Davidson says, "However, it may be a longer term outcome of the project that we find that drugs which leave a definite and measurable signature are the better way to go. It may be possible to design these into the formulation." Drug design may be the next stage of the research, analogous to adding fluorescent markers so that chemistry can be followed more readily. However, this is pure speculation and Davidson points out that, "It is drug efficacy that we are trying to measure, not just drug concentration in the blood stream—this is where the problem lies."

http://www.maths.dundee.ac.uk/~fdavidso/

http://www.cyclacel.com/home.htm