DNA damage, caused by external agents such as UV radiation and smoking, or by oxygen radical byproducts of intracellular metabolism, has serious consequences if left unrepaired. Normally cells employ a host of DNA repair pathways to correct damage, but when these systems fail, a range of disorders may ensue including cancer, premature ageing and infertility. Recent research into DNA repair pathways in humans suggests that these pathways can be successfully targeted by therapeutics used to treat several of these conditions.

According to Professor Steve Jackson, who works on DNA damage and repair systems at the Gurdon Institute in Cambridge: "Most people are aware of the fact that exposure to too much DNA damage can lead to cancer, and for me, research into the DNA damage and repair pathways has more to offer oncology than almost any other field."

Professor Jackson has set up Kudos Pharmaceuticals Limited, a company which has developed several drugs that could potentially revolutionize cancer treatment by exploiting the sensitivity of cancer cells to DNA damage. This sensitivity arises from the rapid division of cancer cells in comparison to normal cells, which leaves little time for DNA repair to take place. Additionally, cancer cells often have impaired DNA repair pathways making them more reliant on remaining functional back up systems that can also repair DNA.

This sensitivity to DNA damage is already exploited widely by radiotherapy and most chemotherapies, which cause double-stranded breaks to form in DNA. Unlike normal cells, tumour cells cannot repair these breaks, so die in response to treatment.

Some drugs specifically target tumour cells with mutations in their DNA repair systems. These drugs were first developed by Professor Leland Hartwell- winner of the 2001 Nobel Prize in Physiology or Medicine-and his colleague Dr Stephen Friend. Using yeast cells that contained genetic mutations characteristic of specific tumours, they set up a drug discovery program to identify drugs and their targets that would have practical applications in the treatment of tumour cells.

Recent research into DNA damage repair pathways has lead to the development of drugs that increase the effectiveness of radiotherapy by further hindering DNA repair systems. Several of these drugs have been developed by Kudos Pharmaceuticals, who recently initiated a phase I clinical trial in patients to establish a safe, tolerable dose of a drug called a PARP-inhibitor. PARP is a DNA damage detection protein. Therefore, inhibiting PARP using a drug renders a major DNA repair pathway non-functional.

"If you treat normal cells with a PARP-inhibitor to knock out this repair system, the cells end up with damage that can only be repaired by one other backup pathway," explains Professor Jackson. This backup pathway involves the action of the BRCA 1 and 2 proteins which are commonly mutated in inherited forms of breast cancer. Whilst a normal cell treated with the PARP-inhibitor can repair the damage using the BRCA pathway, a BRCA-deficient tumour cell cannot repair the damage and the cell dies. In this way, the drug selectively targets BRCA 1 and 2 deficient tumour cells and renders them more susceptible than normal cells to the DNA damage induced by radiotherapy.

Jackson adds that whilst this drug can be used to increase the efficiency of radiotherapy by making the tumour cells less able to cope with DNA damage, researchers are finding that "the PARP inhibitor on its own is killing the cells without any extra damage from radiotherapy- probably because there is a lot of DNA damage going on in cells all the time anyway."

Whilst the PARP-inhibitor can only be used to treat cancers which are BRCA 1 and 2 deficient, Jackson thinks that as we begin to better understand the changes that occur in cancer cells, molecular targeting of tumours will become more useful: "If we can understand the differences between the cancerous and the normal cells, then it is my belief that in the end we should be able to come up with drugs to specifically target every different kind of cancer." The range of diseases potentially affected by impaired DNA damage repair systems is vast, providing a number of potential applications for this area of research. For instance, studies have suggested that inhibition of PARP activity- in addition to helping treat BRCA deficient cancers-could reduce heart damage occurring during a heart attack by up to 40%, and neuronal damage caused by a stroke by 85-90%.The study of DNA repair pathways has much to offer in the world of medicine, and it is expected that this relatively new area of research will yield many effective therapies in the future.

Zoe Smeaton is a third year Natural Scientist specializing in Cell and Developmental Biology