BioWorld International Correspondent

LONDON - There might be a way of making prostate cancer sensitive to a range of chemotherapeutic drugs, researchers believe, thanks to a study at the Weatherall Institute of Molecular Medicine in Oxford, UK, which has identified a method of blocking the growth of prostate cancer cells and makes them vulnerable to cancer drugs to which they previously were resistant.

The team, led by Valentine Macaulay, now wants to find out if that approach can bring about improvement in an animal model of prostate cancer.

Macaulay, senior clinical research fellow at Cancer Research UK, told BioWorld International: "If we can get a similar effect, then I think there will be great interest in using this strategy, either alone or in combination with DNA-damaging cytotoxic drugs, in the clinic. It is possible this could happen within just a couple of years, as work on potential agents is already well advanced."

An account of the study appears in the Oct. 22, 2004, issue of Cancer Gene Therapy in a paper titled "Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer." The work was funded by both Cancer Research UK and the Health Foundation.

Prostate cancer is the most common cancer in men, and the second most common cause of male cancer deaths in the U.S. and the UK. Surgery can cure it if it is confined to the prostate gland, but if it has spread, treatment aimed at blocking the effect of male hormones on the cancer generally is effective for about 18 months. After that, cytotoxic drugs can be given with varying effectiveness.

A key feature of prostate cancer cells is the presence of high levels of the Type I insulin-like growth factor receptor, otherwise known as the IGF receptor. Metabolic pathways switched on by stimulation of that receptor allow the cells to grow in a way specific to cancer cells - known as anchorage-independent growth - and to resist the call to undergo apoptosis.

Macaulay and colleagues examined what would happen to prostate cancer cells in culture if they were to block production of the IGF receptor.

They did that using small interfering RNA, a strategy that takes advantage of the normal machinery that cells use to switch off genes. In that case, it involved introducing into the cells short double-stranded RNA molecules corresponding to the gene that encodes the IGF receptor. Once in the cells, the RNA strands dissociate, and the antisense strand becomes incorporated into an enzyme complex that triggers breakdown of the corresponding messenger RNA.

The team's experiments showed that the treated cells had lower levels of IGF receptor within them, were less likely to survive and more likely to undergo apoptosis. The study also showed that those effects could be induced even in cells that had mutations in genes encoding enzymes that operate downstream of the IGF receptor - a common abnormality in prostate cancer cells.

Macaulay said: "These results allow us to conclude that, even in prostate cancer cells that have a functional abnormality that is common in clinical prostate cancer, there is still potential therapeutic benefit to be had by blocking IGF receptor production by RNA interference."

Further experiments aimed at finding out if blocking the IGF receptor could sensitize the cancer cells to cytotoxic drugs to which they are not normally susceptible. Those showed that blocking the IGF receptor made the cells about twice as sensitive to drugs that work by damaging DNA and to radiotherapy, which also damages DNA. But, to the team's surprise, there was no effect on sensitivity to drugs that operate in other ways.

Macaulay said: "These findings are important for two reasons. First, they tell us that the IGF system is playing an important role in the cellular response to DNA damage. Secondly, this work will help us to choose which drugs will be best to combine with IGF receptor inhibitors in the clinic."