Nutlins flip the switch on cancer cells

Newly discovered molecules may prove to be a
major cancer fighter. Score one for New Jersey

By Katherine Addelman

The p53 gene protects the DNA in our cells from damage that can be caused by radiation or carcinogens. When this tumour-suppressing gene is working properly, it detects when DNA has been injured and then stops the cells from dividing. While the cell is in this suspended state, it has time to let its DNA-repairing machinery fix the damage. But if the DNA is too far gone, the p53 triggers an auto-destruct process of apoptosis, or cell suicide, to make sure that the genetic damage isn't passed on to the next generation of cells. This process stops tumours before they start. The p53 gene, which lives on the short arm of chromosome 17, is now a widely accepted marker for malignancies. In fact, non-functioning p53 is implicated in most human cancers.

CELLS BREAKING DOWN
About 50% of p53 breakdowns are the result of simple-point mutations -- a single change or switch of one nucleotide, the building blocks of DNA and RNA. The other half of the time p53 activity gets turned off by an overproduction of inhibitors produced in the cell itself. One of these inhibitors is called MDM2. A team of molecular oncologists led by Lyubomir Vassilev at the Hoffmann-La Roche labs in Nutley, New Jersey, has identified a class of small molecules that can turn fully functional, healthy p53 activity back on. In their enthusiasm, the researchers have called their molecules "Nutlins" in honour of the site of their discovery. Their results were published in the January 2 issue of Science.

The Nutlins get p53 working again by preventing the p53 blocker, MDM2, from binding to the p53 gene. So even if the gene that produces MDM2 becomes overactive, as happens in many cancers, its gene products have nowhere to go and can't do their dirty work. Previously, researchers had discovered other proteins and peptides that block MDM2 binding. But the beauty of the Nutlins is that they are much tinier than previous MDM2 blockers. This means that they can be taken orally and are therefore much more promising for drug development.

MOLECULES GO TO WORK
So far, the Nutlin investigators have tested their first product, Nutlin-1, in cultured tumour cells that had functional p53. The Nutlin actually boosted p53 activity. The result? Cell division stopped and the cells started disintegrating. In another experiment, Nutlin-3 was fed to mice that had transplanted human tumours inside them. The tumour growth in the mice was inhibited by 90%. According to Dr Vassilev, that's "as good or better than established drugs." And to top it off, the researchers couldn't detect any sign of adverse effects in the mice.

David Heimbrook of Hoffmann-La Roche's cancer drug unit cautioned that the work was "still in the very early stages," and warned that it was difficult to say when they would have something suitable for clinical testing. Many sarcoma-type cancers (malignant tumours of the connective tissues including fat, blood vessels, nerves, bones, muscles, deep skin tissues and cartilage) and some lung tumours produce very high levels of MDM2. These would be the most appropriate cancers to test with the Nutlins.