Monday, November 14, 2011

New class of drugs can selectively kill cancer cells

Killing cancer cells without the side-effect of hurting healthy cells is one of the most important features of cancer drugs that are in development. A recent study has yielded surprising results, as a new way of inhibiting a much studied enzyme seems to be very effective in selectively killing cancer cells. The enzyme, dubbed RAF, is involved the cell cycle: a process that regulates growth and proliferation of the cell. This is obviously an interesting feature for cancer cells, that wish to grow and proliferate as fast as possible. A new drug inhibits RAF in an unusual way. But it does so without side-effects, making it a very interesting therapeutic agent.

Instead of blocking the active site of the enzyme, which is common for most enzyme-inhibiting drugs, it changes the entire shape of RAF. Oddly enough, this is enough to selectively inhibit it in cancer cells, eventually leading to cell death. That is because the drug in question, called KG5, affects only cells that are in a state of rapid proliferation. After changing the shape of RAF, it renders it unable to function in the cell cycle. A cell that can not progress in the cell cycle can not proliferate, and if this is not resolved, it will eventually die. Also interesting to note is that by changing the shape of the enzyme, drug resistance of cancer cells could be overcome. All in all, this is of course exactly what we want.

KG5 was tested on cancer cells, human cancer tissue obtained from patients, and in animal studies. All experiments showed that the drug was able to kill the malicious cells. Because of its property of only targeting cells that progress rapidly through the cell cycle with the aid of RAF, the scientists do not expect any toxicity to occur. It works by allowing the active site of the enzyme to stay functional, so it can still perform its normal biological function. Its altered shape does however prevents a certain cellular function that  is predominantly found in tumours, but which is not the enzyme's main activity.

Because of its beneficial effect in cancer, without apparent side-effects, the scientists have created a 100 times stronger version of the KG5 drug, which they hope to use in clinical trials soon. That is when it gets really exciting: to see whether we can actually use it as a novel treatment for cancer. If it works, it is interesting to start research on other enzymes that could have therapeutical benefits by altering its structure, instead of just blocking the active site.

The cell cycle describes the processes that are needed for cell division in chronological fashion. It starts off with the growing phase G1. Then, once the cell managed to pile up enough mass, the cycle progresses to the S phase, which is marked by DNA replication. During that phase all the genetic code that is wrapped onto chromosomes is copied, so that we have an extra set for the daughter cell that is to be created. That step is followed by G2: another growth phase in which the cell passes all sorts of checkpoints that determine whether the cell is ready to replicate itself. If all is well, the M phase follows.
The cell cycle. G0 is added as a rest phase.
The M phase is when the actual creation of a daughter cell takes place, in a process called mitosis. The so-called mitotic spindle is formed, which splits the chromosomes from their copied versions. They are separated and invagination causes two cells to branch off from each other. Each with their own set of DNA, and a complete set of cellular machinery needed to fulfill its functions. KG5 acts on RAF to affect its role in formation of the mitotic spindle.
Chromosome copies are formed, and seperated by the mitotic spindle, giving each daughter cell  a set.

There are several checkpoints devised by the cell that determine whether the cell is allowed to progress to the next phase. Various proteins have a regulatory function in the cell that is able to induce cell cycle arrest. P53 is such a protein, and it plays a very important role in cancer. P53 senses genome instability, after which the cell will be arrested in the cycle. That gives the cell time to repair the damage. If this is not possible, the cell will start a sequence of events that lead to cell death, also governed by P53. This programmed suicide is called apoptosis, and is extremely important in regulating tissue function. It is not surprising that P53, sometimes dubbed the 'guardian of the genome', is often targeted in anti-cancer drugs: if this protein is not functional, then cells with genomic instability are allowed to proliferate, and genomic instability is needed to develop cancer.

No comments:

Post a Comment