Molecular brain surgery

By: David Bradley

A set of molecular scissors might one day be used to chop up a type of brain tumour that is a big cancer killer in the young, cutting out the need for expensive and risky surgery if Norwegian research proves successful. Glioma-type tumour cells produce a large amount of a molecule known as PKC-alpha to help them propagate widely. Mouldy Sioud and Dag Sorensen of the Institute of Cancer Research at the Norwegian Radium Hospital in Oslo figured that chopping up PKC-alpha would stop the cancer in its tracks and set about finding something to do the job. They have come up with a synthetic version of ribozyme, a natural molecule involved in cutting and pasting messenger RNAs (mRNAs) that make proteins.

To stop their ribozyme from being chopped up itself by protective enzymes in the brain they simply swapped its natural building blocks for artificial versions that would not stop it working but that would make it unrecognisable to these damaging enzymes.

In their preliminary experiments, which appeared in Nature Biotechnology recently (1998, June, p 556), the molecular 'scissors' were injected into solid human brain tumours that had been transplanted into rats. The rats were injected with the molecular scissors directly into the tumour, and says Sioud this led to the death of almost all the cancer cells in less than three weeks treatment.

Malignant glioma is the third biggest cancer killer in the young and resists current treatments. Julian Downward of the Imperial Cancer Research Fund is not convinced of the ribozyme's potential, however, 'It may well be that in the case of these gliomas, these researchers are managing to inhibit tumour growth with the anti-PKC ribozyme. However, they are directly injecting it into the tumour: these molecules would be very hard to deliver any other way and would not cross the blood-brain barrier,' he explains, 'Perhaps after another decade of basic research it might be getting somewhere,' he adds, 'but I strongly suspect they will be overtaken by other emerging technologies.'

Sioud and Sorensen, however, believe that molecular surgery directed at PKC-alpha and/or other proteins such as the cell survival molecule BcLx1 or to proteins involved in the formation of new blood vessels (angiogenesis) within the tumour will help combat malignant glioma.

Sioud adds that there are many gene products responsible for cancer cell proliferation and that stable ribozymes, such as his, could be used to treat other cancers too. He points out that pancreatic cancer is usually diagnosed too late for surgery, radiotherapy or standard chemotherapy but ribozymes might help reduce tumour size and allow, for instance, surgery to be carried out nevertheless.

TB fixes heart

A compound usually associated with the killer disease tuberculosis could provide a clue to blocking further damage to the heart cardiac arrest survivors.

Professor of medicine and cardiology at the University of Colorado Health Sciences Center, Lawrence Horwitz, studies the effects of heart attack caused by the reconnection of the blood supply to the heart tissue - so-called reperfusion where the influx of oxygen can cause massive tissue damage. A serendipitous conversation at a family gathering with his brother, Marcus a scientist at UCLA's School of Medicine, led to the two thinking about the possibilities of compounds that might reduced the damaging effects of repurfusion.

Marcus studies tuberculosis and was aware of a group of compounds known as the exochelins, which are siderophores used by the TB bug to mop up iron from its environment for nutritional purposes.

The brothers reasoned that this iron-scavenging ability might be useful in preventing further damage during repurfusion. (Proc Natl Acad Sci USA, 1998, 95, 5263).

There have been numerous advances in treating heart attacks themselves so that sufferers have an increasingly good chance of surviving. Angioplasty and clot-busting drugs, for instance, reopen blocked arteries and so cut down on the number of deaths from heart attack. The trouble is that this reperfusion process inadvertently introduces high concentrations of damaging hydroxy radicals (.OH) mediated by iron ions, which causes tissue damage leaving some patients with congestive heart failure. A debilitating condition that would best be avoided.

The two doctors decided to establish a joint study to see whether exochelins might be able to reduce iron levels and so cut down hydroxy radical formation and so reduce damage. Working with UCLA and Colorado colleagues they isolated the exochelins from TB and began testing their effect on reperfusion injury - with positive results.

It seems strange that a compound that helps TB survive could one day become a drug for treating heart attack victims to save them the alleged 60%damage caused by reperfusion. Lawrence Horwitz suspects that similar mechanisms might be controlled in other disorders, such as stroke, where blood supply is temporarily lost to an organ or part of an organ, in that case the brain.

An open and shut viral case

A virus from which the genetic material has been removed has been used for the first time as a molecular container by US researchers for carrying drugs and other small molecules. The discovery offers the possibility of tailoring the viral coat - virion - to provide a highly targeted and very specific drug delivery system allowing a smaller dose to be given and cutting down on side-effects caused by peripheral damage to healthy tissue.

Vaccines are the classic example of producing a useful medical response with a virus and the use of viruses as carriers, or vectors, for gene therapy is currently being investigated in earnest. Now, chemist Trevor Douglas of Temple University and Montana State University plant pathologist Mark Young in research described in the 14th of May issue of Nature, have used a simple plant virus as a nanoscale drug capsule.

Douglas and Young have subverted a pH-dependent reversible gating mechanism of the virion in which swelling produces openings through which viral nucleic acids can be removed and a new payload inserted.

To demonstrate the technique, the researchers used a polyanetholesulphonic acid analogue of heparin - a routine drug for treating coronary thrombosis - and successfully inserted it into the empty husk of a cowpea chlorotic mottle virus. 'Even [in] the smallest "container" we are loading many (tens, hundreds or thousands) of copies of any molecule/drug,' adds Douglas.

Not only has the team successfully subverted a virus function but they can also routinely (but not easily, admits Douglas) go one step further and modify the design of the virion outer surface. This means that the loaded virus can be altered to target certain types of cells (such as cancer cells) and holds the promise of highly targeted drug delivery. (T Douglas and M Young, Nature, 1998, 393, 152).

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