Magic bullet homes in
New candidate cancer drug does damage only in tumours.
A new drug turns lethal only when it reaches cancer cells. In healthy cells it is harmless. Though not yet shown to work in humans, it is a step towards a magic bullet to knock out tumour cells selectively, with minimal side effects.
The drug works in mice implanted with human tumours, say chemists Lutz Tietze and colleagues at the University of Gottingen in Germany. Before being treated with the drug, the mice are given an enzyme to activate it that sticks only to the human tumour cells, ignoring healthy mouse cells. So the drug is safe until the enzyme activates it in the tumour. Then it destroys the cancerous cells1.
The researchers report that the tumours shrank without inducing any visible side effects in the mice. They think that the same principles could be used in people. The activating enzyme could be tailored to latch onto malignant tissues and bypass normal human cells.
“We are now in contact with the pharmaceutical industry, and will start clinical tests”, says Tietze.
Most existing chemotherapy is toxic to normal cells as well as cancerous ones. This causes severe side effects, such as a depressed immune system. Cancer researchers long for a magic bullet: a drug that works only where it is needed.
The warhead of the Gottingen antitumour molecule is a ring of three carbon atoms. This ring is highly strained and apt to burst open. Open, it is a reactive molecule that wreaks havoc among the nucleic acid molecules essential for normal cell function. The chemists copied this trick from a highly toxic antibiotic produced by a fungus.
So that their molecular bomb does not detonate everywhere in the body, the team have made a ’prodrug’. This is like the natural antibiotic but without the strained ring and with a sugar safety-catch. Once the sugar is clipped off, the molecule rearranges itself into a three-atom ring, and proceeds to do its toxic business.
Tietze’s team uses an enzyme to cut away the sugar safety-catch. An antibody on the enzyme acts as a tumour-specific hook. Such antibodies linked to toxic or radioactive molecules have long been explored for making magic-bullet drugs; none has yet found clinical use.
The advantage of this enzyme-activated approach, originally developed in the 1980s, is that the drug isn’t even activated until it reaches the target site. The selectivity of the damage still depends on antibody’s ability to hook onto the right cells, and on the absence of other enzymes in the body that also activate the prodrug.
Whether the idea will work cleanly enough in humans remains to be seen.
- Tietze, L. F. et al. Proof of principle in the selective treatment of cancer by antibody-directed enzyme prodrug therapy: the development of a highly potent prodrug. Angewandte Chemie International Edition, 41, 759 – 761, (2002).
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