Angewandte Chemie International Edition

Cover image for Vol. 54 Issue 5

Editor: Peter Gölitz, Deputy Editors: Neville Compton, Haymo Ross

Online ISSN: 1521-3773

Associated Title(s): Angewandte Chemie, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemistryOpen, ChemPlusChem, Zeitschrift für Chemie

For full article and contact information, see Angew. Chem. Int. Ed. 2002, 41 (5), 759 - 761

No. 5/2002

Gentle Chemotherapy

Cytotoxin formed from a nontoxic precursor
exclusively in tumors

Chemotherapy is an important weapon in the fight against cancer, but it has a serious disadvantage: it can only scarcely discriminate between a tumor and healthy tissue. This results in substantial side-effects, which limit the doses that can be administered. A new therapy now promises relief. In this technique, the therapeutic agents are produced enzymatically from a nontoxic precursor, a "prodrug", in the immediate vicinity of the tumor.

Chemists and physicians at the University of Göttingen have developed such a prodrug and have proven its effectiveness. The team working with Lutz Tietze drew their initial inspiration from an antibiotic that comes from the fungus streptomyces zelensis. This strong cytotoxin consists of a complex ring-system with a highly reactive three-carbon-atom ring, which attacks nucleic acids and thus inhibits cell growth. The researchers synthesized a substance with a very similar ring system, but without the three-membered ring. To this molecule, they attached a galactose molecule - a sugar. Now here’s the crucial bit: this new compound is nontoxic, but as soon as the sugar is cleaved off by means of the enzyme galactosidase, the ring system rearranges itself, forming a three-carbon ring and transforming itself into a highly effective toxin.

In Göttingen, the researchers tested their prodrug system on mice, into which human tumors had been implanted. The mice are first given the enzyme, galactosidase - but not in its pure form, it is coupled to an antibody. This antibody recognizes human tissue and therefore does not bind to mouse tissue, only to the tumor cells. The prodrug is then injected, and is only converted into a cell-killer when it reaches the immediate vicinity of the glactosidase-spiked tumor cells. This enzyme does not naturally occur in the mouse’s serum, so the prodrug remains harmless in the rest of the mouse’s body. This treatment did indeed cause the tumors to shrink. The researchers did not observe any side-effects.

The Göttingen prodrug system can also be applied in human cancer therapy. The antibody merely has to be replaced by one that can differentiate between healthy and malignant tissue. "Such antibodies are now available for several types of tumors," explains Tietze. "In certain cases our prodrug could even be used without the antibody-enzyme conjugate, because some types of cancer release special sugar-cleaving enzymes in larger amounts."