DNA topoisomerases in therapy--tenth conference. 6-8 October 1999, Amsterdam, The Netherlands

The meeting covered basic research on DNA topoisomerases and aspects of DNA topoisomerase-directed therapy, which will be the main topic of this report. In terms of cancer therapy, the focus of the meeting was clearly on camptothecins (CPTs) and related compounds, that stabilize covalent DNA intermediates of topoisomerase I. Results were presented showing that these drugs might act in a tumor-specific manner because tumor cells have defects in degradation pathways of DNA-linked topoisomerase I. On the other hand, a DNA-tyrosine phosphodiesterase has been discovered, which removes topoisomerase I from its covalent DNA-linkage and thus might be a new mechanism of drug resistance. Reports on recent clinical trials of first-generation water soluble CPT analogs (topotecan; SmithKline Beecham, and irinotecan; Yakult Honsha KK), confirmed earlier findings that these drugs have major limitations due to the half-life of the active lactone form and other pharmacokinetic factors, resulting in a major schedule dependency of the toxicity. Solutions to that problem will possibly come from an oral application regimen or liposomal packaging of the drugs. Several new CPT analogs at preclinical stages of development might also improve on these problems by providing a greater stability of the lactone ring, higher DNA-binding affinity, and reduced water solubility. New drugs might be developed from a number of new non-CPT compounds, which inhibit the activity of DNA topoisomerases, but do not stabilize the DNA-linked form of the enzymes. Some of these compounds display reasonable preclinical anticancer activity. A second focus of the meeting was on therapeutic targeting of microbial DNA topoisomerases. On the one hand, the antibiotic potential of the quinolones has been extended to Gram-positive pathogens, particularly Streptococcus pneumoniae. On the other hand, cloning and biochemical characterization of the DNA topoisomerases of eukaryotic parasites, such as Plasmodium falciparum or Candida albicans, have been completed and the search for specific inhibitors targeting these enzymes are under way.