Project Details


The goal of this project is to elucidate the mechanism of action of
camptothecin analogs as topoisomerase poisons in upper GI cancer
patients. DNA topoisomerase -1 (topo-1) is a nuclear enzyme essential
for normal DNA replication, transcription, and a host of other cell
functions. This enzyme functions topologically as a swivel by causing
single strand DNA breakage. Topo-1 therefore serves as an attractive
sub-cellular target for cancer chemotherapy. While many active
chemotherapy compounds act through inhibition of topoisomerase II, one
unique compound, camptothecin, and its analogs inhibit topoisomerase-1. Ample preclinical data demonstrate that camptothecin and its analogs
bind to the topoisomerase-1 : DNA complex to form a "cleavable complex."
The cleavable complex stablizes the unwound and broken DNA, converts
topo-1 to a cellular poison, and leads subsequently to disruption of DNA
continuity and cell death. Other preclinical studies have shown the
importance of structure-function relationships for the camptothecin
analogs and their correlation with in vivo activity in cell lines and
human xenografts. We have also demonstrated increased topoisomerase-1
levels in surgical colon cancer specimens, which may serve as a basis
for an improved therapeutic index. Indeed, analogs effective in curing
human-xenograft bearing mice cause only marginal toxicity. Despite this abundant pre-clinicai information, existence of the
cleavable complex in humans has yet to be demonstrated. In this project
we will develop phase II protocols with clinically available
camptothecin analogs for the treatment of patients with upper GI
cancers. We will refine our techniques for determination of topo-1
levels and cleavable complex for application to endoscopic biopsy
specimens. We will investigate the pharmacokinetics of the camptothecin
analog in patients. All patients will have endoscopically accessible
tumors and will undergo biopsy in the course of treatment to determine
the pharmacodynamics of cleavable complex formation. Finally, we will
use appropriate statistical techniques to correlate clinical anti-tumor
response with topo-1 and cleavable complex levels to prove the
hypothesis that increased levels of topo-1 and cleavable complex
underlie activity of the camptothecin analogs.
Effective start/end date9/30/916/30/95


  • National Institutes of Health
  • National Institutes of Health: $208,780.00
  • National Institutes of Health


  • Medicine(all)

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