CPT-11, which has recently been approved for use against colon cancer, is really a prodrug; meaning it must undergo a change in the body to work. The active drug molecule is packaged in a longer molecule that helps keep the drug stable when injected. Inside the body, a naturally occurring enzyme interacts with the prodrug, snipping off a part of the molecule to release a potent anti-cancer treatment.
The side effects, which include nausea, vomiting and diarrhea, seemed similar to those experienced by some users of Alzheimer's drugs; leading scientists to suspect that a second enzyme with a similar structure that is targeted by the Alzheimer's treatment might be involved. Weizmann Institute scientists Prof. Joel Sussman and Dr. Michal Harel of the Structural Biology Department and Prof. Israel Silman of the Neurobiology Department have been studying this enzyme, acetylcholinesterase (AChE), and its mode of operation for many years, and decided to work with the Dr. Phil Potter and his team of St. Jude researchers to find out how it comes into play during cancer therapy.
The scientists soaked crystals of AChE with a solution of CPT-11, obtaining crystals of the complex of the two. Bouncing powerful X-rays off the protein crystals yielded a three-dimensional image of the dual protein structure, showing them exactly how the prodrug and the enzyme interact.
Comparing the structure of the CPT-11/AChE complex with computer-generated models of the enzymes that convert the drug, they found the cause of the problem to be a physical misfit
Contact: Alex Smith
American Committee for the Weizmann Institute of Science