Rabbit Liver Protein Provides Clues to Improving Cancer Therapy

St. Jude Children's Research Hospital (ALSAC)
Thursday, 2 May 2002

Study from St. Jude Children's Research Hospital shows protein activates anti-cancer drug CPT-11

(Memphis, Tennessee, May 2, 2002) A rabbit liver protein can effectively activate the promising anti-cancer drug CPT-11, according to scientists at St. Jude Children's Research Hospital. This discovery could lead to more effective treatment for patients using CPT-11, improving therapy of solid-tumor cancers in adults and children.

The research, led by Phil Potter, Ph.D., and Mary Danks, Ph.D., of the St. Jude Department of Molecular Pharmacology, is presented in the May issue of the journal Nature Structural Biology.

The study describes the structure of a rabbit liver protein, called a carboxylesterase, which activates CPT-11 (Camptosar, Irinotecan). Rabbit proteins and human proteins are similar, so the rabbit protein can be used to predict the structure of the human enzymes that might activate the drug.

The St. Jude scientists identified the protein by screening a variety of commercially available proteins, or esterases.

The study marks the first time a mammalian carboxylesterase has been crystallized. When a protein is crystallized, it can be put into an X-ray beam and the actual structure of the protein can be determined. This process allows scientists to understand properties of the protein, including the function of the particular amino acids and how the protein interacts with drugs.

"Essentially, crystallization is a major step forward as compared to guessing these properties by looking at a string of amino acids on a piece of paper," Potter said.

The study's implications are far-reaching for cancer patients.

"Our research may allow us not only to develop new, improved anti-cancer drugs," Potter said, "but we may be able to design specific inhibitors of carboxylesterases, which would allow us to prevent some of the toxicities associated with CPT-11."

CPT-11, which has been approved by the Food and Drug Administration for the treatment of adult colon cancer, is currently in Phase II clinical trials at St. Jude for pediatric solid tumors such as neuroblastoma and rhabdomyosarcoma.

Carboxylesterases metabolize a range of drugs, including cocaine and heroin. Therefore, the St. Jude study might also lead scientists to develop better inhibitors that could be used to treat patients suffering from drug overdoses.

St. Jude Children's Research Hospital, in Memphis, Tennessee, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital's work is supported through funds raised by ALSAC. ALSAC covers all costs not covered by insurance for medical treatment rendered at St. Jude Children's Research Hospital. Families without insurance are never asked to pay.

For more information, or to contact St. Jude Children's Research Hospital (ALSAC), see their website at: www.stjude.org