Then the group screened about 16,000 compounds searching for inhibitors of SK. Four types of compounds were found to be very effective and were more potent than any other previously described SK inhibitors.
"These compounds are anti-proliferative in small concentrations and are effective against tumor cells that have shown resistance to other cancer therapies," Smith said. "Additionally, all of the compounds cause the tumor cells to undergo apoptosis. These effects are consistent with the hypothesized consequence of reducing S1P levels."
It was then necessary to determine if the new SK inhibitors do in fact promote anti-tumor activity in an intact animal. The group synthesized a variant of one of the inhibitors, and tested its effects on tumors growing in mice (following the procedures and protocols approved by the Animal Care and Use Committee of Penn State College of Medicine.) These studies showed that tumors in mice that were treated with the SK inhibitor had between 50 percent and 85 percent less growth than tumors in untreated animals. Importantly, there were no significant differences in the body weights of those animals treated with the SK inhibitor, suggesting that it was not toxic to the animals. Body weight decrease is one of the first ways an investigator might recognize toxicity of a new compound.
"Overall, these studies demonstrate that halting S1P production by targeting sphingosine kinase will stop tumor growth and cause the tumor cells to die," Smith said. "The compounds we have identified show promise for further development, and may lead to new targeted drugs for our arsenal to fight cancer."
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Contact: Valerie Gliem
vgliem@psu.edu
814-865-9481
Penn State
15-Sep-2003