EMBARGOED FOR RELEASE UNTIL 5 P.M. EST, MONDAY, MAY 1 An anti-cancer compound initially slated to enter clinical trials within months could harm a patient, according to a University of Pittsburgh report in the May issue of Nature Medicine. The Pittsburgh scientists found that the compound TNF-related apoptosis-inducing ligand (TRAIL) causes catastrophic damage to human liver cells while proving harmless to liver cells from mice and nonhuman primates used in preclinical testing.
Previous studies of TRAIL have shown that this compound only triggered cancer cell death, and this new drug was slated for use in early treatment studies for many types of cancer, including those of the central nervous system. This is the first study indicating that TRAIL also may kill normal, healthy cells. The TRAIL used in this study was synthesized by researchers at the University of Pittsburgh.
"Our findings with TRAIL indicate that results of standard preclinical tests may mislead investigators into believing that an agent is safe for use in humans," said Stephen Strom, Ph.D., associate professor of pathology at the University of Pittsburgh School of Medicine and senior author of the report. "We've shown that differences in the sensitivity of various species to the same compound can prove critical. Significant toxicity could result if TRAIL were used in human cancer therapy."
The researchers used liver cells (hepatocytes) taken from 20 different individuals and exposed them to concentrations of TRAIL used in prior pre-clinical studies. More than half of these hepatocytes died within 10 hours of exposure. The investigators also exposed cultured mouse and monkey hepatocytes to TRAIL but found that this compound did not trigger cell death, thus confirming results of earlier whole-animal studies. Human liver cancer cells proved sensitive to TRAIL, as initially reported.
TRAIL kills a cell by interrupting its normal life cycle, thereby causing it to commit suicide (also called programmed cell death). Subtle molecular differences among species may regulate the sensitivity of cells to TRAIL, according to Dr. Strom. Human hepatocytes carry specific cell receptors known to initiate TRAIL's killing effects. Dubbed "death receptors", these markers are found on most or all cells. Investigations with TRAIL are relatively recent, and it is not clear when and why TRAIL binding leads to cell death and when there is no biological effect. The reasons for these differences are currently under study in the laboratory.
TRAIL had been considered a promising therapeutic alternative to tumor necrosis factor (TNF), a close molecular cousin prized for its ability to boost anti-cancer immunity but impractical to use in the clinic because it causes septic shock and liver failure.
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Journal
Nature Medicine