Anti-Cancer Drug Target Linked to Bone Defects

March 12, 2008

Even brief treatment of young mice with an inhibitor of the Hedgehog cell signaling pathway, a target for anti-cancer drugs, leads to permanent defects in bone development, according to a report in the March issue of Cancer Cell.

WEDNESDAY, March 12 (HealthDay News) -- Even brief treatment of young mice with an inhibitor of the Hedgehog cell signaling pathway, a target for anti-cancer drugs, leads to permanent defects in bone development, according to a report in the March issue of Cancer Cell.

Hiromichi Kimura, Ph.D., from St. Jude Children's Research Hospital in Memphis, Tenn., and colleagues treated young mice genetically engineered with a readout for Hedgehog cell signaling pathway activity by functional imaging with HhAntag, an inhibitor of Smo that is part of the Hedgehog cell signaling pathway.

The researchers found that even brief treatment of 10- to 14-day-old mice with HhAntag for 24 hours inhibited Hedgehog pathway activity that was restored 48 hours after removing the drug. However, HhAntag blocked chondrocyte proliferation and promoted differentiation, leading to expansion of the hypertrophic zone, premature fusion of the growth plate, and inappropriate synthesis of trabecular bone. As a result, HhAntag-treated adult mice had shortened bones and aberrant joint structures.

"These results demonstrate a requirement for uninterrupted Hedgehog pathway signaling during postnatal bone development," Kimura and colleagues conclude. "In addition, our findings raise concerns about the use of Hedgehog pathway inhibitors in pediatric patients, and they point to a broader issue regarding the use of signal transduction inhibitors in children."

Kimura is associated with Takeda Pharmaceuticals.

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