"Camptothecins are FDA-approved cancer drugs that induce replication stress and stop cancer cells dividing, but their clinical antitumor activity is very limited [because of] the relatively rapid emergence of drug resistance, and the mechanisms are poorly understood," said Hunter. "We wondered whether defects in the Chk1 destruction machinery might allow cells to ignore the effects of camptothecin and similar drugs used for chemotherapy."

When Zhang checked cultured cancer cell lines and breast cancer tissue, he found that low levels of Fbx6 predicted high levels of Chk1 and vice versa. But most importantly, he was able to demonstrate that two of the three most camptothecin-resistant cancer cell lines displayed significant defects in camptothecin-induced Chk1 degradation, which seemed to be caused by very low levels of Fbx6 expression.

"Chk1 and Fbx6 clearly play an important role for the regulation of the response to chemotherapy," he says. "One day, they could become an important prognostic marker that predicts patients' responsiveness to drugs such as irinotecan, platinum compounds, and gemcitabine, while Chk1 inhibitors might increase tumor cells' sensitivity to these drugs." Such a combination therapy could overcome clinical resistance or allow doctors to reduce the amount of administered drug, thereby reducing the often debilitating side effects.

SOURCE:  Molecular Cell, August 28, 2009

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