All PARP inhibitors not created equal in terms of PARP-trapping power

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Recent research findings indicate that poly (ADP-ribose) polymerase (PARP) inhibitors vary from one another in their ability to trap PARP proteins, information that might explain differences in the results of clinical trials using distinct PARP inhibitors.

PARP inhibitors have shown promise in the treatment of women with familial breast and ovarian cancers that are linked to BRCA mutations. “Prior to our study, PARP inhibitors were thought to work primarily by blocking the DNA repair function of members of the PARP family of proteins, leading ultimately to cancer cell death,” explained investigator Yves Pommier, MD, PhD, in a statement issued by the American Association for Cancer Research (AACR). Pommier and colleagues' findings appear in the AACR's Cancer Research journal (2012;72:5588-5599).

Pommier, who is chief of the Laboratory of Molecular Pharmacology at the National Cancer Institute's Center for Cancer Research in Bethesda, Maryland, and his fellow researchers initially found that the PARP inhibitor olaparib was more toxic to cultured cells than genetic elimination of PARP1, indicating that this particular agent must have additional modes of action. Further testing demonstrated that olaparib was trapping PARP1 and PARP2 proteins at sites of DNA damage, and that the trapped PARP protein-DNA complexes were highly toxic to cells.

The trapping ability of olaparib was then compared with that of two other PARP inhibitors under clinical development, niraparib and veliparib. Whereas olaparib was the most potent inhibitor of DNA repair function, followed by veliparib and then niraparib, niraparib led the group in trapping potency, followed by olaparib and then veliparib.

These findings demonstrate that PARP inhibitors do not have equivalent PARP-trapping potency, and suggest that these drugs should be categorized according to their power to trap PARP in addition to their ability to inhibit DNA repair.


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