TABLE 1

Summary of the differential effects of the PARP inhibitors, olaparib and veliparib, in combination with temozolomide or camptothecin

TemozolomideCamptothecin
Trapping of PARP-DNA complex++aNoa
PARylation inhibition++b++b
BER inhibition=> TDP1 inactivation
=> Persistent Top1cc
=> Replication fork stalling
Combination indexcOlaparib > > VeliparibVeliparib ≈ Olaparib
  • BER, base excision repair; TDP1, tyrosyl-DNA phosphodiesterase 1; Top1cc, topoisomerase I cleavage complex.

  • a Temozolomide in combination with PARP inhibitors (olaparib > > veliparib) induces the trapping of cytotoxic PARP-DNA complexes, whereas camptothecin does not induce detectable PARP-DNA complexes (see Fig. 3).

  • b The effect of PARylation inhibiton for temozolomide and camptothecin is functionally different (see Discussion), and both olaparib and veliparib effectively inhibit PARylation.

  • c Fa-CI plots (see Fig. 6) revealed that olaparib is more effective than veliparib for temozolomide, whereas veliparib is at least as effective as olaparib.