Taxol, cisplatin, and carboplatin are the most frequently used anticancer drugs, and are highly effective against different types of cancer. However, high-dose carboplatin, cisplatin, or taxol therapy is often accompained by serious side effects affecting the kidney, bone marrow, and peripheral neurons, and this may force termination of the treatment or dose reduction. The exact mechanism of carboplatin, cisplatin, and taxol toxicity is not completely clear. In the case of cisplatin, generation of reactive oxygen species (ROS)1,2 can be involved. Most recently, it has also been indicated that taxol may induce mitochondrial permeability transition of ROS production.3 Therefore, poly(ADP-ribose) polymerase (PARP) inhibitors that protect the cell from oxidative damages can be useful to decrease the toxicity of these drugs. The protective effect of free radical scavangers and antioxidants in cisplatin toxicity supports the central role of oxidative damage in the pathomechanism of disease.4 The mitochondria are a significant source of endogenous free radicals as a consequence of cisplatin and taxol treatment.3,5 It is well documented that ROS induce singlestrand DNA breaks, which, in turn, activate nuclear PARP (EC 126.96.36.199), and activation of PARP has been observed in cisplatin-treated cells.6 Excessive activation of PARP depletes its substrate, NAD+, and subsequently ATP, which eventually leads to cell death.7 PARP inhibitors can prevent overactivation of the enzyme, and also have a protective effect on mitochondria.8,9 They can reduce the mitochondrial ROS production, 8 and, therefore, moderate the subsequent energy crisis thereby saving the cell. Indeed, beneficial effects of PARP inhibition have been documented in various diseases where oxidative damage plays an important role in the pathomechanism.
|Title of host publication||PARP as a Therapeutic Target|
|Number of pages||15|
|ISBN (Print)||0849300738, 9780849300738|
|Publication status||Published - Jan 1 2002|
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Biochemistry, Genetics and Molecular Biology(all)