Rosmediated Cytotoxicity Of Antitumor Drugs

Involvement of free radicals in the mediation of side effects is well documented in the case of cisplatin and adriamycin and may be implicated in the toxicity of other cytostatics as well. High-dose cisplatin therapy produces untoward side effects of nephrotoxicity, bone marrow toxicity, gastrointestinal toxicity, ototoxicity, and peripheral neuropathy.3132 The mechanism of nephrotoxicity is still not understood completely, but generation of free oxygen radicals by the proximal tubular cells has been proposed as a major pathogenic mechanism.33 Cisplatin treatment resulted in depletion of glutathion (GSH) and protein thiols34 in the kidney. Studies performed on renal cortical slices revealed that depletion of mitochonrial GSH was an early event after cisplatin treatment that was followed by increased lipid peroxidation (measured by the amount of thiobarbituric acid reactive substance) and decreased mitochondrial protein concentration.35 The imbalance of the antioxidant system was partly caused by decreased activity of the antioxidant enzymes, as decreased levels of superoxide dismutase (SOD), catalase, and GSH peroxidase activity (GSH-Px) were detected in vivo in cisplatin-treated kidney.36 The dysfunction of mitochondria caused by oxidative damage may maintain a prolonged increase of oxygen free radical production. The role of oxidative damage in the toxicity of cisplatin was further supported by the observations that buthionine sulfoximine, which causes GSH depletion, potentiated the nephrotoxicity of cisplatin,33 whereas treatment with antioxidants (GSH and ebselen) attenuated cisplatin toxicity. Data suggest that the antioxidant system is involved in the pathomechanism of cisplatin toxicity in other organs, as well.37

The anthracyclin antibiotics, like doxorubicin, have been in clinical use for more than 30 years. The extensive research of the mechanism of action of these drugs revealed several biological activities, but the exact mechanisms of the antitumor and toxic effect are still debated. The widely supported mechanism of anthracyclin activity include intercalation into the DNA, DNA alkylation and cross-linking, interference with DNA unwinding, inhibition of topoisomerase II, and free radical formation.38 The quinone structure allows anthracyclines to accept electrons in reactions mediated by oxidoreductive enzymes including xanthine oxidase, cyto-chrome P-450 reductase, and NADH dehydrogenase. The formed semiquinone is a free radical by itself or after interacting with molecular oxygen,39 and can damage DNA. Doxorubicin is capable of generating free radicals through formation of complexes with iron, as well.40 The well-documented protective effect of the iron-chelating agent ICRF-187 against doxorubicin-induced cardiotoxicity41 clearly implicates this mechanism in the toxicity of this drug.

ROS plays a significant role in the cytotoxicity of bleomycins since bleomycins form a complex with Fe2+ and molecular oxygen, and produce ROS to cleave DNA.4243 In addition, metallo-bleomycins can be activated by NADPH-cytochrome P-450 reductase,44 which results in activated ROS formation in the cells. Bleomycin-induced lung fibrosis is caused by elevated ROS level, and can be moderated by antioxidants.4546 Furthermore, it is also known that mitomycin C and 5-fluorouracil increase ROS levels in different tissues,47 48 which can contribute to their side effects. These data show that several anticancer drugs activate ROS formation both in normal tissues and tumors, and elevated ROS level can cause serious damage in well-oxygenated normal tissues. Since elevated ROS level can cause single-strand DNA breaks, anticancer drug treatment can activate PARP and, therefore, induce NAD+ catabolism, defective energy metabolism, and finally cell death. The PARP activation and PARP-related cell damage can be an important pathway in the development of the cytotoxic side effect of anticancer drugs in vital tissues, raising the possibility of introducing nontoxic PARP inhibitors as protective agents against the toxic side effects of anticancer drugs.

8.4 PROTECTIVE EFFECT OF BGP-15, A NOVEL PARP INHIBITOR, AGAINST ANTITUMOR DRUG-INDUCED CYTOTOXICITY

It is well documented that cisplatin increases ROS formation, single-strand DNA breaks, and activates PARP,49 so PARP activation and PARP-dependent cell damage can be important factors in the cytotoxicity of cisplatin. Since PARP inhibitors significantly decrease ROS-induced cell damage in normal tissue,50-53 it is to be expected that PARP inhibitors may decrease the cisplatin-induced damage of normal tissues. Previously, we found that BGP-15 effectively protected Langendorff perfused heart from ischemia-reperfusion-induced injury and that BGP-15 had low toxicity (LD50 = 1203.4 mg/kg i.p. in rats). Therefore, we investigated whether BGP-15 can decrease the mortality caused by cisplatin treatment in mice. Figure 8.2 shows that cisplatin alone caused 67% mortality while BGP-15 reduced the mortality rate to 40% (Figure 8.2). That is, the PARP inhibitor partially protected the mice from cisplatin toxicity. In addition, we found that combined treatment with BGP-15 caused a faster regain of cisplatin-induced body weight loss in mice (data not shown).

FIGURE 8.2 Effect of BGP-15 on the survival of cisplatin-treated mice. Groups of 15 NMRI

mice were treated for 5 consecutive days with cisplatin (3.8 mg/kg i.p.) alone (---) or in combination with BGP-15 (200 mg/kg p.o.) (----). Body weight changes and survival times were recorded. Chi square = 1.268; df = 1; p = 0.06.

FIGURE 8.2 Effect of BGP-15 on the survival of cisplatin-treated mice. Groups of 15 NMRI

mice were treated for 5 consecutive days with cisplatin (3.8 mg/kg i.p.) alone (---) or in combination with BGP-15 (200 mg/kg p.o.) (----). Body weight changes and survival times were recorded. Chi square = 1.268; df = 1; p = 0.06.

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