Department of Molecular Biophysics, University of Lodz, Lodz, Poland.
J Physiol Pharmacol. 2012 Apr;63(2):153-63.
Combination of doxorubicin (DOX) and docetaxel (DTX) is clinically effective against many drug-refractory cancers, nevertheless, enhanced side effects, e.g. cardiotoxicity related to oxidative damage of tissue macromolecules is observed. Nitroxides represent an attractive class of synthetic compounds to ameliorate DOX-DTX toxicity in non-targeted tissues due to their antioxidant and iron-oxidizing properties. The aim of the study was to define the ability of 3-carbamoylpyrroline nitroxyl derivative pirolin (PL) to mitigate oxidative damage to blood plasma proteins and lipids induced by DOX-DTX chemotherapy in Sprague-Dawley rats bearing DMBA-induced mammary tumor. Additionally we also evaluated: i) pro-oxidant and antioxidant activity of pirolin administered as a single agent according to different regimens and ii) differences in biomarkers of the oxidative stress between healthy rats and rats with DMBA-induced mammary tumors. The extent of oxidative stress was evaluated on the basis of its foremost biomarkers: thiol and carbonyl groups, lipid peroxidation products (hydroperoxides, TBARS), activity of antioxidant defense enzyme superoxide dismutase (SOD) and non-enzymatic antioxidant capacity (NEAC). We have found that pirolin alone displayed dual, antioxidant and pro-oxidant activity depending on the regimen of treatment. Daily treatment for 2 weeks increased the amount of thiols, and decreased the protein carbonyl groups. Three administrations of pirolin at 3-week intervals did not influence thiol content but increased hydroperoxides, TBARS and carbonyl groups. Chemotherapy employing DOX-DTX combination caused considerable oxidative stress in the plasma. Significant and dose-dependent oxidative damage to lipids and proteins with concomitant thiol depletion were evident in treated animals. Drugs also increased SOD activity and NEAC. Association of pirolin with DOX-DTX chemotherapy resulted in a partial amelioration of oxidative stress generated by anticancer drugs. This study indicates that a nitroxyl compound pirolin applied as a single agent in vivo can display both antioxidant and pro-oxidant properties but in conjunction with DOX-DTX it is able to protect partially blood plasma against oxidative stress generated by chemotherapy. The outcome, however, seems to be highly dependent on the ratio between the doses of employed anticancer drugs and the nitroxide.
多柔比星（DOX）和多西他赛（DTX）联合用于治疗许多耐药性癌症具有临床疗效，但也会增强副作用，例如与组织大分子氧化损伤相关的心脏毒性。氮氧化物代表一类有吸引力的合成化合物，可通过其抗氧化和铁氧化特性来改善非靶向组织中的 DOX-DTX 毒性。本研究的目的是确定 3-氨甲酰基吡咯啉氮氧化物衍生物吡咯啉（PL）在 DMBA 诱导的乳腺癌荷瘤 Sprague-Dawley 大鼠中减轻 DOX-DTX 化疗诱导的血浆蛋白和脂质氧化损伤的能力。此外，我们还评估了：i）根据不同方案单独给予吡咯啉时的促氧化剂和抗氧化剂活性，以及 ii）健康大鼠和 DMBA 诱导的乳腺癌大鼠之间氧化应激生物标志物的差异。氧化应激的程度是根据其主要生物标志物来评估的：巯基和羰基基团、脂质过氧化产物（氢过氧化物、TBARS）、抗氧化防御酶超氧化物歧化酶（SOD）的活性和非酶抗氧化能力（NEAC）。我们发现，吡咯啉本身具有抗氧化和促氧化剂活性，这取决于治疗方案。连续 2 周每天治疗可增加巯基的含量，减少蛋白质的羰基基团。每 3 周进行 3 次治疗不会影响巯基含量，但会增加氢过氧化物、TBARS 和羰基基团。使用 DOX-DTX 联合化疗会在血浆中引起相当大的氧化应激。在接受治疗的动物中，明显且剂量依赖性的脂质和蛋白质氧化损伤伴随着巯基的消耗。这些药物还增加了 SOD 活性和 NEAC。吡咯啉与 DOX-DTX 化疗联合使用可部分改善抗癌药物引起的氧化应激。本研究表明，体内应用氮氧化物化合物吡咯啉可表现出抗氧化和促氧化剂特性，但与 DOX-DTX 联合使用时，它能够部分保护血浆免受化疗引起的氧化应激。然而，结果似乎高度依赖于所使用的抗癌药物和氮氧化物的剂量比。
