Gadjeva V, Dimov A, Georgieva N
Department of Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria.
J Clin Pharm Ther. 2008 Apr;33(2):179-85. doi: 10.1111/j.1365-2710.2008.00909.x.
Some anticancer drugs can result in increased production of reactive oxygen species (ROS). Alkylating agents are the most frequently used drugs in chemotherapeutic regimens for the treatment of malignant melanoma. It is known that triazenes exhibit in vivo activity by alkylation of nucleic acids and proteins, but there is no data about ROS formation during oxidative metabolism. Single agents of most interest for treatment of malignant melanomas include 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (DTIC) and nitrosoureas such as 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), but complete response to these drugs is rare. The present study aimed to determine whether an oxidative stress occurs during the clinical course of melanoma and the influence of therapy on the antioxidant status of patients with melanoma. For this purpose, we investigated plasma concentrations of MDA as indices of the levels of lipid peroxidation products. In addition, we studied the activities of the antioxidant enzymes superoxide dismutases (SOD) and catalase (CAT) in patients with melanoma before any treatment, after surgical removal of melanoma, and after chemotherapy with DTIC or in combination with CCNU of the operated patients.
Twenty one patients with melanoma were studied. Patients were operated prior to chemotherapy. After recovery for 10-20 days postoperatively, they were studied again for MDA, SOD and CAT activity. The patients were divided into two groups according to the chemotherapy (3-7 treatment cycles): with DTIC-given orally daily for 5 days, every 3 weeks as a single 2200 mg/kg dose and with the combination-DTIC (the same dose) + CCNU-administered orally at a dosage of 120 mg/m(2) once every 40 days in accordance with protocols, approved by the Bulgarian Ministry of Health. The total amount of lipid peroxidation products in plasma was assayed.
Plasma levels of MDA and CAT activity were significantly higher, and erythrocyte SOD activity significantly lower, in patients with melanoma, than in control healthy volunteers (P < 0.0001). Ten to twenty days after surgery, oxidative stress decreased but levels of MDA increased as a result of therapy. Important sources of increased ROS production may be the monocytes, phagocytosis of tumour cells and the cancer tissues. Plasma MDA in patients treated with DTIC + CCNU were significantly higher (P < 0.001), but erythrocyte SOD statistically lower (P < 0.00001), compared with patients treated with DTIC only. However, a combination of DTIC + CCNU did not attenuate oxidative stress, or reduced antioxidant status. Patients treated with this combination are at bigger risk of oxidative injury. Therefore, this disturbance might be due to augmented generation of toxic ROS, possibly from the metabolism of CCNU.
Increased oxidative stress follows an imbalance in antioxidant defence in non-treated patients with melanoma. The impaired antioxidant system favours accumulation of ROS, which may promote the cancer process. After complete removal of melanoma tissues, oxidative stress decreased. The antioxidant status of melanoma patients operated on was influenced by the different chemotherapeutic regimens used and may play an important role in the response. Patients on DTIC + CCNU are at higher risk of oxidative injury. This drug combination probably exerts its toxic activity by ROS, which could be products of the metabolism of CCNU.
一些抗癌药物可导致活性氧（ROS）生成增加。烷化剂是治疗恶性黑色素瘤化疗方案中最常用的药物。已知三氮烯通过核酸和蛋白质的烷基化发挥体内活性，但关于氧化代谢过程中ROS形成的数据尚无报道。治疗恶性黑色素瘤最受关注的单一药物包括5-（3,3-二甲基三氮烯-1-基）-咪唑-4-甲酰胺（DTIC）和亚硝基脲类，如1-（2-氯乙基）-3-环己基-1-亚硝基脲（CCNU），但对这些药物的完全缓解很少见。本研究旨在确定黑色素瘤临床病程中是否会发生氧化应激以及治疗对黑色素瘤患者抗氧化状态的影响。为此，我们检测了血浆中丙二醛（MDA）的浓度，作为脂质过氧化产物水平的指标。此外，我们研究了黑色素瘤患者在未进行任何治疗前、手术切除黑色素瘤后以及对手术患者用DTIC或联合CCNU化疗后的抗氧化酶超氧化物歧化酶（SOD）和过氧化氢酶（CAT）的活性。
研究了21例黑色素瘤患者。患者在化疗前接受手术。术后恢复10 - 20天后，再次检测他们的MDA、SOD和CAT活性。根据化疗方案（3 - 7个治疗周期）将患者分为两组：一组使用DTIC，每日口服1次，每次2200 mg/kg，共5天，每3周给药1次；另一组使用联合方案——DTIC（相同剂量）+ CCNU，按照保加利亚卫生部批准的方案，每40天口服给药1次，剂量为120 mg/m²。检测血浆中脂质过氧化产物的总量。
黑色素瘤患者血浆MDA水平和CAT活性显著高于健康对照志愿者，红细胞SOD活性显著低于健康对照志愿者（P < 0.0001）。手术后10至20天，氧化应激减轻，但由于治疗MDA水平升高。ROS生成增加的重要来源可能是单核细胞、肿瘤细胞的吞噬作用以及癌组织。与仅用DTIC治疗的患者相比，用DTIC + CCNU治疗的患者血浆MDA显著更高（P < 0.001），但红细胞SOD在统计学上更低（P < 0.00001）。然而，DTIC + CCNU联合用药并未减轻氧化应激，或降低抗氧化状态。接受该联合治疗的患者氧化损伤风险更大。因此，这种紊乱可能是由于毒性ROS生成增加，可能源于CCNU的代谢。
未治疗的黑色素瘤患者抗氧化防御失衡导致氧化应激增加。抗氧化系统受损有利于ROS积累，这可能促进癌症进程。黑色素瘤组织完全切除后，氧化应激减轻。接受手术的黑色素瘤患者的抗氧化状态受所用不同化疗方案的影响，可能在反应中起重要作用。接受DTIC + CCNU治疗的患者氧化损伤风险更高。这种药物组合可能通过ROS发挥其毒性作用，ROS可能是CCNU代谢的产物。
