Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study.
Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study.
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DOI：
10.5732/cjc.013.10111
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发表时间：
2014-07
影响因子：
--
通讯作者：
Abd-Allah AA
中科院分区：
文献类型：
--
作者：
El Sayed SM;Mohamed WG;Seddik MA;Ahmed AS;Mahmoud AG;Amer WH;Helmy Nabo MM;Hamed AR;Ahmed NS;Abd-Allah AA
3-溴丙酮酸（3BP）是一种新的具有良好抗癌活性的烷化剂。除了抑制关键的糖酵解酶，包括己糖激酶II和乳酸脱氢酶（LDH），3BP还选择性地抑制癌细胞中的线粒体氧化磷酸化，血管生成和能量产生。此外，3BP诱导癌细胞中过氧化氢的产生（氧化应激效应），并与LDH底物丙酮酸盐和乳酸盐竞争。只有一项已发表的人类临床研究表明，3BP可有效治疗纤维板层型肝细胞癌。LDH是一个很好的肿瘤评估指标，比残留肿瘤块更能预测治疗结果。根据瓦尔堡效应，LDH负责乳酸合成，其促进癌细胞存活、进展、侵袭性、转移和血管生成。通过LDH活性产生的乳酸盐通过代谢共生为肿瘤内的需氧细胞群提供燃料。在最致命的皮肤癌黑色素瘤中，3BP诱导敏感细胞的坏死细胞死亡，而高谷胱甘肽（GSH）含量使其他黑色素瘤细胞对3BP产生抗性。同时使用GSH耗竭剂和3BP可杀死耐药黑色素瘤细胞。黑色素瘤患者的生存率与高血清LDH水平呈负相关，据报道，在随机临床试验中，高血清LDH水平高度预测黑色素瘤治疗。在这里，我们报告一个28岁的男子提出了第四阶段转移性黑色素瘤影响背部，左胸膜，肺。该疾病导致左肺完全破坏和高血清LDH水平（4，283 U/L）。在伦理委员会批准和患者书面知情同意书后，患者接受了3BP静脉输注（1-2.2 mg/kg），但如高血清LDH水平所示，抗癌作用极小。这可能是由于肿瘤GSH含量高。联合口服对乙酰氨基酚，消耗肿瘤GSH，与3BP治疗，血清LDH水平下降最大。虽然缓慢静脉输注3BP似乎具有最小的细胞毒性，但通过这种递送方法的抗癌功效较低。这可能是由于肿瘤GSH含量高，在同时使用GSH耗竭剂对乙酰氨基酚后增加。如果3BP的抗癌效果低于预期，则可能需要与扑热息痛联合使用，以使癌细胞对3BP诱导的作用敏感。
3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.
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DOI：
10.1016/j.bbrc.2004.09.047
发表时间：
2004-11-05
影响因子：
3.1
作者：
Ko, YH;Smith, BL;Pedersen, PL
通讯作者：
Pedersen, PL
影响因子：
45.3
作者：
Balch, Charles M.;Gershenwald, Jeffrey E.;Sondak, Vernon K.
通讯作者：
Sondak, Vernon K.
影响因子：
3
作者：
Ko, Y. H.;Verhoeven, H. A.;Pedersen, P. L.
通讯作者：
Pedersen, P. L.
影响因子：
3.4
作者：
Buijs, Manon;Vossen, Josephina A.;Vali, Mustafa
通讯作者：
Vali, Mustafa
影响因子：
37.3
作者：
Ho J;de Moura MB;Lin Y;Vincent G;Thorne S;Duncan LM;Hui-Min L;Kirkwood JM;Becker D;Van Houten B;Moschos SJ
通讯作者：
Moschos SJ