Boyle Kristopher E, Boger Dale L, Wroe Andrew, Vazquez Marcelo
School of Pharmacy, Loma Linda University, 24745 Anderson St., Loma Linda, CA 92354, United States.
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 Torrey Pines Rd., La Jolla, CA 92037, United States.
Bioorg Med Chem Lett. 2018 Sep 1;28(16):2688-2692. doi: 10.1016/j.bmcl.2018.04.008. Epub 2018 Apr 4.
New treatment modalities for glioblastoma multiforme (GBM) are urgently needed. Proton therapy is considered one of the most effective forms of radiation therapy for GBM. DNA alkylating agents such as temozolomide (TMZ) are known to increase the radiosensitivity of GBM to photon radiation. TMZ is a fairly impotent agent, while duocarmycin SA (DSA) is an extremely potent cytotoxic agent capable of inducing a sequence-selective alkylation of duplex DNA. Here, the effects of sub-nM concentrations of DSA on the radiosensitivity of a human GBM cell line (U-138) to proton irradiation were examined. Radiation sensitivity was determined by viability, apoptosis, necrosis and clonogenic assays. DSA concentrations as low as 0.001 nM significantly sensitized U-138 cells to proton irradiation. DSA demonstrates synergistic cytotoxicity against GBM cells treated with proton radiation in vitro, which may represent a novel therapeutic alternative for the treatment of GBM.
多形性胶质母细胞瘤（GBM）迫切需要新的治疗方式。质子治疗被认为是治疗GBM最有效的放射治疗形式之一。已知像替莫唑胺（TMZ）这样的DNA烷化剂可提高GBM对光子辐射的放射敏感性。TMZ是一种相当低效的药物，而双吲哚碳二亚胺SA（DSA）是一种极其强效的细胞毒性药物，能够诱导双链DNA的序列选择性烷基化。在此，研究了亚纳摩尔浓度的DSA对人GBM细胞系（U - 138）对质子照射的放射敏感性的影响。通过活力、凋亡、坏死和克隆形成试验来确定放射敏感性。低至0.001 nM的DSA浓度可显著提高U - 138细胞对质子照射的敏感性。DSA在体外对接受质子辐射治疗的GBM细胞表现出协同细胞毒性，这可能代表了一种治疗GBM的新型治疗选择。
