Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance.
Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance.
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DOI：
10.1111/cas.15141
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发表时间：
2021-11
期刊：
影响因子：
5.7
通讯作者：
Tomiyama A
中科院分区：
文献类型：
--
作者：
Yamamuro S;Takahashi M;Satomi K;Sasaki N;Kobayashi T;Uchida E;Kawauchi D;Nakano T;Fujii T;Narita Y;Kondo A;Wada K;Yoshino A;Ichimura K;Tomiyama A
胶质母细胞瘤（GBM）经常在连续治疗后获得对替莫唑胺（TMZ）的耐药性，并作为TMZ耐药GBM（TMZ-R-GBM）复发。洛莫司汀（CCNU）和尼莫司汀（ACNU）在TMZ之前曾作为标准治疗药物用于治疗GBM，偶尔也用于TMZ-R-GBM的挽救治疗;然而，尚未彻底检查其疗效。因此，我们研究了CCNU和ACNU对TMZ-R-GBM的抗肿瘤作用。作为TMZ-R-GBM的模型，通过在连续TMZ处理下培养每种GBM细胞，建立人GBM细胞系（U87、U251 MG和U343 MG）的TMZ抗性克隆（TMZ-R-细胞），并在体外和体内分析TMZ、CCNU或ACNU对这些细胞的抗肿瘤作用。因此，尽管在给予每种药物后，所有TMZ-R-细胞都发生了生长停滞和凋亡，但与亲代细胞相比，TMZ对TMZ-R-细胞的抗肿瘤作用显著降低，而CCNU和ACNU对TMZ-R-细胞以及亲代细胞表现出有效的抗肿瘤作用。研究还表明，TMZ-R-细胞的TMZ抗性在DNA损伤反应开始时受到调节。此外，在植入TMZ-R-细胞后，用CCNU或ACNU而不是TMZ全身治疗可显著延长小鼠的生存期。这些结果表明，CCNU或ACNU可作为TMZ-R-GBM的挽救治疗的治疗剂。我们研究了洛莫司汀（CCNU）和尼莫司汀（ACNU）的抗肿瘤作用，这两种药物以前被用作胶质母细胞瘤（GBM）的标准治疗药物，针对人GBM病例的模型细胞，这些细胞在连续接受替莫唑胺（TMZ）治疗后获得了TMZ耐药（TMZ-R-细胞）。我们发现TMZ对TMZ-R-细胞的抗肿瘤作用与亲本细胞相比显著降低，而CCNU和ACNU在体外和体内对TMZ-R-细胞以及亲本细胞均表现出有效的抗肿瘤作用。此外，还证明TMZ-R-细胞的TMZ抗性在DNA损伤反应起始水平上受到调节。这些结果表明，CCNU或ACNU可作为一种治疗药物，挽救治疗GBM的获得性TMZ耐药。
Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ‐resistant GBM (TMZ‐R‐GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ‐R‐GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ‐R‐GBM. As a model of TMZ‐R‐GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ‐R‐cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ‐R‐cells after the administration of each drug, the antitumor effects of TMZ against TMZ‐R‐cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ‐R‐cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ‐R‐cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ‐R‐cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ‐R‐GBM. We investigated the antitumor effects of lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents for glioblastomas (GBM), against the model cells of human GBM cases, which gained acquired temozolomide (TMZ) resistance after continuous treatment by TMZ (TMZ‐R‐cells). We discovered that the antitumor effects of TMZ against TMZ‐R‐cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ‐R‐cells as well as parental cells both in vitro and in vivo. In addition, it was also demonstrated that TMZ resistance of TMZ‐R‐cells was regulated at the level of DNA damage response initiation. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against GBM cases with acquired TMZ resistance.
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