Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance
Autor: | Takashi Fujii, Daisuke Kawauchi, Eita Uchida, Atsuo Yoshino, Yoshitaka Narita, Nobuyoshi Sasaki, Kojiro Wada, Tatsuya Kobayashi, Masamichi Takahashi, Koichi Ichimura, Arata Tomiyama, Kaishi Satomi, Shun Yamamuro, Akihide Kondo, Tomoyuki Nakano |
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Rok vydání: | 2021 |
Předmět: |
Cancer Research
Nitrosourea nitrosourea lomustine Mice Nude Salvage therapy Antineoplastic Agents Methylation Histones Mice chemistry.chemical_compound In vivo Temozolomide medicine Animals Humans U87 nimustine DNA Modification Methylases neoplasms Salvage Therapy Mice Inbred BALB C Brain Neoplasms business.industry Tumor Suppressor Proteins Nimustine glioblastoma temozolomide resistance Original Articles General Medicine Lomustine Xenograft Model Antitumor Assays nervous system diseases DNA Repair Enzymes Drug Discovery and Delivery Oncology chemistry Drug Resistance Neoplasm Apoptosis Cancer research Female Original Article Neoplasm Recurrence Local business Injections Intraperitoneal medicine.drug |
Zdroj: | Cancer Science |
ISSN: | 1349-7006 1347-9032 |
Popis: | 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. |
Databáze: | OpenAIRE |
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