Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response

<p>Abstract</p> <p>Background</p> <p>1-{4-[Bis(2-chloroethyl)amino]phenyl}-3-[2-methyl-5-(4-methylacridin-9-ylamino)phenyl]urea (BO-1051) is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy.</p> <p>Methods</p> <p>The clonogenic assay was used to determine the IC₅₀and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3) following BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by γ-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan-Meier method.</p> <p>Results</p> <p>BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC₅₀, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G₂/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. γ-H2AX foci was greatly increased and sustained by combined BO-1051 and γ-rays, suggested that DNA damage or repair capacity was impaired during treatment. <it>In vivo </it>studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly.</p> <p>Conclusions</p> <p>These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity <it>in vitro </it>and <it>in vivo</it>. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells.</p

Can mixed pure hepatocellular carcinoma and germinoma arise together in the brain?

Intracranial germ-cell tumors (GCTs) represent 10–15% of all pediatric brain tumors in East Asia. There is a wide histopathological spectrum of intracranial GCTs. Germinomas and nongerminomatous GCTs are the two major classifications. It is difficult to distinguish different subtypes of intracranial GCTs based solely on imaging studies, however, some tumor markers, such as α-fetoprotein or β-human chorionic gonadotropin, are helpful for diagnosis. In this study we present the case of a 13-year-old girl with an intracranial mixed GCT containing a hepatocellular carcinoma and germinoma without a primary liver tumor. Based on this unique pathological diagnosis, a series of treatments were applied, including surgery for gross tumor removal, adjuvant radiotherapy, and chemotherapy. Long-term follow up indicates fair disease control