BCNU Research Articles

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Salvage therapy with bendamustine for temozolomide refractory recurrent anaplastic gliomas: a prospective phase II trial

There is no standard therapy for recurrent anaplastic glioma (AG). Salvage therapies include alkylator-based chemotherapy, re-resection with or without carmustine implants, re-irradiation and bevacizumab. Bendamustine is a novel bifunctional alkylator with CNS penetration never previously evaluated in AG. Assess response and toxicity of bendamustine in recurrent AG in a phase II trial. Adults with radiation and temozolomide refractory recurrent AG were treated with bendamustine. A cycle of bendamustine was defined as two consecutive days of treatment (100mg/m2/day) administered once every 4weeks. Success of treatment was defined as progression free survival (PFS) at 6months of 40 % or better. Twenty-six adults [16 males; 10 females: median age 40 years (range 30-65)] were treated, 12 at first recurrence and 17 at second recurrence. Prior salvage therapy included re-resection (14), chemotherapy (11) and re-radiation (2). Grade 3 treatment-related toxicities included lymphopenia (11 patients; Grade 4 in 3), myalgia, pneumonia, diarrhea, leukopenia, allergic reaction and thrombocytopenia in one patient each. One patient discontinued therapy due to toxicity. There were five instances of bendamustine dose delays all due to lymphopenia. There were no dose reductions due to toxicity. The median number of cycles of therapy was 3 (range 1-8). Best radiographic response was progressive disease in 12 (46 %), stable disease in 13 (50 %) and partial response in 1 (4 %). Median, 6- and 12-month PFS was 2.7months (range 1-52), 27 and 8 % respectively. In patients with recurrent AG refractory to Z, bendamustine has manageable toxicity and modest single agent activity though not meeting pre-specified study criteria.

Natural Bioactive Compounds: Alternative Approach to the Treatment of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM characteristically exhibits aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. The current standard of care of surgical resection followed by radiotherapy and chemotherapy with temozolomide is not very effective. The inefficacy of the chemotherapeutic agents may be attributed to the challenges in drug delivery to the tumor. Several epidemiological studies have demonstrated the chemopreventive role of natural, dietary compounds in the development and progression of cancer. Many of these studies have reported the potential of using natural compounds in combination with chemotherapy and radiotherapy as a novel approach for the effective treatment of cancer. In this paper, we review the role of several natural compounds individually and in combination with chemotherapeutic agents in the treatment of GBM. We also assess the potential of drug delivery approaches such as the Gliadel wafers and role of nanomaterial based drug delivery systems for the effective treatment of GBM.

240 - Decreased Intracellular Glutathione in Peripheral Neutrophils Decreases Chemotactic Behaviour towards Interleukin 8 and FMLP

The innate immune system is the first line of defence against invading microorganisms, and neutrophils are the most abundant leukocyte and the first to arrive at a site of infection. Periodontitis is a highly prevalent chronic non communicable disease and in its most severe form is the sixth most prevalent human disease, affecting 11.2% of the world’s population. It has been associated various systemic diseases and conditions, such as diabetes. In periodontitis it is known that neutrophils have aberrant chemotactic behaviour (Roberts et al PMID: 25360483), as well as increased reactive oxygen species production whilst resting (hyper activity) and when stimulated (hyper-reactivity) (Matthews et al PMID: 17223966). This combination may lead to enhanced tissue damage in the periodontal lesion. We have also shown that levels of glutathione in the periodontal lesion (Grant et al PMID: 19968740) and within circulating peripheral neutrophils (Dias et al PMID: 23826097) are decreased, demonstrating a loss in redox buffering and capacity. Previous studies have shown the importance of glutathionylation of actin in chemotactic movement of neutrophils (Sakai et al 2012 PMID: 23159440). With the long term aim to examine how diminished glutathione levels in periodontitis effect chemotaxis, we examined the effect of glutathione modulation by buthioninesulfoximine (BSO), N-acetylcysteine (NAC), bis-chloroethylnitrosourea (BCNU) and 1-chloro-2,4-dinitrobenzene (CDNB) on neutrophil intracellular glutathione, viability and chemotaxis towards interleukin 8 and N-formylmethionyl-leucyl-phenylalanine (fMLP). BSO, BCNU and CDNB decreased the chemotaxis and glutathione levels in peripheral neutrophils isolated from healthy donors. Future studies will translate this work into a periodontal cohort and examine protein glutathionylation by mass spectrometry.

Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review.

Since 2003, only two chemotherapeutic agents, evaluated in phase III trials, have been approved by the US Food and Drug Administration for treatment of newly diagnosed high-grade glioma (HGG): Gliadel wafers (intracranially implanted local chemotherapy) and temozolomide (TMZ) (systemic chemotherapy). Neither agent is curative, but each has been shown to improve median overall survival (OS) compared to radiotherapy (RT) alone. To date, no phase III trial has tested these agents when used in sequential combination; however, a number of smaller trials have reported favorable results. We performed a systematic literature review to evaluate the combination of Gliadel wafers with standard RT (60 Gy) plus concurrent and adjuvant TMZ (RT/TMZ) for newly diagnosed HGG. A literature search was conducted for the period of January 1995 to September 2015. Data were extracted and categorized, and means and ranges were determined. A total of 11 publications met criteria, three prospective trials and eight retrospective studies, representing 411 patients who received Gliadel plus standard RT/TMZ. Patients were similar in age, gender, and performance status. The weighted mean of median OS was 18.2 months (ten trials, n = 379, range 12.7 to 21.3 months), and the weighted mean of median progression-free survival was 9.7 months (seven trials, n = 287, range 7 to 12.9 months). The most commonly reported grade 3 and 4 adverse events were myelosuppression (10.22 %), neurologic deficit (7.8 %), and healing abnormalities (4.3 %). Adverse events reflected the distinct independent safety profiles of Gliadel wafers and RT/TMZ, with little evidence of enhanced toxicity from their use in sequential combination. In the 11 identified trials, an increased benefit from sequentially combining Gliadel wafers with RT/TMZ was strongly suggested. Median OS tended to be improved by 3 to 4 months beyond that observed for Gliadel wafers or TMZ when used alone in the respective phase III trials. Larger prospective trials of Gliadel plus RT/TMZ are warranted.

Bendamustine for anaplastic gliomas.

2051 Background: There is no standard therapy for recurrent anaplastic glioma (AG). Salvage therapies include alkylator-based chemotherapy (temozolomide [TMZ] or lomustine [CCNU]), re-resection with or without carmustine implants, re-irradiation and bevacizumab. Bendamustine is a novel bifunctional alkylator with CNS penetration but never evaluated in AG. Objective: Assess response and toxicity of bendamustine in bevacizumab naïve recurrent AG following prior radiotherapy (RT) and TMZ in a prospective Phase II trial. Methods: 26 adults (16 males; 10 females: median age 40 years {range 30-65}) with RT and TMZ refractory recurrent AG (14 anaplastic astrocytoma, 7 anaplastic oligodendroglioma, 5 anaplastic oligoastrocytoma) were treated with bendamustine. 12 patients were treated at 1st and 14 at 2nd recurrence. Prior salvage therapy included re-resection in 14 (12 with 2nd and 2 with 3rd resection), chemotherapy in 11 and re-RT in 2. A cycle of bendamustine was defined as 2 consecutive days of treatment (100mg/m2/day) administered once every 4 weeks (maximum number of cycles 6). Success of treatment was defined as progression free survival (PFS) at 6 months > 40%. Results: Grade 3 treatment-related toxicities included lymphopenia (11 patients), myalgia, pneumonia, diarrhea, leukopenia, allergic reaction and thrombocytopenia in 1 patient each. Three patients had grade 4 lymphopenia. No grade 5 toxicities were seen. One patient discontinued therapy due to toxicity (allergic reaction). Bendamustine dose was delayed in 3 patients (total of 5 events). There were no dose reductions. The median number of cycles of therapy was 3 (range 1-8). Best radiographic response was progressive disease in 12 (46%), stable disease in 13 (50%) and partial response in 1 (4%). Response did not differ by histology. Median PFS was 2.7 months (range 1-52 months), 6-month PFS was 27% and 12-month PFS was 8%. Conclusions: In this small prospective series of patients with recurrent AG refractory to TMZ and bevacizumab naive, bendamustine appears to have modest single agent activity though not meeting pre-specified criteria (40% 6-month PFS) and manageable toxicity. The study was supported in part through research funds provided by TEVA Pharmaceuticals and the National Comprehensive Cancer Network. Clinical trial information: NCT00823797.

283. In Vivo Selection of MGMT(P140K) Gene Modified Hematopoietic Cells in the Nonhuman Primate Unmasks a Dormant Pool of Repopulating Clones with Progenitor Cell Ontology

Previously published gene modified cell transplantation studies in nonhuman primate models have described several key features of hematopoietic reconstitution (Kim, S. et al., 2014 and Wu, C. et al., 2014). These studies applied either retrovirus integration site analysis (ISA) or DNA barcode sequencing (DBS) to identify hematopoietic clones in bone marrow or peripheral blood cells. However, these distinct methods detected long-term clones at different time points (1 year after transplant by ISA; ~3 months after transplant by DBS), and neither evaluated reconstitution in the context of selective advantage, which is often the case in gene therapy. Here, we tracked tens of thousands of unique clones in 8 pigtail macaques for up to 10 years following myeloablative transplantation with autologous, lentivirus (LV) gene-modified CD34+ cells. Seven animals received cells gene modified with the P140K mutant methylguanine methyltransferase transgene, conferring resistance to O6- benzylguanine (O6BG) and bis-chloroethylnitrosourea (BCNU) chemotherapy. In two animals, MGMT(P140K)-expressing LVs were DNA barcoded, permitting simultaneous ISA and DBS tracking. Gene marking in peripheral blood cells ranged from 2.3% to 66%. Direct comparison of ISA and DBS demonstrated that abundant clones (&gt 1% of sequence reads) are readily detected by both methods, but DBS captures up to 2-fold more lower abundance clones. Before in vivo selection with O6BG/BCNU, we observed a cell dose-dependent, successive pattern of hematopoietic reconstitution by ISA analysis, with short-term clones declining within 100 days after transplantation. Long-term clones were observed as early as 1 month after transplant. In the first year after transplant, persistent clones ranged from 8% to 54% of clones detected at a &gt 1% frequency, and remained stable in the absence of selective pressure. Importantly, when O6BG/BCNU was administered we observed novel clonal patterns, which directly correlated with transplanted cell dose and time of chemotherapy administration after transplant. In all animals, chemotherapy induced emergence of previously undetected clones. In animals receiving cell doses exceeding 35×106 CD34+ cells/kg (n = 2), chemotherapy more than 1 year after transplant induced a completely novel clonal repertoire. Gene ontology analysis of integration loci among early, long-term and dormant clonal populations identified the greatest functional overlap between early and dormant pools. These data suggest that some short-term repopulating clones revert to a dormant phase within the first year after transplant. Additionally, these data indicate that transplant of excess CD34+ cell numbers results in early dormancy of a large proportion of early repopulating clones. Together, these findings suggest that previous estimates of short- and long-term clonal frequency are an underestimate of true graft repopulation potential.

The Johns Hopkins Hunterian Laboratory Philosophy: Mentoring Students in a Scientific Neurosurgical Research Laboratory.

After over 50 years of scientific contribution under the leadership of Harvey Cushing and later Walter Dandy, the Johns Hopkins Hunterian Laboratory entered a period of dormancy between the 1960s and early 1980s. In 1984, Henry Brem reinstituted the Hunterian Neurosurgical Laboratory, with a new focus on localized delivery of therapies for brain tumors, leading to several discoveries such as new antiangiogenic agents and Gliadel chemotherapy wafers for the treatment of malignant gliomas. Since that time, it has been the training ground for 310 trainees who have dedicated their time to scientific exploration in the lab, resulting in numerous discoveries in the area of neurosurgical research. The Hunterian Neurosurgical Laboratory has been a unique example of successful mentoring in a translational research environment. The laboratory's philosophy emphasizes mentorship, independence, self-directed learning, creativity, and people-centered collaboration, while maintaining productivity with a focus on improving clinical outcomes. This focus has been served by the diverse backgrounds of its trainees, both in regard to educational status as well as culturally. Through this philosophy and strong legacy of scientific contribution, the Hunterian Laboratory has maintained a positive and productive research environment that supports highly motivated students and trainees. In this article, the authors discuss the laboratory's training philosophy, linked to the principles of adult learning (andragogy), as well as the successes and the limitations of including a wide educational range of students in a neurosurgical translational laboratory and the phenomenon of combining clinical expertise with rigorous scientific training.

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Patterns of Recurrence After Resection of Malignant Gliomas With BCNU Wafer Implants: Retrospective Review in a Single Institution

Bis-chloroethylnitrosourea (BCNU) wafers have been demonstrated to be effective for prolonging survival for patients with malignant glioma and have been approved worldwide. BCNU wafers are implantable and have a unique feature of delivering chemotherapeutic drug at high concentration at tumor margin over time after resection. BCNU wafers presumably, by this mechanistic rationale, have a beneficial effect on local tumor control and thus could change the pattern of recurrence, which is most frequently local. However, no studies have demonstrated such phenomenon after BCNU wafer implants. To investigate whether the surgeries with BCNU wafers alter the predominant tendency of local recurrence pattern, we retrospectively reviewed 8 malignant glioma patients treated with BCNU wafers (BCNU wafer group), together with 22 glioma patients who did not receive BCNU wafers (no-BCNU wafer group) for comparison. Out of 6 patients in BCNU wafer group who exhibited recurrence, 1 showed local, 2 showed diffuse, and 3 showed a distant recurrence pattern, which was away from resection cavity. On the other hand, out of 18 patients in the no-BCNU wafer group who exhibited recurrence, 10 showed a local pattern, 8 showed a diffuse pattern, and no cases showed distant pattern. Distant pattern was observed significantly more frequently in the BCNU wafer group than in the no-BCNU wafer group. These results suggest that BCNU wafers could have a beneficial effect on local tumor control and may provide BCNU wafers with a new profile that could be considered for establishing future chemotherapeutic strategy for glioma patients.

Safety and efficacy of carmustine (BCNU) wafers for metastatic brain tumors.

Background:Carmustine (BCNU) wafers (Gliadel) prolongs local disease control and progression-free survival (PFS) in patients with malignant gliomas. However, in metastatic brain tumors, there is a paucity of evidence in support of its safety and efficacy. The goal of this study was to assess the safety and efficacy of Gliadel wafers in patients with metastatic brain tumors.Methods:We retrospectively reviewed the University of Washington experience with Gliadel wafers for metastatic brain tumors between 2000 and 2015.Results:Gliadel wafers were used in 14 patients with metastatic brain tumors during the period reviewed. There were no postoperative seizures, strokes, or hemorrhages. There was one postoperative wound infection necessitating return to the operating room. The mean time to tumor progression (n = 7) and death (n = 5) after Gliadel wafer implantation was 2.5 and 2.9 years, respectively. Age was the only variable affecting PFS in patients receiving Gliadel wafers. Patients <53 years old (n = 7) had a PFS of 0.52 years, whereas patients >53 years old (n = 7) had a PFS of 4.29 years (P = 0.02). There was no significant difference in PFS in relation to presenting Karnofsky Performance Status (P = 0.26), number of brain metastasis (P = 0.82), tumor volume (P = 0.54), prior surgery (P = 0.57), or prior radiation (P = 0.41). There were no significant differences in the mean survival in relationship to any variable including age.Conclusions:BCNU wafers are a safe and a potentially efficacious adjunct to surgery and radiation for improving local disease control in metastatic brain tumors. Larger studies, however, are needed to examine overall efficacy and tumor specific efficacy.

In Vivo Selection Unmasks a Dormant Pool of Repopulating Hematopoietic Clones

Long-term clonal tracking studies utilizing hematopoietic stem and progenitor cells (HSPCs) in nonhuman primates receiving myeloablative transplantation demonstrate a successive pattern of repopulation: short-term repopulating cells are succeeded by long-term clones. However, the duration of short-term repopulation and the numbers of clones contributing to either short or long-term repopulation are unclear. Here, we tracked >11,000 unique clones in 8 pigtail macaques for up to 9 years following myeloablative transplantation with autologous, lentivirus gene-modified CD34+ HSPCs. Seven of these animals received cells expressing the P140K mutant methylguanine methyltransferase transgene, which is resistant to the combination of O6-benzylguanine (O6BG) and bis-chloroethylnitrosourea (BCNU) chemotherapy, thus conferring a selective advantage to gene-modified cells in vivo. After transplantation and before in vivo selection with O6BG/BCNU, we observed a successive pattern of hematopoietic reconstitution, with short-term clones declining within 100 days after transplantation. Within the first year after transplant, the percent of persistent clones varied from animal-to-animal, ranging from 8% to 54% of clones detected at a >1% frequency, and remained stable in the absence of selective pressure. Importantly, when animals engrafted with P140K-expressing cells were administered O6BG/BCNU we observed novel clonal patterns, which directly correlated with transplanted cell dose and time of chemotherapy administration after transplant. In all animals, chemotherapy induced emergence of previously undetected clones. In animals receiving ≤12x106 CD34+ cells/kg at the time of transplant (n = 4), chemotherapy also induced a re-emergence of previously declined short-term repopulating clones or a stabilization (i.e. decreased fluctuation) of repopulating clones identified between 100 days and 1 year after transplant. However, in animals receiving robust cell doses, ≥35x106 CD34+ cells/kg (n = 2), chemotherapy more than 1 year after transplant induced a completely novel clonal repertoire. In one animal receiving 22x106 CD34+ cells/kg at transplant, chemotherapy administration beginning <1 year (253 days) after transplant induced clonal stability, which was maintained through two additional chemotherapy treatments. These data suggest that some short-term repopulating clones may have long-term repopulation ability, but revert to a dormant phase within the first year after transplant. Additionally, these data indicate that transplant of excess repopulating cells results in early dormancy of a large proportion of repopulating clones. Together, these findings suggest that previous estimates of HSPC frequency based on clone tracking are an underestimate of true graft repopulation potential. DisclosuresNo relevant conflicts of interest to declare.

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Biodegradable interstitial release polymer loading a novel small molecule targeting Axl receptor tyrosine kinase and reducing brain tumour migration and invasion.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour. The neoplasms are difficult to resect entirely because of their highly infiltration property and leading to the tumour edge is unclear. Gliadel wafer has been used as an intracerebral drug delivery system to eliminate the residual tumour. However, because of its local low concentration and short diffusion distance, patient survival improves non-significantly. Axl is an essential regulator in cancer metastasis and patient survival. In this study, we developed a controlled-release polyanhydride polymer loading a novel small molecule, n-butylidenephthalide (BP), which is not only increasing local drug concentration and extending its diffusion distance but also reducing tumour invasion, mediated by reducing Axl expression. First, we determined that BP inhibited the expression of Axl in a dose- and time-dependent manner and reduced the migratory and invasive capabilities of GBM cells. In addition, BP downregulated matrix metalloproteinase activity, which is involved in cancer cell invasion. Furthermore, we demonstrated that BP regulated Axl via the extracellular signal-regulated kinases pathway. Epithelial-to-mesenchymal transition (EMT) is related to epithelial cells in the invasive migratory mesenchymal cells that underlie cancer progression; we demonstrated that BP reduced the expression of EMT-related genes. Furthermore, we used the overexpression of Axl in GBM cells to prove that Axl is a crucial target in the inhibition of GBM EMT, migration and invasion. In an in vivo study, we demonstrated that BP inhibited tumour growth and suppressed Axl expression in a dose-dependent manner according to a subcutaneous tumour model. Most importantly, in an intracranial tumour model with BP wafer in situ treatment, we demonstrated that the BP wafer not only significantly increased the survival rate but also decreased Axl expression, and inhibited tumour invasion. These results contribute to the development of a BP wafer for a novel therapeutic strategy for treating GBM invasion and increasing survival in clinical subjects.

MGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel

We examined the relationship between the O6-methylguanine-methyltransferase (MGMT) methylation status and clinical outcomes in newly diagnosed glioblastoma multiforme (GBM) patients who were treated with Gliadel wafers (Eisai, Tokyo, Japan). MGMT promoter methylation has been associated with increased survival among patients with GBM who are treated with various alkylating agents. MGMT promoter methylation, in DNA from 122 of 160 newly diagnosed GBM patients treated with Gliadel, was determined by a quantitative methylation-specific polymerase chain reaction, and was correlated with overall survival (OS) and recurrence-free survival (RFS). The MGMT promoter was methylated in 40 (32.7%) of 122 patients. The median OS was 13.5 months (95% confidence interval [CI] 11.0–14.5) and RFS was 9.4 months (95% CI 7.8–10.2). After adjusting for age, Karnofsky performance score, extent of resection, temozolomide (TMZ) and radiation therapy (RT), the newly diagnosed GBM patients with MGMT methylation had a 15% reduced mortality risk, compared to patients with unmethylated MGMT (hazard ratio 0.85; 95% CI 0.56–1.31; p=0.46). The patients aged over 70years with MGMT methylation had a significantly longer median OS of 13.5months, compared to 7.6months in patients with unmethylated MGMT (p=0.027). A significant difference was also found in older patients, with a median RFS of 13.1 versus 7.6months for methylated and unmethylated MGMT groups, respectively (p=0.01). Methylation of the MGMT promoter in newly diagnosed GBM patients treated with Gliadel, RT and TMZ, was associated with significantly improved OS compared to the unmethylated population. In elderly patients, methylation of the MGMT promoter was associated with significantly better OS and RFS.

The role of Gliadel wafers in the treatment of newly diagnosed GBM: a meta-analysis.

BackgroundStandard treatment for high-grade glioma (HGG) includes surgery followed by radiotherapy and/or chemotherapy. Insertion of carmustine wafers into the resection cavity as a treatment for malignant glioma is currently a controversial topic among neurosurgeons. Our meta-analysis focused on whether carmustine wafer treatment could significantly benefit the survival of patients with newly diagnosed glioblastoma multiforme (GBM).MethodWe searched the PubMed and Web of Science databases without any restrictions on language using the keywords “Gliadel wafers”, “carmustine wafers”, “BCNU wafers”, or “interstitial chemotherapy” in newly diagnosed GBM for the period from January 1990 to March 2015. Randomized controlled trials (RCTs) and cohort studies/clinical trials that compared treatments designed with and without carmustine wafers and which reported overall survival or hazard ratio (HR) or survival curves were included in this study. Moreover, the statistical analysis was conducted by the STATA 12.0 software.ResultsSix studies including two RCTs and four cohort studies, enrolling a total of 513 patients (223 with and 290 without carmustine wafers), matched the selection criteria. Carmustine wafers showed a strong advantage when pooling all the included studies (HR =0.63, 95% confidence interval (CI) =0.49–0.81; P=0.019). However, the two RCTs did not show a statistical increase in survival in the group with carmustine wafer compared to the group without it (HR =0.51, 95% CI =0.18–1.41; P=0.426), while the cohort studies demonstrated a significant survival increase (HR =0.59, 95% CI =0.44–0.79; P<0.0001).ConclusionCarmustine-impregnated wafers play a significant role in improving survival when used for patients with newly diagnosed GBM. More studies should be designed for newly diagnosed GBM in the future.

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Malignant Cerebral Edema Secondary to Gliadel Wafers in the Early Postsurgical Period

High grade gliomas are the commonest intrinsic brain tumours and account for more average years of life lost than all the common cancers. It has become the commonest cause of cancer death in men under the age of 45 and women under the age of 35. Although surgical resection can greatly reduce tumour bulk, complete excision is virtually impossible due to the infiltrative nature of these tumours. In an attempt to treat the infiltrating tumour cells, there has been much interest in using local therapies inserted at the time of surgery. The authors report a case of fatal cerebral edema unresponsive to aggressive medical and surgical assessment that finally evolved to premature death in the early postsurgical period, after the craniotomy and implantation of Gliadel wafers. They note that high doses of dexamethasone were insufficient to prevent cerebral edema and death. A search for corticosteroid use and dosing for patients treated with Gliadel wafers in the published literature revealed no recommendations on the doses of steroids to be administered. In our opinion this is a very important issue and maybe the key point for the treatment of this disease, and may need to be addressed with treatment guidelines in the near future in order to ensure better results on patient’s survival. Prior to this case review there had been two similar report but a later presentation. So we think that this is the first case report of acute fulminant cerebral edema secondary to gliadel wafers in the early period.

Redox proteomics reveal stress responsive proteins linking peroxiredoxin-1 status in glioma to chemosensitivity and oxidative stress

The combined deletion of chromosomal arms 1p and 19q has been described as a prognostic marker for oligodendroglial tumors. These tumors show a better response to chemotherapy and radiotherapy. Recently, we found a lower abundance of peroxiredoxin 1 (PRDX1) in oligodendroglial tumors with 1p/19q deletion, suggesting a potential role of this enzyme in the clearance of therapy induced reactive oxygen species (ROS). Here, we confirmed the importance of PRDX1 in tumor cell survival by PRDX1 knockdown and overexpression in A-172 cells treated with the alkylating agent bis-chloroethyl nitrosourea (BCNU). Overexpression of PRDX1 resulted in a higher resistance of cells to BCNU treatment. In addition, BCNU challenged cells showed higher levels of ROS in PRDX1 knockdown cells. We applied a modified version of the redox two dimensional difference gel electrophoresis approach to analyze ROS mediated effects on protein thiols after BCNU treatment by labeling protein thiols with fluorescent dyes. Altogether eleven proteins were identified showing PRDX1 dependent altered labeling, many of them have been previously linked to stress response processes. Furthermore, 30 additional potentially redox active proteins were identified. The majority of them is involved in therapy associated processes like cellular stress response, DNA damage and regulation of cell death and therewith suggests that tumor cells maintain a network of redox sensitive proteins to escape chemotherapy. This article is part of a Special Issue entitled: Medical Proteomics.