Dai Ishii

IFN-β down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide

Alkylating agents, such as temozolomide, are among the most effective cytotoxic agents used for malignant gliomas, but responses remain very poor. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in cellular resistance to alkylating agents. IFN-beta can act as a drug sensitizer, enhancing toxicity against a variety of neoplasias, and is widely used in combination with other antitumor agents such as nitrosoureas. Here, we show that IFN-beta sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide. By means of oligonucleotide microarray and RNA interference, we reveal that the sensitizing effect of IFN-beta was possibly due to attenuation of MGMT expression via induction of the protein p53. Our study suggests that clinical efficacy of temozolomide might be improved by combination with IFN-beta using appropriate doses and schedules of administration.

EGFR mutations in patients with brain metastases from lung cancer: Association with the efficacy of gefitinib

Gefitinib--a specific inhibitor of epidermal growth factor receptor (EGFR)-associated tyrosine kinase--has demonstrated efficacy in a subgroup of patients with non-small-cell lung carcinoma (NSCLC) who fail conventional chemotherapy. It is also reported to have an antitumor effect in brain metastases from NSCLC. Additionally, EGFR mutations have shown a strong association with gefitinib sensitivity for NSCLC. Here, we assessed the efficacy of gefitinib in brain metastases from NSCLC and evaluated the association of this efficacy with EGFR mutations. We retrospectively reviewed eight cases in which patients were suffering from brain metastases before the initiation of gefitinib treatment. Brain tumor response could be evaluated by MRI in these patients; EGFR gene analyses were also available. We evaluated whether objective tumor response was observed after gefitinib treatment and assessed the efficacy of gefitinib as effective, noneffective, or not assessable in consideration of the influence of previous radiotherapy. Of the eight patients, the efficacy of gefitinib was assessed as effective in three and as noneffective in three. All three patients demonstrating effective efficacy had EGFR mutations in the tyrosine kinase domain (deletion mutation in two patients and point mutation in one patients), whereas none of the three patients demonstrating noneffective efficacy had EGFR mutations. Gefitinib appears to be effective in treating brain metastases in a subgroup of patients. Our data suggested a possible association between the efficacy of gefitinib in the treatment of brain metastases and EGFR mutations.

Long-term outcomes of Gamma Knife surgery for cavernous sinus meningioma

OBJECT The aim of this study was to evaluate long-term outcomes, including tumor control and neurological function, in patients with cavernous sinus meningiomas treated using Gamma Knife surgery (GKS). METHODS One hundred fifteen patients with cavernous sinus meningiomas, excluding atypical or malignant meningiomas, were treated with GKS between 1991 and 2003. Forty-nine patients (43%) underwent GKS as the initial treatment. The mean tumor volume was 14 cm3, and the mean maximum and margin doses applied to the tumor were 27 and 13 Gy, respectively. The median follow-up period was 62 months. During the follow-up, 111 patients were able to be evaluated with neuroimaging. RESULTS The actuarial 5- and 10-year progression-free survival rates were 87 and 73%, respectively. Similarly, the actuarial 5- and 10-year focal tumor control rates were 94 and 92%, respectively. Regarding functional outcomes, 43 patients (46%) experienced some degree of improvement, 40 (43%) remained stable, and 11 (12%) had worse preexisting or newly developed symptoms. Patients who underwent GKS as the initial treatment experienced significant improvement of their symptoms (p = 0.006). CONCLUSIONS Gamma Knife surgery is a safe and effective treatment over the long term in selected patients with cavernous sinus meningiomas. Tumor progression is more likely to occur from the lesion margin outside the treatment volume. In small to medium-sized tumors, GKS is an excellent alternative to resection, preserving good neurological function. For relatively large-sized tumors, low-dose radiosurgery (< or = 12 Gy) is acceptable for the prevention of tumor progression.

Gamma Knife surgery for skull base chordomas and chondrosarcomas

OBJECT The purpose of this study was to evaluate radiosurgical outcomes in skull base chordomas and chondrosarcomas, and to determine which tumors are appropriate for stereotactic radiosurgery as adjuvant therapy following maximum tumor resection. METHODS Thirty-seven patients (48 lesions) were treated using Gamma Knife surgery (GKS); 27 had chordomas, seven had chondrosarcomas, and three had radiologically diagnosed chordomas. The mean tumor volume was 20 ml, and the mean maximum and marginal doses were 28 and 14 Gy, respectively. The mean follow-up period was 97 months from diagnosis and 59 months from GKS. RESULTS The actuarial 5- and 10-year survival rates after GKS were 80 and 53%, respectively. The actuarial 5- and 10-year local tumor control (LTC) rates after single or multiple GKS sessions were 76 and 67%, respectively. All patients with low-grade chondrosarcomas achieved good LTC. A tumor volume of less than 20 ml significantly affected the high rate of LTC (p = 0.0182). No patient had adverse radiation effects, other than one in whom facial numbness worsened despite successful tumor control. CONCLUSIONS As an adjuvant treatment after resection, GKS is a reasonable option for selected patients harboring skull base chordomas or chondrosarcomas with a residual tumor volume of less than 20 ml. Dose planning with a generous treatment volume to avoid marginal treatment failure should be made at a marginal dose of at least 15 Gy to achieve long-term tumor control.

Asymmetric hydrogenation via architectural and functional molecular engineering

RuCl2 (phosphine) 2 (1,2-diamine) complexes, coupled with an alkaline base in 2-propanol, allows for preferential hydrogenation of a C=O function over coexisting conjugated or nonconjugated C=C linkages, a nitro group, halogen atoms, and various heterocycles. The functional group selectivity is based on the novel metal-ligand bifunctional mechanism. The use of appropriate chiral diphosphines and diamines results in rapid and productive asymmetric hydrogenation of a range of aromatic, hetero-aromatic, and olefinic ketones. The versatility of this method is manifested by the asymmetric synthesis of various biologically significant chiral compounds.

A combination of IFN-β and temozolomide in human glioma xenograft models: implication of p53-mediated MGMT downregulation

PurposeMethylation of the O6-methyguanine-DNA methyltransferase (MGMT) gene promoter in gliomas has been reported to be a useful predictor of the responsiveness to temozolomide (TMZ). In our previous experiments, we observed that IFN-β sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this study, (1) we explored the synergistic effect of IFN-β and TMZ in the animal model, and (2) clarified the role of IFN-β induced TP53 in the human MGMT promoter.Methods(1) Nude mice with either subcutaneous T98 (TMZ-resistant) or U251SP (TMZ-sensitive) tumor were treated with IFN-β/TMZ for 5 consecutive days. (2) The MGMT promoter activity was assayed by a luciferase reporter system in Saos2 (p53-null) cells transduced with a p53-adenoviral vector, and T98 glioma cells treated with IFN-β.Results(1) A combination of IFN-β/TMZ had significant synergistic antitumor activity on the growth of both T98 and U251SP tumors. (2) MGMT promoter activity was suppressed by either adenovirally transduced p53 or IFN-β.ConclusionsIt would be appealing to consider a prospective clinical trial in which genetic markers are used for personalized drug selection, eliciting other forms of treatment or inhibition of MGMT for those with MGMT expression. In this context, IFN-β inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ.

Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas

OBJECT The aim of this study was to evaluate the outcomes in patients with convexity, parasagittal, or falcine meningiomas treated using Gamma Knife surgery (GKS) and to determine management strategy considering a risk of radiation-induced edema. METHODS One hundred twelve patients who harbored 125 convexity, parasagittal, or falcine meningiomas were assessed. Forty-six patients underwent GKS as the initial treatment. The median tumor diameter was 25 mm, and median tumor volume was 8 cm(3). The median maximum and margin doses were 30 and 16 Gy, respectively. RESULTS The median follow-up period was 72 months. The actuarial 5- and 10-year progression-free survival rates were 78% and 55%, respectively. The actuarial 5- and 10-year local tumor control rates were 87% and 71%, respectively. Of 29 tumors that developed postradiosurgical edema, 7 were symptomatic. The actuarial symptomatic radiation-induced edema rate was 7%. The incidence of this complication was significantly higher in patients who underwent GKS as the initial treatment. Six of 46 patients for whom GKS was the initial treatment had preradiosurgical edema. Of these 6 patients, 4 developed severe panhemispheric edema after GKS (2 patients with parasagittal tumors, 1 with a falx tumor, and 1 with a convexity tumor). CONCLUSIONS Gamma Knife surgery is an effective treatment for convexity, parasagittal, and falcine meningiomas as the initial or adjuvant treatment. However, GKS should be restricted to small- to medium-sized tumors, particularly in patients with primary tumors, because radiation-induced edema is more common in convexity, parasagittal, and falcine meningiomas than skull base meningiomas.