Irinotecan: a potential new chemotherapeutic agent for atypical or malignant meningiomas

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Object

There is currently no effective chemotherapy for meningiomas. Although most meningiomas are treated surgically, atypical or malignant meningiomas and surgically inaccessible meningiomas may not be removed completely. The authors have investigated the effects of the topoisomerase I inhibitor irinotecan (CPT-11) on primary meningioma cultures and a malignant meningioma cell line in vitro and in vivo.

Methods

The effects of irinotecan on cellular proliferation in primary meningioma cultures and the IOMM-Lee malignant meningioma cell line were measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide assay and flow cytometry. Apoptosis following drug treatment was evaluated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and the DNA laddering assays. The effects of irinotecan in vivo on a meningioma model were determined with a subcutaneous murine tumor model using the IOMM-Lee cell line.

Irinotecan induced a dose-dependent antiproliferative effect with subsequent apoptosis in the primary meningioma cultures (at doses up to 100 μM) as well as in the IOMM-Lee human malignant meningioma cell line (at doses up to 20 μM) irinotecan. In the animal model, irinotecan treatment led to a statistically significant decrease in tumor growth that was accompanied by a decrease in Bcl-2 and survivin levels and an increase in apoptotic cell death.

Conclusions

Irinotecan demonstrated growth-inhibitory effects in meningiomas both in vitro and in vivo. Irinotecan was much more effective against the malignant meningioma cell line than against primary meningioma cultures. Therefore, this drug may have an important therapeutic role in the treatment of atypical or malignant meningiomas and should be evaluated further for this purpose.

Abbreviations used in this paper:DMEM = Dulbecco modified Eagle medium; EMA = epithelial membrane antigen; FBS = fetal bovine serum; GFAP = glial fibrillary acidic protein; HPLC = high-pressure liquid chromatography; MTT = 3-(4,5-dimethyl-2-thia-zolyl)-2,5-diphenyl tetrazolium bromide; PBS = phosphate-buffered saline; TUNEL = terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling.

Article Information

Address reprint requests to: Thomas C. Chen, M.D., Ph.D., Department of Neurosurgery, University of Southern California, 1200 North State Street #5046, Los Angeles, California 90089. email: tcchen@usc.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Photomicrographs of representative primary meningioma cells showing the results of immunohistochemical analysis. Cytopreps prepared from early-passage primary cultures of meningioma were immunostained for CD11 (CD-11b), GFAP, factor VIII, smooth muscle actin (SMA), and EMA. Positive staining for EMA is indicative of meningioma, whereas GFAP, S100 protein, and vimentin are known to be negative in this tumor type.

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    Bar graphs showing inhibition of cellular proliferation of primary meningioma cultures by irinotecan (CPT-11) as measured by the MTT assay. Primary meningioma cultures (A) and cells from the IOMM-Lee cell line (B) were treated with irinotecan for 48 hours, after which cellular proliferation was determined by the MTT assay. Values shown are the means ± standard errors (SEs) from six measurements.

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    Bar graph depicting inhibition by irinotecan of IOMM-Lee cell colony formation. One hundred IOMM-Lee cells were plated in six-well plates and treated with indicated doses of irinotecan for 48 hours. Cell colonies were allowed to form over the following 8 days, after which they were stained with methylene blue and counted. Values shown are the means ± SEs from three measurements.

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    Photomicrographs demonstrating induction of apoptosis by irinotecan in primary meningioma cells as measured by the TUNEL assay. Primary meningioma cells treated with 10, 100, and 250 μM irinotecan for 48 hours were subjected to TUNEL assay. Increased positive staining (red) for apoptosis was detected in cells treated with irinotecan.

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    Western blot demonstrating induction of apoptosis by irinotecan in primary meningioma cells as measured by the DNA fragmentation assay. Primary meningioma cells were treated with irinotecan at 10, 100, and 200 μM for 48 hours, after which the cells were harvested and genomic DNA was isolated and separated by agarose gel electrophoresis.

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    Bar graph showing the effect of irinotecan on cell cycle distribution in primary meningioma cells. Primary human meningioma cells were subjected to varying doses of irinotecan for 48 hours. The cells were isolated, stained with propidium iodide, and subjected to flow cytometry. Values shown are the mean percentages of cells in the various cell cycle phases ± SEs.

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    Western blot showing decreased Bcl-2/Bax ratio with irinotecan treatment in the IOMM-Lee cell line. The IOMM-Lee cells were harvested after being treated with varying concentrations of irinotecan for 48 hours, and total cell lysates were prepared and analyzed by Western blot analysis with specific antibodies to Bcl-2 and Bax.

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    Graph showing tumor growth inhibition after irinotecan treatment in a xenograft model. Athymic nude mice were implanted subcutaneously with IOMM-Lee human meningioma cells. After palpable tumors (~ 0.1 cm3) developed, the animals were divided into two groups of five animals each: control (PBS treatment only) and treatment (irinotecan [CPT-11]; 30mg/m2/day × 5 days × two cycles). Starting on Day 3 of Cycle 1, differences in tumor volume between the control (PBS) group and the treatment group (CPT-11) became apparent; they had reached high statistical significance (p = 0.0002) at the termination of the experiment on Day 26. Values shown represent the mean tumor volumes ± SEs for the five animals in each group.

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    Photomicrographs demonstrating the in vivo detection of Bcl-2, Bax, survivin, and apoptosis via TUNEL assay in tumors treated with irinotecan. Tumor sections were obtained from irinotecan-treated and control animals after the first treatment cycle (5 days irinotecan or 5 days PBS), and were subjected to immunohistochemical analysis using specific antibodies to Bcl-2, Bax, or survivin or the TUNEL assay. Positive cells are red.

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