Induction of apoptosis in multi-drug resistant (MDR) human glioblastoma cells by SN-38, a metabolite of the camptothecin derivative CPT-11 |
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Authors: | Shouji Nakatsu S Kondo Yasuko Kondo Dali Yin John W Peterson Rami Kaakaji Tatsuo Morimura Haruhiko Kikuchi Juji Takeuchi Gene H Barnett |
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Institution: | (1) Department of Neurosurgery, Faculty of Medicine, Kyoto University, Kyoto 606, Japan, JP;(2) Department of Neurosurgery, Brain Tumor Center/Cancer Center, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA Fax 216-444-9170, US;(3) Department of Neurosurgery, National Utano Hospital, Kyoto 616, Japan, JP;(4) Department of Neurosciences, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA, US |
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Abstract: | The overexpression of the multidrug resistance (mdr1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumors. Recent studies
demonstrate that SN-38, a metabolite of the camptothecin (CPT) derivative CPT-11, has antitumor effects on several tumors,
but the mechanisms responsible for its cytotoxicity remain unclear. We therefore determined whether SN-38 has cytotoxic effects
on MDR human glioblastoma GB-1 cells and non-MDR human glioblastoma U87-MG cells. Furthermore, we determined what role SN-38
plays in the induction of cytotoxicity in these tumor cells. In this study, we demonstrated that SN-38 had significantly stronger
antitumor effects on GB-1 and U-87MG cells than did CPT (P<0.01 and P<0.05, respectively). In addition, findings obtained using a DNA fragmentation assay, Hoechst 33258 staining, in situ end-labeling
and cell cycle analysis demonstrated that SN-38 induced apoptosis in these tumors. Our results suggest that SN-38 has a stronger
antitumor effect on malignant glioma cells regardless of MDR expression than does CPT, and therefore can be considered a new
chemotherapeutic agent potentially effective in the treatment of human primary or recurrent malignant gliomas resistant to
chemotherapy.
Received: 6 October 1995/Accepted 29 June 1996 |
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Keywords: | Apoptosis Chemotherapy Camptothecin SN-38 Multidrug resistance Glioma |
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