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[Cancer Research 61, 7501-7506, October 15, 2001]
© 2001 American Association for Cancer Research

Experimental Therapeutics

Low-dose Chemotherapy Combined with an Antiangiogenic Drug Reduces Human Glioma Growth in Vivo1

Lorenzo Bello2, Giorgio Carrabba, Carlo Giussani, Valeria Lucini, Francesca Cerutti, Francesco Scaglione, Julien Landré, Mauro Pluderi, Giustino Tomei, Roberto Villani, Rona S. Carroll, Peter McL Black and Andreas Bikfalvi

Institute of Neurosurgery, University of Milano, Ospedale Maggiore Policlinico, IRCCS, Milan, Italy [L. B., G. C., C. G., M. P., G. T., R. V.], Department of Pharmacology, University of Milano, Milan, Italy [V. L., F. C., F. S.], Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts [R. S. C., P. M. B.], and Institut National de la Santé et de la Recherche Médicale Unit EPI 0113, Molecular Mechanisms of Angiogenesis & Growth Factor and Cell Differentiation Laboratory, University of Bordeaux I, Talence, France [J. L., A. B.]

This study evaluates the efficacy of the combination of an antiangiogenic drug and conventional chemotherapeutics for the treatment of experimental human gliomas. As an antiangiogenic, we used recombinant human PEX, a fragment of matrix metalloproteinase-2 that we have previously shown to have a significant antimitotic, anti-invasive, and antiangiogenic properties against human glioblastoma in vitro and in vivo. We used carboplatin and etoposide as the two chemotherapeutic drugs routinely used in our institution (Ospedale Maggiore de Milano) for the treatment of malignant gliomas. Conventional chemotherapeutic drugs were administered at high dose or at a low and semicontinuous regimen. Combined treatment of high-dose chemotherapy and PEX did not produce an improvement of survival in comparison with chemotherapy alone, but it was associated with a decrease in tumor volume, vascularity, and proliferative index and an increased apoptosis. All of these animals experienced severe side effects. The longest survival was documented in animals submitted to low and semicontinuous chemotherapy and antiangiogenic treatment. This regimen was associated with no side effects, marked decrease in tumor volume, vascularity, and proliferative index, and an increased apoptosis. Our data suggest that low-dose chemotherapy in combination with PEX can be successfully used against human malignant glioma in vivo.




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