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In vivo antitumor activity of S16020, a topoisomerase II inhibitor, and doxorubicin against human brain tumor xenografts

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Abstract

New active drugs are needed for the treatment of primary brain tumors in both children and adults. S16020 is a cytotoxic olivacine derivative that inhibits topoisomerase II. The aim of the study was to determine its antitumor activity in athymic mice bearing subcutaneous medulloblastoma (IGRM33, 34, 57) and glioblastoma (IGRG88, 93, 121) xenografts treated at an advanced stage of tumor growth in comparison with that of doxorubicin. Animals were randomly assigned to receive i.v. S16020 or doxorubicin weekly for three consecutive weeks. The optimal dose was 80 mg/kg per week. S16020 demonstrated a significant antitumor activity in two out of three medulloblastoma xenografts. IGRM57 xenografts were highly sensitive with 100% tumor regressions and a tumor growth delay (TGD) of 102 days, while one of eight IGRM34 xenografts showed a partial regression with a TGD of 16 days. Doxorubicin was significantly more active than S16020 in these two models. IGRM33, a model established from a tumor in relapse after chemotherapy and radiotherapy, was refractory to both drugs. S16020 demonstrated a significant antitumor activity in the three glioblastoma xenografts evaluated. The wild-type p53 IGRG93 xenograft was highly sensitive with 100% tumor regressions and a TGD of 54 days. IGRG121 (wt p53) and IGRG88 (mutant p53) were moderately sensitive with TGDs of 33 and 23 days, respectively. Doxorubicin showed greater activity in two of these models. All six xenografts exhibited low expression of mdr1 as quantitated by RT-PCR, and no correlation was found with the activity of either drug. Conversely, a low activity of the two drugs was significantly associated with a high expression of MRP1 in medulloblastomas. Finally, no relationship was observed between drug sensitivity to either drug and expression of their target, topoisomerase IIα. In conclusion, S16020 and doxorubicin showed significant antitumor activity in brain tumor xenografts treated at an advanced stage of tumor growth. Their activity was related to MRP1 expression in medulloblastomas.

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Acknowledgements

We thank Patrice Ardouin and the Staff of the Animal Experimentation Unit, Institut Gustave Roussy, for care of the animals.

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Authors and Affiliations

  1. UPRES EA 3535 Pharmacology and New Treatments of Cancers, Institut Gustave-Roussy, Villejuif, France

    Gilles Vassal, Geneviève Aubert & Jackie Morizet

  2. Department of Pediatric Oncology, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805, Villejuif cedex, France

    Gilles Vassal, Jacques Grill & Chantal Kalifa

  3. Laboratory of Oncology Research, Centre Alexis Vautrin, Nancy, France

    Jean-Louis Merlin

  4. Department of Pathology, Institut Gustave-Roussy, Villejuif, France

    Marie-José Terrier-Lacombe

  5. Department of Neurosurgery, Hopital Bicêtre, Le Kremlin-Bicêtre, France

    Fabrice Parker

  6. Pediatric Neurosurgery, Hôpital Necker, Paris, France

    Christian Sainte-Rose

  7. Institut Curie, Paris, France

    Nicolas Sévenet

  8. Institut de Recherches Internationales Servier, Courbevoie, France

    Marie-Gwenaëlle Poullain & Catherine Lucas

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  1. Gilles Vassal
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Correspondence to Gilles Vassal.

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Vassal, G., Merlin, JL., Terrier-Lacombe, MJ. et al. In vivo antitumor activity of S16020, a topoisomerase II inhibitor, and doxorubicin against human brain tumor xenografts. Cancer Chemother Pharmacol 51, 385–394 (2003). https://doi.org/10.1007/s00280-003-0584-1

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  • DOI: https://doi.org/10.1007/s00280-003-0584-1

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