ABSTRACT
BACKGROUND: Resistance to chemotherapeutic agents and poor blood-brain barrier penetration are major limitations in the treatment of malignant glioma. To improve drug delivery across the blood-brain barrier, the authors used doxorubicin as liposomal encapsulated formulation (Caelyx, Scheringh-Plough, Munich, Germany) in therapy of recurrent malignant glioma. METHODS: Fifteen patients with recurrent high-grade gliomas were included in the study. Of these, 13 patients could be evaluated, including 6 patients with glioblastoma, 1 patient with gliosarcoma and 6 patients with anaplastic astrocytoma. The treatment consisted of liposomal doxorubicin (20 mg/m(2)), applied intravenously every 2 weeks. RESULTS: Stabilization of the disease was observed in 54% (7 of 13) of patients. Partial response and complete response (CR) were not observed. Median time-to-progression was 11 weeks. Progression free survival at 12 months was 15%. Median overall survival (OS) after doxorubicin therapy was 40.0 weeks, whereas the median OS after diagnosis reached 20.0 months (87.0 weeks). Doxorubicin was well tolerated, with main side effects being palmoplantar erythrodysesthesia occurring in 38% and myelotoxicity (World Health Organization Grade 3-4) in 31% of the patients. CONCLUSIONS: Doxorubicin has been shown to be a safe treatment with moderate activity that may lead to long-term stabilization in recurrent high-grade glioma patients. Of note, median OS after all and after initiation of recurrence therapy was prolonged in comparison with the OS in other Phase II studies, as recently described by Wong et al. (Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999;17:2572.).
Subject(s)
Antineoplastic Agents/therapeutic use , Central Nervous System Neoplasms/drug therapy , Doxorubicin/therapeutic use , Glioma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Doxorubicin/administration & dosage , Drug Administration Schedule , Female , Humans , Liposomes , Male , Middle Aged , Remission Induction , Survival AnalysisABSTRACT
Transforming growth factors-beta 1 and -beta 2 (TGF-beta 1 and -beta 2) are important growth-regulatory proteins for astroglial neoplasms. We analyzed their role in tumor-cell proliferation in 12 glioma cell lines, employing phosphorothioate antisense oligodeoxynucleotides (S-ODNs, 14 mer), specifically targeted against the coding sequences of TGF-beta 1-mRNA and TGF-beta 2-mRNA. TGF-beta 1-S-ODNs inhibited cell proliferation in 5 of 12 gliomas, whereas TGF-beta 2-S-ODNs reduced the cell proliferation in all glioma cell lines, compared to nonsense-S-ODN-treated and S-ODN-untreated cells as controls. The efficacy and specificity of antisense effects was validated by Northern-blot analysis and determination of protein concentrations in culture supernatants (ELISA). Exogenous hrTGF-beta 1 either stimulated or inhibited the cell lines, whereas pnTGF-beta 2 stimulated the proliferation of most glioma cells. Blocking the extracellular pathway of TGF-beta by neutralizing antibodies only slightly inhibited those cell lines, which were markedly stimulated by TGF-betas. As the effects of TGF-beta 2-S-ODNs were much stronger than those of TGF-beta neutralizing antibodies, we postulate that the endogenously produced TGF-beta 2 control glioma-cell proliferation, in part by an intracellular loop.
