Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme.

Abstract

PURPOSE:

Glioblastoma multiforme (GBM) represents the prototype of an angiogenic tumor. Recently, the continuous low-dose scheduling of chemotherapeutic drugs in combination with an inhibition of cyclooxygenase-2 (COX-2) has been suggested as a novel anti-angiogenic approach. The aim of this study was to evaluate the safety and activity of continuous low-dose temozolomide (TMZ) plus the COX-2 inhibitor rofecoxib in patients with newly diagnosed GBM.

METHODS:

In vitro, endothelial cells were characterized by a tenfold higher sensitivity to TMZ than glioma cells. Consequently, a subgroup of patients with incompletely resected GBM (n=13) was divided into three groups aiming at a dose escalation to 1/10 of the daily MTD for TMZ: (A) TMZ 10 mg/m2 every third day and rofecoxib 25 mg/d; (B) TMZ 10 mg/m2/d and rofecoxib 25 mg/d; (C) TMZ 5 mg/m2 twice a day and rofecoxib 12.5 mg twice a day. COX-2, VEGF, VEGF Receptor-2, and CD34 were assessed immunohistochemically, in the clinical setting.

RESULTS:

The mean follow-up period was 15 months. We observed no severe toxicity attributable to the therapy. Quality of life was not impaired. For the whole study population, median time to progression and overall survival were 8 months and 16 months, respectively. Immunohistochemistry suggested that tumors with higher vessel densities were characterized by a significantly better control than those with lower vessel densities.

CONCLUSIONS:

Continuous low-dose TMZ plus rofecoxib is feasible, safe, and maintains good quality of life. This study is indicative of an anti-angiogenic efficacy of continuous low-dose TMZ plus rofecoxib in GBMs, especially in those tumors that are characterized by a high angiogenic activity.

• Authors: Jochen Tuettenberg, Rainer Grobholz, Tobias Korn, Frederik Wenz, Ralf Erber, Peter Vajkoczy
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 131 Issue 1 Pg. 31-40 (Jan 2005) ISSN: 0171-5216 [Print] Germany
• PMID: 15565458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents, Alkylating
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Isoenzymes
• Lactones
• Membrane Proteins
• Sulfones
• rofecoxib
• Dacarbazine
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Temozolomide

Topics

• Adult
• Angiogenesis Inhibitors (adverse effects, therapeutic use)
• Antineoplastic Agents, Alkylating (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Brain Neoplasms (secondary)
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (adverse effects, therapeutic use)
• Dacarbazine (administration & dosage, analogs & derivatives)
• Disease-Free Survival
• Drug Administration Schedule
• Female
• Glioblastoma (blood supply, drug therapy, enzymology)
• Humans
• Immunohistochemistry
• Isoenzymes (antagonists & inhibitors)
• Lactones (administration & dosage)
• Male
• Membrane Proteins
• Middle Aged
• Neovascularization, Pathologic (enzymology, prevention & control)
• Prostaglandin-Endoperoxide Synthases
• Sulfones (administration & dosage)
• Survival Analysis
• Temozolomide