Abstract
Abstract INTRODUCTION Evidence suggests that captopril might inhibit matrix metalloproteinase-2 (MMP-2), an endopeptidase that selectively breaks down elements of the extracellular matrix and that is associated with glioma cell migration. We analyzed the effects of captopril on MMP-2 expression in gliosarcoma cells in Vitro and on survival in an in Vivo murine intracranial gliosarcoma model. METHODS For survival, F344 rats were implanted intracranially with 9 L gliosarcoma tumor fragments, and were then divided into groups: (1) control, receiving no treatment; (2) oral captopril, 30 mg/kg/day on days 5 to 14; (3) oral temozolomide (TMZ), 50 mg/kg on days 5 to 9; and (4) oral TMZ and oral captopril. For immunohistochemistry, on day 0, additional F344 rats were implanted intracranially with 9 L gliosarcoma cells and divided into groups: (1) control; and (2) oral captopril, 30 mg/kg/day. Rats from each group were sacrificed on days 6, 8, and 11. To assess the MMP-2 protein level, cultured 9 L gliosarcoma cells were treated with either 100, 150, or 200 μg/mL of captopril or ultrapure water as the vehicle, and protein expression was assessed via Western blots at 24, 48, 72, and 96 h. RESULTS Captopril in Vivo extended survival in a murine intracranial gliosarcoma model significantly. Within a period of 30 d, adjuvant captopril presented a statistically significant survival advantage compared to the control, captopril-only, and TMZ-only groups (27.5 d versus 14, 16, and 23 d, P < .001, < .001, and .02, respectively). Immunohistochemistry analysis of treated animal brains demonstrated a dose-dependent decrease in MMP-2 expression with captopril, while Western blots of treated 9 L cells in Vitro demonstrated a decreased MMP-2 expression. CONCLUSION Captopril as adjuvant therapy to TMZ increased survival in a rat intracranial gliosarcoma model. A dose-dependent reduction in MMP-2 expression with captopril was demonstrated in Vitro. Captopril may serve as a potential adjuvant to TMZ therapy and deserves further investigation.
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