Calcium channel antagonists augment hydroxyurea- and ru486-induced inhibition of meningioma growth in vivo and in vitro.
OBJECTIVE
Although the chemotherapy drug hydroxyurea (HU) and the antiprogesterone mifepristone (RU486) have been used to treat meningiomas for which surgical and radiation therapies have failed, results have been disappointing. The addition of calcium channel antagonists (CCAs) to chemotherapeutic drugs enhances tumor growth inhibition in other tumor types, and the authors demonstrated that CCAs can block meningioma growth in vitro and in vivo. The purpose of this study was to test the effects of the addition of a CCA to HU or RU486 on meningioma growth.


METHODS
Primary and malignant (IOMM-Lee) meningioma cell lines were treated with HU, RU486, or either of these plus diltiazem or verapamil. Assays for cell growth, apoptosis, and fluorescent-activated cell sorting were performed on in vitro cultures. Similar cell lines were implanted into nude mice and were treated with HU or RU486, in combination with a CCA. Tumors were analyzed by light microscopy, MIB-1, and factor VIII immunohistochemical staining studies.


RESULTS
The addition of diltiazem or verapamil to HU or RU486 augmented meningioma growth inhibition by 20 to 60% in vitro. In vivo, tumors treated with combination drugs were smaller; and immunohistochemical analysis of the IOMM-Lee tumors showed a 10% decrease in the MIB-1 ratio (from 0.41 to 0.30) and an approximate 75% decrease in microvascular density.


CONCLUSIONS
The addition of diltiazem or verapamil to HU or RU486 augments meningioma growth inhibition in vitro by inducing apoptosis and G1 cell-cycle arrest. The combination of HU and diltiazem inhibited the growth of meningiomas in vivo by decreasing proliferation and microvascular density. These results suggest a possible role for these drugs as an additional adjuvant therapy for recurrent or unresectable meningiomas.
Ragel
Brian T
BT
Department of Neurosurgery, University of Utah, 30 North 1900 East, Suite 3B409, Salt Lake City, UT 84132, USA.
Gillespie
David L
DL
Kushnir
Vitaly
V
Polevaya
Nika
N
Kelly
David
D
Jensen
Randy L
RL
D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D008579:Meningioma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D015735:Mifepristone / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D015735:Mifepristone; D006918:Hydroxyurea