Hydroxyurea for treatment of unresectable and recurrent meningiomas. I. Inhibition of primary human meningioma cells in culture and in meningioma transplants by induction of the apoptotic pathway

Abstract

Meningiomas, which invade intracranial bone structures and the adjacent connective tissue, are frequently unresectable because of their aggressive and recalcitrant growth behavior. They have a high recurrence rate, and in approximately 10% of these tumors there is an increased risk of malignancy. Significant morbidity and mortality rates associated with recurrent meningiomas demand nonsurgical approaches. To date, adjuvant hormonal treatment has not proven beneficial. The anticancer drug hydroxyurea was therefore tested for its potential use in the treatment of meningiomas. Early-passaged cell cultures were established from 20 different meningiomas. The addition of 5 x 10(-4) and 10(-3) M hydroxyurea over a period of 5 to 9 days resulted in a remarkable decrease in cell proliferation and even blocked tumor cell growth when compared with untreated cells. A significant arrest of meningioma cell growth in the S phase of the cell cycle was revealed on DNA flow cytometry. Electron micrographs of hydroxyurea-treated tumor cells showed ultrastructural features consistent with apoptosis, and light microscopy demonstrated DNA fragmentation by in situ DNA strand break labeling. Short-term treatment of meningioma cell cultures with hydroxyurea for 24 to 48 hours resulted in discrete oligonucleosomal fragments (DNA ladder), another characteristic sign of apoptosis. In addition to the in vitro studies, tissue from five different meningiomas was transplanted into nude mice followed by treatment with 0.5 mg/g body weight hydroxyurea over 15 days. In situ DNA strand break labeling demonstrated DNA fragmentation in distinct regions with different tumor cell densities in all hydroxyurea-treated meningioma transplants. These data provide evidence that hydroxyurea is a powerful inhibitor of meningioma cell growth, most likely by causing apoptosis in the tumor cells. Thus, hydroxyurea may be a suitable chemotherapeutic agent for the long-term treatment of unresectable or semi- to malignant meningiomas, or for preventing recurrent growth of meningiomas after resection.

Technetium-99m Sestamibi Single Photon Emission Computed Tomography Findings Correlated With P-glycoprotein Expression, Encoded by the Multidrug Resistance Gene-1 Messenger Ribonucleic Acid, in Intracranial Meningiomas

“…Recently, hydroxyurea, a ribonucleotide reductase inhibitor, was used in adjuvant chemotherapy for patients with recurrent or unresectable meningioma, and was effective in halting the growth of enlarging benign meningiomas but not malignant meningiomas. 21,28,31) Hydroxyurea may inhibit the growth of meningioma cell lines through an apoptotic mechanism. 30) Interestingly, in vitro exposure of renal cancer cells to low-dose hydroxyurea causes loss of chromosomal aberration, decrease in the number of MDR-1 gene copies, and increased sensitivity to vinblastine.…”

Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea

“…[13] The decision to introduce hydroxyurea in the treatment of unresectable and recurrent meningiomas was ultimately based on our experimental findings in cell cultures and in tumor cell transplants in nude mice, which demonstrated that hydroxyurea stopped cell growth by triggering the apoptotic cascade. [31,32] Hydroxyurea has never been used in the treatment of meningiomas and response rates of up to 70% within 1 year of initiation of oral administration reflect extraordinary success in the treatment of this solid tumor. By analogy with our experimental data, [31,32] we suggest that induction of apoptosis is also the cause of tumor regression in our patients.…”

“…[31,32] Hydroxyurea has never been used in the treatment of meningiomas and response rates of up to 70% within 1 year of initiation of oral administration reflect extraordinary success in the treatment of this solid tumor. By analogy with our experimental data, [31,32] we suggest that induction of apoptosis is also the cause of tumor regression in our patients. The activation of this mechanism gives hope that long-term treatment with hydroxyurea can lead to a true remission.…”

“…This chemotherapeutic drug drastically inhibits the growth of human meningioma cells and meningioma transplants in nude mice by triggering the apoptotic cascade. [31,32] This is the first report of a successful use of hydroxyurea in the medical treatment of unresectable and recurrent benign as well as malignant meningiomas.…”

Ensayos de quimiosensibilidad en cultivos primarios de tumores cerebrales

“…Se analizaron fármacos correspondientes a familias distintas de quimioterápicos, algunos de uso habitual en determinados tumores, donde ya han mostrado su eficacia 4,17,18 , todos ellos con un margen de concentración de 10-2 hasta 10-12 M.…”