HYDROXYUREA FOR TREATMENT OF UNRESECTABLE AND RECURRENT MENINGIOMAS .1. INHIBITION OF PRIMARY HUMAN MENINGIOMA CELLS IN CULTURE AND IN MENINGIOMA TRANSPLANTS BY INDUCTION OF THE APOPTOTIC PATHWAY

Meningiomas, which invade intracranial bone structures and the adjacen t connective tissue, are frequently unresectable because of their agre ssive and recalcitrant growth behavior. They have a high recurrence ra te, and in approximately 10% of these tumors there is an increased ris k of malignancy. Significant morbidity and mortality rates associated with recurrent meningiomas demand nonsurgical approaches. To date, adj uvant hormonal treatment has not proven beneficial. The anticancer dru g hydroxyurea was therefore tested for its potential use in the treatm ent of meningiomas. Early-passaged cell cultures were established from 20 different meningiomas. The addition of 5 x 10(-4) and 10(-3) M hyd roxyurea over a period of 5 to 9 days resulted in a remarkable decreas e in cell proliferation and even blocked tumor cell growth when compar ed with untreated cells. A significant arrest of meningioma cell growt h in the S phase of the cell cycle was revealed on DNA flow cytometry. Electron micrographs of hydroxyurea-treated tumor cells showed ultras tructural features consistent with apoptosis, and light microscopy dem onstrated DNA fragmentation by in situ DNA strand break labeling. Shor t-term treatment of meningioma cell cultures with hydroxyurea for 24 t o 48 hours resulted in discrete oligonucleosomal fragments (DNA ladder ), another characteristic sign of apoptosis. In addition to the in vit ro studies, tissue from five different meningiomas was transplanted in to nude mice followed by treatment with 0.5 mg/g body weight hydroxyur ea over 15 days. In situ DNA strand break labeling demonstrated DNA fr agmentation in distinct regions with different tumor cell densities in all hydroxyurea-treated meningioma transplants. These data provide ev idence that hydroxyurea is a powerful inhibitor of meningioma cell gro wth, most likely by causing apoptosis in the tumor cells. Thus, hydrox yurea may be a suitable chemotherapeutic agent for the long-term treat ment of unresectable or semi- to malignant meningiomas, or for prevent ing recurrent growth of meningiomas after resection.