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hydroxyurea figure 2.13

alkylating agent, cross-linking DNA. Dibromodulcitol is administered orally and undergoes rapid and complete absorption from the gastrointestinal tract [167]. The first use of dibromodulcitol was as a sensitizer during radiation therapy of malignant gliomas [168]. Studies of single-agent dibromodulcitol have demonstrated activity against a variety of PBT [169,170]. Levin and colleagues administered dibromodulcitol (100-150 mg/m2 per day) to patients with recurrent PBT and noted moderate efficacy in patients with medulloblastoma and ependymoma [169]. In a recent randomized trial of 238 patients with high-grade astrocytoma, Elliot and associates found that dibromodulcitol (200 mg/m2 days 1-10 every 5 weeks) demonstrated efficacy similar to that of intravenous BCNU [170]. The median survival was 41 weeks in both arms of the study, with identical median times to progression (22 weeks). Other investigators have used dibromodulcitol in multi-drug regimens that usually include BCNU and PCB [147,171,172]. Although these regimens have activity against malignant gliomas, it remains unclear if there is a significant survival advantage over single-agent temozolomide or intravenous BCNU. The major toxicity of dibromodulcitol is myelosuppression; nausea, emesis, nephrotoxicity, and hepatotoxicity are mild.

Hydroxyurea. Hydroxyurea is a cell-cycle-specific urea analog that inhibits the enzyme ribonucleotide diphosphate reductase, thereby interfering with DNA synthesis by reducing the available pool of deoxy-ribonucleotides (see Fig. 2.13) [8,21]. It is administered orally and is well absorbed by the gastrointestinal tract. Hydroxyurea is most often used as a radiation sensitizer or in combination with other agents for the treatment of malignant PBT [8,147]. Recently, other investigators have evaluated hydroxyurea as a therapy for unresectable and recurrent meningiomas [173-177]. Meningioma cell cultures were inhibited after the treatment with hydroxyurea and exhibited arrest in S-phase of the cell cycle [173]. Ultrastructural evaluation of the affected cells was consistent with the induction of the apoptotic pathway. Similar findings were noted in tumors transplanted into nude mice. The same authors administered hydroxyurea (20 mg/kg per day) to four patients with unresectable meningiomas [174]. Objective shrinkage occurred in 3 of the 4 patients, ranging from 15 to 75 per cent, while the fourth patient remained stable. Toxicity was mild and consisted mainly of myelo-suppression. Several larger phase II studies have demonstrated activity against meningioma, but had infrequent objective responses [175-177]. For more information regarding the chemotherapy of menin-giomas, see Chapter 34.

Mifepristone (RU 486). Mifepristone is an anti-progestin derived from norethindrone that has recently been evaluated as a therapy for patients with unresectable meningiomas [21,178]. Its mechanism of action is to block the progesterone receptors, which occur at higher concentrations (60-75 per cent) in meningiomas and are involved in mitogenic pathways [179]. When used on meningioma cultures, mifepristone demonstrated 18-36 per cent growth inhibition [180]. Grunberg and colleagues performed a phase II trial of mifepristone (200 mg/day orally) in 14 patients with unresectable meningiomas [181]. Four patients had minor regression of tumor by computed tomograpy or MRI; one patient had stable disease with improvement of visual fields. The most common side effect of mifepristone was fatigue; less frequent side effects included hot flashes, gynecomastia, alopecia, and cessation of menses. A large, multicenter phase III randomized, placebo-controlled, trial of mifepristone has recently been reported and did not reveal a significant difference in survival between the treatment arm and the placebo [182].

Tamoxifen. Tamoxifen is a nonsteroidal antiestro-gen that is used most often for the treatment of breast cancer patients. However, recent research suggests that tamoxifen also inhibits the activity of protein kinase C, a cytoplasmic enzyme involved in intracel-lular signaling pathways that can induce cell proliferation [183,184]. Glioma cells strongly express protein kinase C and known mitogens of glioma cells, such as fibroblast growth factor and epidermal growth factor are able to enhance protein kinase C activity. Cultured glioma cells are inhibited by clinically relevant concentrations of tamoxifen, with concomitant decrease in 3H-thymidine incorporation [184]. Couldwell and colleagues administered tamoxifen (80-100 mg bid orally) to 11 patients with recurrent malignant gliomas that had failed irradiation [185]. Three patients had objective responses that lasted longer than 12 months; one patient had

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