azo-PCB into two separate azoxy-PCB derivatives, which have significantly greater antitumor activity than PCB or azo-PCB [90,91]. Once activated, PCB alkylates DNA at the O6 position of guanine [92]. In addition, PCB can induce DNA strand breakage and inhibit DNA, RNA, and protein synthesis. PCB has further pharmacological properties, including activity as a monoamine oxidase-inhibitor and a disulfiram-like effect [8,21]. Potential interactions (i.e., acute hypertension) can occur if PCB is taken concomitantly with sympathomimetic drugs, antihis-tamines, tricyclic antidepressants, and food, high in tyramine content (e.g., wine, beer, cheese, chocolate, bananas, and yogurt) [93]. Due to the disulfiram-like effect, alcohol should be avoided while taking PCB, or severe gastrointestinal distress will develop. Although water soluble, PCB and its metabolites readily cross the blood-brain barrier, with rapid equilibration between plasma and cerebrospinal fluid.

Procarbazine has been used to treat malignant PBT as a single-agent or in multi-agent regimens [8,21,71-73]. As mentioned above, single-agent PCB was compared to intravenous BCNU, methylprednisolone, and intravenous BCNU plus methylpred-nisolone in a randomized trial of malignant glioma patients by Green and colleagues [85]. Overall median survival was similar for the PCB (47 weeks) and BCNU (50 weeks) groups. Although the survival percentage was similar for PCB and BCNU at 12 months (44.0 versus 48.5 per cent), long-term survival at 18 and 24 months was superior in the PCB group (28.8 and 22.8 per cent versus 23.8 and 15.6 per cent, respectively). Newton and colleagues found PCB beneficial for glioma patients after failure of irradiation and nitrosourea chemotherapy [94]. In a series of 35 patients they noted 2 complete responses, 7 partial responses, and 11 patients with stable disease. Furthermore, when responses were compared in a cohort of malignant glioma patients who were initially treated with BCNU and then received PCB (after BCNU failure), there was a significant difference in time to progression between the groups [95]. The PCB group had a greater percentage of patients without disease progression at 6 and 12 months as compared to BCNU (48 and 35 per cent versus 26 and 3 per cent, respectively). Other investigators have found singleagent PCB to be less efficacious, with fewer complete and partial responses [96].

The most commonly used multi-agent regimen that incorporates PCB is PCV (PCB 60 mg/m2 per days, 8-21, CCNU 110 mg/m2 day 1, vincristine 1.4 mg/m2 days 8 and 28; every 8 weeks) [8,21,71-73]. Numerous reports document the efficacy of PCV against anaplastic oligodendrogliomas, anaplastic astrocytomas, recurrent oligodendrogliomas, and mixed gliomas. The most dramatic results have been in patients with anaplastic or recurrent oligodendro-gliomas [97-99]. Cairncross and colleagues have determined that anaplastic oligodendrogliomas are relatively chemosensitive, especially to PCV. Several series of patients have reported durable response rates in excess of 50 per cent [73,97-99]. A recent report suggests that anaplastic oligodendrogliomas with a specific molecular genetic profile are more sensitive to PCV [99]. Those patients with tumors that had allelic deletion or loss of heterozygosity of chromosomes 1p and 19q had significantly longer recurrence-free and overall survival than patients that retained 1p and 19q. The use of PCV appears to be beneficial for recurrent typical (i.e., WHO grade II) oligodendroglioma as well, especially after failure of non-PCV regimens [100]. Mixed gliomas with an oligodendroglial component also appear sensitive to PCV [101,102]. PCV has also been used for the treatment of anaplastic and mixed astrocytoma by Levin and colleagues [103]. They found PCV superior to BCNU when comparing time to progression and overall survival. Other multi-agent regimens for malignant gliomas combine PCB with vincristine and either mechlorethamine or etoposide (VP-16) [74,104]. Results with these regimens are similar to that reported for intravenous BCNU.

The most frequent acute toxicity of PCB is nausea and emesis (80-85 per cent) [94,95]. Other less common side effects include fatigue (17 per cent), rash, and neurotoxicity (usually when administered intravenously). For most patients, the dose-limiting toxicity is a combination of neutropenia and throm-bocytopenia.

Platinum compounds. Cisplatin and carboplatin are divalent platinum coordination compounds that act as bifunctional alkylating agents in a cell-cycle-nonspecific manner (see Figs. 2.4A,B) [8,21,71-73]. Alkylation occurs at the N7 position of guanine, producing intra- and inter-strand DNA cross-links [105]. Both the agents are water soluble, excreted primarily in the urine, and demonstrate poor penetration

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