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TMZ has been discussed in detail.57 Decarboxylation of 40 affords a common intermediate of TMZ and dacarbazine: 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (41 or 44, MTIC). For dacarbazine metabolic activation via cytochrome P450 oxidation yields 43,58,59 which upon formal loss of formaldehyde affords MTIC. Tautomerization of 41 to 44, followed by protonation yields 5-aminoimidazole-4-carboxamide (45, AIC) and methyl diazonium cation (46), the agent responsible for the cytotoxic activity of the triazenes. A key difference between the triazenes (TMZ, DTIC) and the mustard-based cytotoxics is that these agents are incapable of creating DNA cross-links. Nucleophilic capture of 46 by DNA yields lesions at the following positions and percentages: N7 (70%) and O6 (5%) positions of guanine and the N3 (9%) of adenine.60 The DNA-base selectivity preference toward guanine from MTIC has been argued for both steric and electronic reasons.60 Although the carboxamide (C8, for TMZ) does not participate in either the metabolism of 42 or the decomposition of 38, this functionality has been postulated to play a key role in aligning the prodrugs along runs of guanines in DNA.61

The methylation of O6 guanine, although only formed in minor amounts relative to the N7 lesion, has been proposed to be the key lesion responsible for cytotoxicity. Gerson has indicated that about 6000 of these lesions are needed for cell death versus only 5-10 cross-links derived from nitrosourea treatment.62 During DNA replication, the preferred base pair to O6-methylguanine is thymine,63 not cytosine, creating a net mismatch. During the course of mismatch repair (MMR), long single-stranded gaps are generated64; in doing so, double-stranded breaks can occur if another lesion is present on the opposite strand.65,65a The presence of multiple DNA single or double-stranded gaps/breaks eventually leads to apoptosis.66 Tumor lines with either increased levels of AGT67 or deficient mismatch repair68 tend to be resistant to the triazene class of cytotoxics.

7.06.4.2 Clinical Use 7.06.4.2.1 Dacarbazine (42)

The clinical use of dacarbazine is primarily for metastatic melanoma69 and as a component of the AVBD (doxorubicin, vinblastine, bleomycin, dacarbazine) regimen for treating Hodgkin's lymphoma.70,703 The dosing regimen for metastatic melanoma is 250 mgm _ 2 for 5 days, repeated every 3 weeks. For Hodgkin's disease, DTIC is dosed at 150 mgm _ 2 for 5 days, repeated every 4 weeks. An alternative dosing schedule for DTIC in the AVBD regimen is to administer 42 at 350-375 mgm_2 on the first day of dosing and repeat every 15 days.71 Intravenous administration of DTIC results in biphasic elimination of the parent compound with the initial half-life of 19 min, and the terminal half-life of 5 h, although for patients with renal and hepatic impairment, significantly increased half-lives are witnessed.72 As discussed previously, metabolic activation of DTIC is required for cytotoxic activity, however, up to 40% of the drug is excreted unchanged in the urine. The inability of the body to effectively metabolize the entire dose of DTIC has hampered the effectiveness of this agent. In addition, the use of dacarbazine for melanoma can actually select a more aggressive melanoma, by promoting the increased expression of both interleukin-8 and vascular endothelial growth factor.73

7.06.4.2.2 Temozolomide (37)

Temozolomide is an orally active agent that is currently used for the treatment of adult anaplastic astrocytoma and glioblastoma multiforme.74 The dose and duration of drug used are highly dependent on the identity of the tumor, the expression levels of AGT, and on MMR functional status.75 TMZ has also been used, off label, for the treatment of metastatic melanoma. The results from a randomized phase III clinical trail revealed that TMZ was superior to DTIC in median progression-free survival time, and improvement in quality of life parameters with respect to reduced fatigue and insomnia.76

TMZ is readily absorbed, although a pronounced food effect can occur, and is highly metabolized upon oral administration. The lipophilic nature of TMZ allows for a large volume of distribution and blood-brain barrier penetration, achieving 20% of the concentration found in plasma.77 The ring-opened intermediates have been shown to preferentially partition into tissue versus plasma, and higher levels of TMZ were found in tumor tissue as compared to normal tissue.78

The major dose-limiting toxicity of TMZ is myelosuppression. In contrast to the toxicity witnessed with 38, the hematological-based toxicity of TMZ is predictable with the nadir occurring between 21 and 28 days after administration. Temozolomide's myelosuppressive toxicity does not appear to be cumulative and its nonhematological toxicities range from mild to moderate and include the following: nausea/vomiting, fatigue, constipation, and headache.79

7.06.4.3 Resistance to the Triazenes

For the triazenes, principally TMZ, the combination therapies that have been developed to overcome resistance mediated through DNA repair processes encompass: AGT, MMR, and a newer strategy that involves inhibition of poly(ADP-ribose) synthetase (PARP).80 For AGT, detection of an O6-alkyl group on guanine causes the enzyme to utilize the conserved active-site cysteine to irreversibly remove the alkyl group; thereby, inactivating the protein.81'813 For maximal cytotoxicity, TMZ requires a large amount of these types of lesions to be present; therefore, repair of these lesions via elevated concentrations of AGTallows for decreased cell death. This has been shown experimentally, in that high concentrations of AGT in vivo predicts for resistance to TMZ,82 and the related chloroethylating agents, like 52.83 Fortunately, most cells have fully functional MMR, which is crucial for TMZ-derived lesions to eventually lead to cell death. However, cells that are MMR deficient are highly resistant to TMZ, regardless of the levels of AGT. Recent research has demonstrated that both the effectiveness of MMR and the levels of AGT together affect the sensitivity of a given cell line.84 These results suggest that maximal TMZ sensitivity may be associated with low levels of AGT and fully functional MMR.

The methods that have been employed to sensitize previously resistant cells to TMZ involve either dose modification of TMZ, or use of an AGT inhibitor, like O6-benzylguanine (BG, 48). TMZ has been shown to act as an indirect inhibitor of AGT, which can lead to AGT depletion and increased cellular sensitivity to chemotherapy. Acceptable dosing of TMZ for glioblastoma multiforme was either 150 mgm _ 2 day _ 1 or 200 mg m _ 2 day _ 1 for 5 days in every 28 days.85 The higher dose was used for chemotherapy-pretreated patients. Unfortunately, increasing the dose of TMZ, as a mechanism for AGT depletion, leads to increased toxicity. However, an alternative dosing schedule of 75 mgm_2 day_ 1, once daily for 6-7 weeks, for a group of 24 patients, 17 with malignant glioma, yielded an overall response rate of 33%. A net twofold increase in drug exposure was observed compared to the aforementioned 200 mgm_2 day_ 1 regimen, without an increase of dose-limiting toxicity.86 Tolcher has demonstrated that prolonged administration of TMZ leads to prolonged depletion of AGT, which could lead to increased therapeutic activity.87

The second strategy for overcoming AGT-mediated resistance has been to use the specific and potent inhibitor of AGT, BG. The mechanism by which BG depletes AGT, O6-benzylguanine (48, BG) is shown in Figure 10. The nucleophilic active-site sulfur of AGT reacts with BG causing transfer of the O6-benzyl group liberating the masked guanine 49. Irreversible alkylation of AGT results in net sensitization of cells toward TMZ-based therapy.88 For example, treating TMZ-resistant T98G glioblastoma cells with BG prior to TMZ results in a significant decrease in cell viability.89 Friedman and co-workers have demonstrated in a murine model of malignant glioma that a triple combination of TMZ, BG, and irinotecan yielded growth delays greater than the combination of TMZ and irinotecan alone (150 versus 43 days). The impressive activity in vivo of the combination of TMZ, BG, and irinotecan has prompted the design of a phase I clinical trial to develop an optimal dosing regimen.90

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