O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: Results of a phase II study

Abstract

O6‐Methylguanine‐DNA methyltransferase (MGMT) is a major determinant of resistance to temozolomide. Its levels are depleted in lymphocytes after drug administration, but there is partial recovery by 24 hr, the usual time of subsequent dosing. Administering subsequent doses of temozolomide at the MGMT nadir could enhance its effectiveness, by increasing the amount of O6‐methylguanine (O6‐meG) in DNA. We evaluated the efficacy of such a schedule of temozolomide and determined the kinetics of MGMT depletion and O6‐meG formation in DNA following treatment. Thirty patients with advanced malignant melanoma were treated with temozolomide 1,000 mg/m2 equally split into 5 doses over a 16 hr period every 28 days. O6‐meG formation was determined in peripheral blood mononuclear cell (PBMC) DNA and, in a subset of patients, in tumor tissue during the first treatment cycle. MGMT levels fell rapidly with dosing, reaching a nadir in PBMCs of 18.0 ± 2.26% of initial levels. O6‐meG levels increased during the treatment period, peaking at 11.1 ± 1.25 μmol/mol dG in PBMCs and at 4.25 ± 0.79 μmol/mol dG in tumor biopsies. The main toxicities were grade IV thrombocytopenia in 12 patients (42.8%) and grade IV neutropenia in 11 patients (39.2%), associated with fever in 8 cases. There were 7 responses (1 complete), for an overall response rate of 23.3%; median overall survival was 6.1 months. The compressed schedule has activity against melanoma, with greater MGMT depletion and O6‐meG formation than previously reported for O6‐alkylating agent regimens. Myelosuppression precludes its wider application, but MGMT in PBMCs predicted the dose intensity of temozolomide that patients could sustain, suggesting a means by which individuals suitable for this approach might be identified. Int. J. Cancer 88:469–473, 2000. © 2000 Wiley‐Liss, Inc.

Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies

“…In the present study, baseline PBMC MGMT activity exhibited a very wide range with values between 2.8 and 52.5 (mean 14.171.0) Fm mg À1 DNA. This was somewhat higher than previous values (Middleton et al, 2000b: range 2.2 -25.6, mean 12.6) but similar to other ongoing studies (range 2.3 -51.6, mean 15.5: GPM unpublished results). Another study of adult patients has reported a range of B0.6 to B19 Fm mg À1 DNA and a much lower mean of 6.974.7 Fm mg À1 DNA (Tolcher et al, 2003).…”

“…Previous studies reporting MGMT in adult PBMCs have also shown a range of extents of depletion by temozolomide. A variety of dose regimen and schedules have been examined but complete depletion of MGMT has been observed in very few patients and very wide variations in depletion are always observed (Lee et al, 1994;Gander et al, 1999;Middleton et al, 2000b;Tolcher et al, 2003). The reasons for this have yet to be established.…”

“…Although our evaluations are in a limited number of samples and need to be confirmed and extended by further studies, they are supported by previous studies. Thus, lower MGMT activities in PBMCs have been associated with increased haematological toxicity in a phase II study of temozolomide in adult melanoma patients (Middleton et al, 2000b) and inactivation of MGMT was correlated with haematological toxicity in a phase I study of temozolomide (Tolcher et al, 2003). Nevertheless, to address the questions of MGMT inactivation by cisplatin in relation to tumour responses and toxicities, it would be necessary to undertake larger studies, ideally in direct comparison with equivalent numbers of patients receiving temozolomide alone.…”

Drug-resistance in human melanoma

“…24 Other studies of the same group demonstrated, in contrast, improved survival in patients with tumors expressing low levels of MGMT after treatment with temozolamide. 25 The relationship between MGMT levels, activity and response to chemotherapy with alkylating agents in melanoma patients needs further investigation.…”

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

“…Bioavailability of temozolomide is nearly 100% when administered orally, with good distribution to tissue (Baker et al, 1999;Brada et al, 1999). Activity has been demonstrated against a number of tumours (Bleehen et al, 1995;Dhodapkar et al, 1997;Middleton et al, 2000b). In malignant melanoma, activity was comparable to that of dacarbazine (Middleton et al, 2000a, b).…”