Metastatic melanoma (MM) is an incurable chemoresistant cancer with poor prognosis. Until now, only few drugs have shown some activity. So this tumor represents an opportunity to verify new and more effective treatment strategies.
Presently, Dacarbazine (DTIC) remains the standard chemotherapy for MM with an overall response rate of approximately 10-15% with complete response in less than 5% of patients and a survival about 8-10 months [1, 2]. No other agents have demonstrated better results than DTIC in phase III studies also when utilized as polichemotherapy or in association to immunotherapy [3–6].
Temozolomide (TMZ) has been recently utilized in MM. It is a novel oral alkylating agent having a high oral bioavailability and extensive tissue distribution, including penetration through the blood-brain barrier. Patients with MM achieved overall response rates of nearly 20% with single-agent TMZ as similar as DTIC [7–9]. Also nitrosureas are considered drugs of any activity in MM including patients with brain metastatic. Among nitrosurea analogs, fotemustine (FM) has been more extensively studied in MM, especially in Europe. It is a third generation chloroethylnitrosourea that has demonstrated significant antitumoral effects in MM with a response rate averaging 20%. However, its use is somewhat limited by its myelotoxic side effect, especially when old schedules are utilized [10–12].
The activity of alkylating agents depends on their capacity to form alkyl adducts with DNA, in some cases causing cross-linking of DNA strands. However, the antineoplastic activity of these agents is limited by cellular resistance principally induced by the DNA repair enzyme O(6)-methylguanine DNA-methyltransferase (MGMT), a DNA suicide enzyme which removes alkyl groups from alkylated DNA strands [13–16]. In tumor cell lines and xerografts an inverse correlation between the level of this protein and the sensibility to the cytotoxic effects of nitrosureas including FM has been demonstrated [17, 18]. Moreover, studies evaluating the tumor MGMT levels in patients with brain tumors receiving nitrosureas reported a positive correlation between low level content of MGMT and a better survival [19, 20].
Preclinical studies and recent clinical experiences also support the concept that continuous exposure to alkylating agent TMZ, streptozocin, procarbazine, and DTIC, can effectively deplete cells of MGMT, which is the primary mechanism of tumor resistance to nitrosureas, thus reversing the resistance to these chemotherapeutic agents [21–23]. In particular, sequential administration of TMZ and FM is able to induce depletion of MGMT both in blood lymphocytes and in tumoral tissue .
Recent clinical experiences have confirmed that continuous exposure to alkilating agent procarbazine in association with FM is an active treatment in patients with recurrent malignant gliomas . At present, in spite of numerous experimental experience, very few data exist regarding the clinical use of TMZ as chemomodulating agent in MM patients. In particular, no established doses, timing and schedules are known.
Thus, we planned this study in MM patients to verify the hypothesis that depletion of MGMT induced by low dose TMZ could render melanoma cells more susceptible to FM. We used two different schedules of sequential combination of TMZ and FM in to assess their profile of toxicity and efficacy.