Local treatment of cutaneous and subcutaneous metastatic malignant melanoma with fotemustine

Abstract

Fotemustine is a highly reactive chloroethyl-nitrosourea anti-tumor drug that is currently undergoing phase III clinical trials in stage IV metastatic malignant melanoma. The drug is a potent alkylating agent and rapidly chloroethylates the active sites of the important thioproteins thioredoxin reductase (TR), glutathione reductase (GR) and ribonucleotide reductase (RR). These enzymes control ribonucleotide reduction and, consequently, DNA synthesis in the S phase of the cell cycle. Side effects are minor due to the rapid metabolism of the drug. [14C]Fotemustine exhibited a half-life of 90 min in the vascular system after the administration of 100 mg/m2. Fotemustine was shown to yield the volatile degradation product acetylene (a) in distilled water (4.1%/h), (b) in melanoma cell culture medium (MCDB) supplemented with 10% fetal calf serum (33%/h) and (c) in fotemustine-sensitive human melanoma cells in culture medium (70.5%/h). Due to its rapid metabolism and its low toxicity, high concentrations of fotemustine (55 x 10(-3) M) were injected directly into cutaneous and subcutaneous melanoma metastases (n = 36) of seven patients, resulting in minor necrosis followed by total remission of the metastases. Untreated metastases adjacent to the treated tumors were not affected by fotemustine, confirming that rapid local metabolism of this drug occurs only in the vicinity of injected tumors without producing any systemic effects.