Cystemustine (N'-(2-chloroethyl)-N-(2-(methylsulphonyl)ethyl)-N'-nitrosourea), a new anticancer chloroethylnitrosourea (
CENU) is being tested in a phase II clinical trial of disseminated
melanoma. The antitumour effect of this
drug is mainly due to DNA damage in malignant melanocytes. Recently, we have shown that this damage can induce apoptosis in some
melanoma cell lines. In others, apoptosis is not clearly observed, although there is a strong
cytostatic effect. In this paper, we have characterized the cytological effect of
cystemustine on murine malignant melanocytes (B16 cell line) which are resistant to apoptosis induced by this
CENU. The results show that 3 days after
cystemustine treatment, these melanocytes had accumulated in phase G2 of the cell cycle. There was then a strong morphological modification during a long
cytostatic phase up to 30 days
after treatment. During this
cytostatic phase, there was uncontrolled
DNA synthesis and marked swelling. Also,
tyrosinase activity,
melanin content and the number of mature melanosomes were greatly increased. These results suggest that when malignant melanocytes are not able to undergo apoptosis
after treatment with
CENU, they accumulate in G2 and this is followed by enhancement of melanogenesis.