Melanoma-cell toxicity of cystemustine combined with O6-benzyl-N2-acetylguanosine.
Cystemustine (N'-(2-chloroethyl)-N-(2-(methylsulphonyl)ethyl)-N'-nitrosourea) is a new chloroethylnitrosourea (CENU) being used in phase II clinical trials of disseminated melanoma. Clinical results show that tumour regression has only been observed in 25% of melanomas treated by CENUs. Tumour resistance to CENU is known to be mainly due to a DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT). The poor remission rate of melanoma with CENUs is attributed to the fact that metastases contain high MGMT levels. Previously, we have shown that O6-benzyl-N2-acetylguanosine (BNAG), an MGMT inhibitor, can be combined with cystemustine by intravenous administration, and increases the antitumour effect of cystemustine in resistant human melanoma. In the work presented here, we investigated the in vitro pharmacological effect of this combination on the DNA of human melanoma cells (M3Dau cells). A quantitative polymerase chain reaction (QPCR) assay was used to measure DNA damage in a fragment (2.7 kb) of the hprt gene. The results show that treatment with BNAG enhances the number of lesions in the DNA of cystemustine-treated resistant malignant melanocytes, which may account for the high tumour-cell toxicity of the combination of cystemustine and BNAG.
Buchdahl
C
C
INSERM U484 (ext U71), Clermont-Ferrand, France.
Rolhion
C
C
Glasser
A L
AL
Debiton
E
E
Mounetou
E
E
Madelmont
J C
JC
Laval
F
F
D000970:Antineoplastic Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity; D006151:Guanosine / Q000031:analogs & derivatives* / Q000633:toxicity; D006801:Humans; D008544:Melanocytes / Q000201:enzymology; D008545:Melanoma; D009607:Nitrosourea Compounds / Q000633:toxicity*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009607:Nitrosourea Compounds; C090349:O(6)-benzyl-N-acetylguanosine; D006151:Guanosine; C051263:N'-(2-chloroethyl)-N-(2-(methylsulfonyl)ethyl)-N'-nitrosourea; D019853:O(6)-Methylguanine-DNA Methyltransferase