Cytotoxicity and DNA damaging effects of a new nitrosourea, fotemustine, diethyl- 1-(3-(2-chloroethyl)-3-nitrosoureido) ethylphosphonate-S10036.
Fotemustine is a new chloroethylnitrosourea which has recently entered a Phase II clinical trial. Using standard cytotoxicity analyses, Fotemustine was shown to be preferentially active in two Mer- cell lines, human colon BE and human lung A427. Comparative cell kill in the Mer+ counterparts HT29 and A549 (respectively) was significantly lower. In a mouse cell line, P388, alkaline elution studies showed that Fotemustine caused fewer DNA strand breaks and total crosslinks (including DNA-protein) than either BCNU or MeCCNU at equivalent cytotoxic concentrations. In addition, the removal of DNA damage caused by Fotemustine was more rapid than of damage, three times as much Fotemustine was required. These data suggest that the cytotoxic mechanism of Fotemustine, although subject to the same repair mechanisms as other nitrosoureas, may not be entirely dependent upon DNA as the sole drug target. The previously reported reduced mutagenicity of this agent may also be a function of the less extensive nucleic acid damage. The encouraging early clinical trial results with this drug may reflect its improved pharmacokinetics and bioavailability, rather than any significant modification in its cellular pharmacology when compared to other nitrosoureas.
Tapiero
H
H
Institut de Cancérologie et d'Immunogénétique, Hopital Paul-Brousse, Villejuif, France.
Yin
M B
MB
Catalin
J
J
Paraire
M
M
Deloffre
P
P
Rustum
Y
Y
Bizzari
J P
JP
Tew
K D
KD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D012673:Semustine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D012673:Semustine; C054368:fotemustine; D002330:Carmustine