We previously have found that 2-chloroethyl-3-sarcosinamide-1-nitrosourea (
SarCNU) is a selective
cytotoxin that enters cells via the
extraneuronal transporter for monoamine transmitters (EMT). Both in vitro and in vivo studies demonstrated that
SarCNU was more effective than
BCNU against human
gliomas. To clarify whether EMT expression correlates with antitumor efficacy of
SarCNU, we determined human EMT (EMTh) and
O(6)-methylguanine-DNA methyltransferase (MGMT) expression in nine human xenograft models using semiquantitative reverse-transcription polymerase chain reaction. These results were compared with the antitumor effects of
SarCNU and the standard chloroethylnitrosourea
antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea (
BCNU). There was no significant correlation between EMTh expression and antitumor efficacy of
SarCNU or
BCNU. Also, there was no significant correlation between MGMT expression and
SarCNU efficacy. However, a significant correlation was found between MGMT expression and
BCNU antitumor efficacy. Interestingly, multiple regression analysis demonstrated a significant correlation between
SarCNU efficacy and EMTh plus MGMT expression, whereas there was no correlation between
BCNU efficacy and MGMT plus EMTh expression. Thus, the absence of a linear correlation between
SarCNU efficacy and EMTh expression appears to be due, at least in part, to the presence of DNA repair, specifically, MGMT, in these xenograft models. These studies suggest that MGMT expression alone correlates with
BCNU activity, whereas both EMTh and MGMT expression are important determinants of
SarCNU activity against human
tumor xenograft models.
SarCNU is in clinical trials and these results may have important clinical implications.