We previously have found that 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a selective cytotoxin that enters cellsvia the extraneuronal transporter for monoamine transmitters(EMT). Both in vitro and in vivo studies demonstrated thatSarCNU was more effective than BCNU against human gliomas.To clarify whether EMT expression correlates with antitumorefficacy of SarCNU, we determined human EMT (EMTh)and O6-methylguanine-DNA methyltransferase (MGMT) expressionin nine human xenograft models using semiquantitativereverse-transcription polymerase chain reaction. These resultswere compared with the antitumor effects of SarCNU andthe standard chloroethylnitrosourea antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). There was no significantcorrelation between EMTh expression and antitumor efficacy ofSarCNU or BCNU. Also, there was no significant correlationbetween MGMT expression and SarCNU efficacy. However, asignificant correlation was found between MGMT expressionand BCNU antitumor efficacy. Interestingly, multiple regressionanalysis demonstrated a significant correlation betweenSarCNU efficacy and EMTh plus MGMT expression, whereasthere was no correlation between BCNU efficacy and MGMTplus EMTh expression. Thus, the absence of a linear correlationbetween SarCNU efficacy and EMTh expression appears to bedue, at least in part, to the presence of DNA repair, specifically, MGMT, in these xenograft models. These studies suggest thatMGMT expression alone correlates with BCNU activity, whereas both EMTh and MGMT expression are important determinantsof SarCNU activity against human tumor xenograftmodels. SarCNU is in clinical trials and these results may haveimportant clinical implications.