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陈忠平, ZHONG-PING CHEN, ZHI-MIN WANG, CHRISTOPHER A. CARTER, MICHAEL C. ALLEY, GERARD MOHR, and LAWRENCE C. PANASCI
JPET 296: 712-715, 2001,-0001,():
-1年11月30日
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.
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陈忠平, Zhong-Ping Chen, Jun Pan, Qiang Huang, Zhi-Fang Sun, Li-Ying Zhou and An-Dong Wang
Journal of Neuro-Oncology 51: 19-24, 2001.,-0001,():
-1年11月30日
Treatment of malignant brain tumors with chloroethylnitrosoureas (CENUs) in addition to surgical resection andradiotherapy remains the foundation of glioma therapy. However, the clinical response to CENUs is at best modest.A novel analogue of nitrosoureas, 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), as compared tothe standard CENU, 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), has been demonstrated to have increased anticancereffects both in vitro and in vivo. Unfortunately, many human tumors have been known to be resistant toCENUs since they express DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In order toassess whether SarCNU has an effect on MGMT positive tumors, we evaluated its antitumor efficacy using anMGMT positive human glioma (SF-767) nude mouse xenograft model. Since SF-767 has high MGMT levels,BCNU treatment (20mg/kg, Q4D 3 i.p.) alone did not result in a satisfactory anticancer effect (p>0:05). Asexpected, O6-benzylguanine (O6-BG) (100mg/kg), which was given prior to BCNU treatment, by depletingMGMTactivity, significantly enhanced BCNU antitumor efficacy (p<0:001). Moreover, SarCNU treatment (167mg/kg,Q4D 3 i.p.) alone had a better antitumor effect than O6-BG plus BCNU treatment (FD 51:7, pD 0:0004). However,in this xenograft model, O6-BG did not significantly enhance the anticancer efficacy of SarCNU (FD 0:8, pD 0:411). The SF-767 human glioma xenograft is positive for extraneuronal monoamine transporter EMT (EMT)as determined by reverse-transcription polymerase chain reaction (RT-PCR). Our present results suggest that Sar-CNU is also effective for MGMT positive tumor if they exhibit EMT.
brain tumor,, chemotherapy,, extraneuronal monoamine transporter,, glioma xenograft,, 2-chloroethyl-3-sarcosinamide-1-nitrosourea
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