Antitumor efficacy of SarCNU in a human glioma xenograft model expressing both MGMT and extraneuronal monoamine transporter.
Treatment of malignant brain tumors with chloroethylnitrosoureas (CENUs) in addition to surgical resection and radiotherapy 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 to the standard CENU, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), has been demonstrated to have increased anticancer effects both in vitro and in vivo. Unfortunately, many human tumors have been known to be resistant to CENUs since they express DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In order to assess whether SarCNU has an effect on MGMT positive tumors, we evaluated its antitumor efficacy using an MGMT positive human glioma (SF-767) nude mouse xenograft model. Since SF-767 has high MGMT levels, BCNU treatment (20 mg/kg, Q4D x 3 i.p.) alone did not result in a satisfactory anticancer effect (p > 0.05). As expected, O6-benzylguanine (O6-BG) (100 mg/kg), which was given prior to BCNU treatment, by depleting MGMT activity, significantly enhanced BCNU antitumor efficacy (p < 0.001). Moreover, SarCNU treatment (167 mg/kg, Q4D x 3 i.p.) alone had a better antitumor effect than O6-BG plus BCNU treatment (F = 51.7, p = 0.0004). However, in this xenograft model, O6-BG did not significantly enhance the anticancer efficacy of SarCNU (F = 0.8, p = 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 SarCNU is also effective for MGMT positive tumor if they exhibit EMT.
Chen
Z P
ZP
Department of Neurosurgery/Neuro-Oncology, Cancer Center, Sun Yat-Sen University of Medical Sciences, Guangzhou, People's Republic of China. chenzp@gzsums.edu.cn
Pan
J
J
Huang
Q
Q
Sun
Z F
ZF
Zhou
L Y
LY
Wang
A D
AD
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy*; D002330:Carmustine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D027701:Organic Cation Transport Proteins; D014183:Transplantation, Heterologous; D000099254:Organic Cation Transporter 3
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D002330:Carmustine; D002352:Carrier Proteins; D003849:Deoxyguanosine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D027701:Organic Cation Transport Proteins; D000099254:Organic Cation Transporter 3; C088636:O(6)-benzyl-2'-deoxyguanosine; C044565:2-((((2-chloroethyl)nitrosoamino)carbonyl)amino)propanamide