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.