Marathi U K, Dolan M E, Erickson L C
Department of Pharmacology, Loyola University Chicago, Maywood, IL 60153.
Biochem Pharmacol. 1994 Nov 29;48(11):2127-34. doi: 10.1016/0006-2952(94)90514-2.
The purpose of this study was to evaluate the anti-tumor activity of sequenced administration of O6-benzylguanine (BG), streptozotocin (STZ), and 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU) in vitro and in vivo. We measured the recovery of O6-methylguanine DNA methyltransferase (MGMT) and BCNU cytotoxicity in the human glioma SF767 cell line, and anti-tumor activity against xenografts following exposure to BG, STZ or the combination of BG + STZ combined with BCNU. In SF767 cells, the combination of BG (10 microM) + STZ (0.05 mM) produced sustained inhibition of MGMT activity for at least 24 hr, and a greater potentiation of BCNU cytotoxicity than either agent alone. The combined treatment of BG + STZ increased BCNU-induced cell kill by 0.5 to 1.0 log over BG or STZ alone. The maximally tolerated doses of the combination of BG + STZ + BCNU administered to nude mice i.p. were the following: BG (80 mg/kg), STZ (100 mg/kg), and BCNU (15 mg/kg). Utilizing these doses of BG and STZ, the depletion and repletion profile of MGMT activity in SF767 xenografts was measured. STZ at 100 mg/kg did not affect xenograft MGMT activity. Subsequent to BG treatment, xenograft MGMT activity was inactivated completely for 12 hr, and the tumors gradually recovered approximately 40% of control activity by 24 hr. The combination of BG + STZ produced sustained inhibition of MGMT activity for 24 hr in the xenografts with complete recovery of MGMT activity by 48 hr. Administration of the combination of BG + BCNU to nude mice bearing SF767 tumor resulted in significant inhibition of tumor growth for 23 days. However, the addition of STZ to this combination provided no greater anti-tumor activity than that observed with BG + BCNU. The three-drug combination of BG, STZ, and BCNU produced no more than 2.4 to 13.0% weight loss with occasional lethal toxicity. Collectively, these data suggest that prolonged depletion of MGMT might be required for optimal reversal of BCNU resistance both in vitro and in vivo.
本研究的目的是评估O6-苄基鸟嘌呤（BG）、链脲佐菌素（STZ）和1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）序贯给药在体外和体内的抗肿瘤活性。我们测定了人胶质瘤SF767细胞系中O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）的恢复情况以及BCNU的细胞毒性，并检测了暴露于BG、STZ或BG + STZ联合BCNU后对异种移植瘤的抗肿瘤活性。在SF76-7细胞中，BG（10 microM）+ STZ（0.05 mM）的组合可使MGMT活性持续抑制至少24小时，且比单独使用任何一种药物对BCNU细胞毒性的增强作用更大。BG + STZ联合处理使BCNU诱导的细胞杀伤比单独使用BG或STZ增加了0.5至1.0个对数级。腹腔注射给裸鼠的BG + STZ + BCNU组合的最大耐受量如下：BG（80 mg/kg）、STZ（100 mg/kg）和BCNU（15 mg/kg）。利用这些剂量的BG和STZ，测定了SF767异种移植瘤中MGMT活性的消耗和恢复情况。100 mg/kg的STZ不影响异种移植瘤的MGMT活性。BG处理后，异种移植瘤的MGM活性在12小时内完全失活，到24小时时逐渐恢复至对照活性的约40%。BG + STZ联合处理使异种移植瘤中的MGMT活性持续抑制24小时，到48小时时MGMT活性完全完全恢复。给已植入SF767肿瘤的裸鼠联合注射BG + BCNU可显著抑制肿瘤生长23天。然而，在此联合方案中加入STZ并未比BG+BCNU观察到更大的抗肿瘤活力。BG、SIZ和BCU三者联合用药引起的体重减轻不超过2.4%~13.0%，偶尔有致命危险。总的来说，这些数据表明无论体內还是体外，可能均需要长时间消耗MCNU才能最佳逆转BCNU耐药性。
