Badruddoja Michael A, Keir Stephen T, King Ivan, Zeidner Joseph, Vredenburgh James J, Muhlbaier Lawrence H, Bigner Darell D, Friedman Henry S
Center for Neurosciences, University of Arizona, Tucson, AZ 85721, USA.
Neuro Oncol. 2007 Jul;9(3):240-4. doi: 10.1215/15228517-2007-011. Epub 2007 May 23.
VNP40101M, or 1,2-bis(methylsulfonyl)-1-(2-choloroethyl)-2-(methylamino)carbonylhydrazine (Cloretazine), is a bifunctional prodrug that belongs to a class of DNA-modifying agents-the sulfonylhydrazines-that has been synthesized and been shown to have activity against a wide spectrum of xenografts. The current study was designed to assess the activity of VNP40101M administered at a dose of 18 mg/kg daily for five days against a panel of human adult and pediatric CNS tumors growing subcutaneously or intracranially in athymic nude mice. The results demonstrated statistically significant (p < 0.05) growth delays of 15.0, 8.3, 51.0, 60+, 60+, and 60+ days in subcutaneous xenografts derived from childhood glioblastoma multiforme (D-456 MG), childhood ependymoma (D-528 EP and D-612 EP), childhood medulloblastoma (D-425 MED), and adult malignant glioma (D-245 MG and D-54 MG), respectively, with corresponding tumor regressions in 10 of 10, 4 of 10, 8 of 10, 9 of 10, 9 of 10, and 10 of 10 treated mice, respectively. Delayed toxicity was seen more than 60 days after treatment, with 23 deaths in 100 treated animals, despite a median weight loss of only 0.06%. In mice bearing intracranial D-245 MG xenografts, treatment with VNP40101M at a dose of 18 mg/kg daily for five days produced a 50% increase in median survival compared with controls. Additional experiments conducted against subcutaneous D-245 MG xenografts by using reduced doses of 13.5 or 9.0 mg/kg daily for five days demonstrated tumor growth delays of 82.2 and 53.5 days, with corresponding tumor regressions in 8 of 9 and 9 of 10 treated mice, respectively (all values, p < 0.001), with one toxic death. These findings suggest that VNP40101M is active in the treatment of a wide range of human central nervous system tumors and warrants translation to the clinic.
VNP40101M，即1,2 - 双（甲基磺酰基）- 1 -（2 - 氯乙基）- 2 -（甲基氨基）羰基肼（氯雷他嗪），是一种双功能前药，属于一类DNA修饰剂——磺酰肼类，已合成并显示对多种异种移植瘤具有活性。本研究旨在评估以每日18 mg/kg的剂量连续给药五天的VNP40101M对一组在无胸腺裸鼠皮下或颅内生长的成人和儿童中枢神经系统肿瘤的活性。结果表明，源自儿童多形性胶质母细胞瘤（D - 456 MG）、儿童室管膜瘤（D - 528 EP和D - 612 EP）、儿童髓母细胞瘤（D - 425 MED）以及成人恶性胶质瘤（D - 245 MG和D - 54 MG）的皮下异种移植瘤的生长延迟具有统计学意义（p < 0.05），分别为15.0、8.3、51.0、60 +、60 +和60 +天，相应地，在接受治疗的小鼠中，10只中有10只、10只中有4只、10只中有8只、10只中有9只、10只中有9只以及10只中有10只出现肿瘤消退。治疗后60多天出现延迟毒性，100只接受治疗的动物中有23只死亡，尽管体重中位数仅下降0.06%。在携带颅内D - 245 MG异种移植瘤的小鼠中，以每日18 mg/kg的剂量连续五天给予VNP40101M治疗，与对照组相比，中位生存期增加了50%。对皮下D - 245 MG异种移植瘤进行的额外实验，采用每日13.5或9.0 mg/kg的降低剂量连续五天给药，结果显示肿瘤生长延迟分别为82.2和53.5天，相应地，在接受治疗的小鼠中，9只中有8只和10只中有9只出现肿瘤消退（所有数值，p < 0.001），有1只出现毒性死亡。这些发现表明VNP40101M在治疗多种人类中枢神经系统肿瘤方面具有活性，值得转化到临床应用。
