Vassal G, Boland I, Terrier-Lacombe M J, Watson A J, Margison G P, Vénuat A M, Morizet J, Parker F, Lacroix C, Lellouch-Tubiana A, Pierre-Kahn A, Poullain M G, Gouyette A
Laboratory of Pharmacotoxicology and Pharmacogenetics (Centre National de la Recherche Scientifique URA 147, Institut Gustave-Roussy, Villejuif, France.
Clin Cancer Res. 1998 Feb;4(2):463-8.
Fotemustine is a chloroethylnitrosourea with antitumor activity in disseminated melanoma and adult primary brain tumors. Because new drugs are required for the treatment of medulloblastoma in children, we evaluated the preclinical antitumor activity of fotemustine in four s.c. medulloblastoma xenografts, in comparison with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Both drugs were administered as a single i.p. injection to nude mice bearing advanced-stage tumor. Fotemustine displayed significant antitumor activity in three of four medulloblastoma xenografts; two, IGRM34 and IGRM57, were highly sensitive, with 37 and 100% tumor-free survivors, respectively, more than 120 days after treatment at the highest nontoxic dose (50 mg/kg). Fotemustine was also highly active in a malignant glioma xenograft (IGRG88; five of six tumor-free survivors on day 177). Fotemustine proved to be significantly more active than BCNU in IGRM34 and the glioma xenograft IGRG88. The DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) was detected in all tumor xenografts, ranging in activity from 6 to 892 fmol/mg protein. The high in vivo sensitivity to fotemustine and BCNU observed in three xenografts was clearly associated with a low ATase activity (> 20 fmol/mg), whereas the two poorly sensitive or refractory medulloblastoma xenografts showed high ATase activity (> 500 fmol/mg). Alkylpurine-DNA N-glycosylase activity was detected in all tumor xenografts but at levels ranging only from 513 to 1105 fmol/mg/h; no consistent relationship was found between alkylpurine-DNA N-glycosylase activity and the in vivo sensitivity to the two chloroethylnitrosoureas. The improved activity and tolerance of fotemustine in comparison with BCNU in pediatric medulloblastoma xenografts strongly support the clinical development of this agent in children with brain tumors, in which ATase should be examined as a potential prognostic indicator.
福莫司汀是一种氯乙基亚硝脲，对播散性黑色素瘤和成人原发性脑肿瘤具有抗肿瘤活性。由于儿童髓母细胞瘤的治疗需要新的药物，我们评估了福莫司汀在四种皮下髓母细胞瘤异种移植模型中的临床前抗肿瘤活性，并与1,3-双（2-氯乙基）-1-亚硝脲（卡莫司汀，BCNU）进行了比较。两种药物均通过腹腔内单次注射给予荷晚期肿瘤的裸鼠。福莫司汀在四种髓母细胞瘤异种移植模型中的三种中显示出显著的抗肿瘤活性；其中两种，IGRM34和IGRM57，高度敏感，在最高无毒剂量（50mg/kg）治疗后120多天，无瘤生存率分别为37%和100%。福莫司汀在恶性胶质瘤异种移植模型（IGRG88）中也具有高活性（在第177天，六只中有五只无瘤存活）。在IGRM34和胶质瘤异种移植模型IGRG88中，福莫司汀被证明比卡莫司汀活性显著更高。在所有肿瘤异种移植模型中均检测到DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶（ATase），活性范围为6至892fmol/mg蛋白。在三种异种移植模型中观察到的对福莫司汀和卡莫司汀的高体内敏感性显然与低ATase活性（>20fmol/mg）相关，而两种低敏感性或难治性髓母细胞瘤异种移植模型显示出高ATase活性（>500fmol/mg）。在所有肿瘤异种移植模型中均检测到烷基嘌呤-DNA N-糖基化酶活性，但水平仅在513至1105fmol/mg/h范围内；未发现烷基嘌呤-DNA N-糖基化酶活性与对两种氯乙基亚硝脲的体内敏感性之间存在一致关系。与卡莫司汀相比，福莫司汀在儿童髓母细胞瘤异种移植模型中的活性和耐受性有所提高，这有力地支持了该药物在患有脑肿瘤儿童中的临床开发，其中应将ATase作为一种潜在的预后指标进行检测。
