Vassal G, Pondarré C, Cappelli C, Terrier-Lacombe M J, Boland I, Morizet J, Bénard J, Vénuat A M, Ardouin P, Hartmann O, Gouyette A
Laboratory of Pharmacotoxicology and Pharmacogenetics (URA CNRS 147), Villejuif, France.
Eur J Cancer. 1997 Oct;33(12):2011-5. doi: 10.1016/s0959-8049(97)00296-7.
DNA-topoisomerase I is the nuclear target of new anticancer drugs, namely camptothecin and its derivatives. In order to establish the rational basis for their clinical development in paediatric oncology, the antitumour activity of irinotecan (CPT-11) and topotecan, two camptothecin water-soluble derivatives, was studied in nude mice bearing neuroblastoma xenografts. The panel was composed of 4 previously established subcutaneous xenograft lines (IGR-N835, IGR-N91, IGR-NB3, IGR-NB8) that exhibited the common biological markers of poor prognosis in children (MYCN amplification, 1p deletion, paradiploidy and/or MDR1 overexpression). Irinotecan and topotecan were administered i.v. or i.p. over 5 consecutive days in animals bearing tumours. Irinotecan (40 mg/kg/day) induced 20-100% complete regressions with tumour growth delays ranging from 20 to 46 days. Two out of 10 IGR-N91 bearing animals were tumour free more than 120 days after treatment with the top dose (50 mg/kg/day). Topotecan (2.7 mg/kg/day) induced 0-67% complete regressions with tumour growth delays ranging from 23 to 50 days. One out of 8 IGR-NB3 bearing mice was tumour free at the end of the experiment. The antitumour activity of both drugs was clearly sustained at a lower dose level. Topoisomerase I activity was assayed in 15 neuroblastomas, 3 ganglioneuroblastomas and 2 normal adrenal glands, using a DNA relaxation assay. Topoisomerase I activity ranged from 69 to 1304 arbitrary units/mg of protein, and was significantly higher in immature neuroblastomas than in ganglioneuroblastomas and adrenal glands. In conclusion, irinotecan and topotecan are active against neuroblastoma xenografts. Their target is expressed in patients' tumour samples. Clinical development of topoisomerase I inhibitors in children with neuroblastoma is warranted.
DNA拓扑异构酶I是新型抗癌药物（即喜树碱及其衍生物）的核靶点。为了为它们在儿科肿瘤学中的临床开发奠定合理基础，研究了两种喜树碱水溶性衍生物伊立替康（CPT-11）和拓扑替康对携带神经母细胞瘤异种移植瘤的裸鼠的抗肿瘤活性。该研究组由4个先前建立的皮下异种移植瘤系（IGR-N835、IGR-N91、IGR-NB3、IGR-NB8）组成，这些瘤系表现出儿童预后不良的常见生物学标志物（MYCN扩增、1p缺失、亚二倍体和/或MDR1过表达）。在荷瘤动物中，连续5天静脉注射或腹腔注射伊立替康和拓扑替康。伊立替康（40mg/kg/天）诱导20%-100%的完全消退，肿瘤生长延迟时间为20至46天。在用最高剂量（50mg/kg/天）治疗后，10只携带IGR-N91的动物中有2只在120多天后无肿瘤。拓扑替康（2.7mg/kg/天）诱导0%-67%的完全消退，肿瘤生长延迟时间为23至50天。8只携带IGR-NB3的小鼠中有1只在实验结束时无肿瘤。两种药物在较低剂量水平时抗肿瘤活性明显持续。使用DNA松弛试验在15个神经母细胞瘤、3个神经节神经母细胞瘤和2个正常肾上腺中检测拓扑异构酶I活性。拓扑异构酶I活性范围为69至1304任意单位/毫克蛋白质，在未成熟神经母细胞瘤中显著高于神经节神经母细胞瘤和肾上腺。总之，伊立替康和拓扑替康对神经母细胞瘤异种移植瘤有活性。它们的靶点在患者肿瘤样本中表达。拓扑异构酶I抑制剂在神经母细胞瘤患儿中的临床开发是有必要的。
