Jansen W J, Kolfschoten G M, Erkelens C A, Van Ark-Otte J, Pinedo H M, Boven E
Department of Medical Oncology, Academic Hospital, Vrije Universiteit, Amsterdam, The Netherlands.
Int J Cancer. 1997 Dec 10;73(6):891-6. doi: 10.1002/(sici)1097-0215(19971210)73:6<891::aid-ijc22>3.0.co;2-6.
CPT-11, a semi-synthetic derivative of camptothecin, was investigated for its activity in panels of 15 human ovarian-cancer lines and 10 human soft-tissue sarcoma lines grown s.c. in nude mice. Various factors were analyzed that may be of influence on the extent of tumor-growth inhibition induced by CPT-11. At equitoxic doses, CPT-11 was more effective in the daily x5 schedule than the weekly x2 schedule, although a 2-fold higher dose was administered in the weekly x2 schedule. Since i.p. and i.v. injections were similarly effective, the selected treatment schedule was 20 mg/kg i.p. daily x5, starting when tumors measured approximately 150 mm3. Growth inhibition of > or = 75% was obtained in 8/15 human ovarian-cancer lines and in 6/10 human soft-tissue sarcoma lines. A weak correlation was found between topoisomerase-I mRNA in xenograft tissues and sensitivity to CPT-11. Relative topoisomerase-I expression was highest in MRI-H-207 and WLS-160 xenografts, in which CPT-11 was able to induce cures of all tumors. The high efficacy in the 2 panels of human tumor lines suggests over-prediction of its potential clinical activity in these tumor types. The difference in efficacy of CPT-11 between species may be related to the metabolism of the drug, since CPT-11 is converted more efficiently into SN-38 in mice. In addition, mice may be less sensitive to SN-38-induced side-effects. On the basis of the preclinical data, frequent administration of lower doses of CPT-11 should be considered in order to increase response rates in the clinic.
喜树碱-11（CPT-11）是一种喜树碱的半合成衍生物，研究了其对15种人卵巢癌细胞系和10种人软组织肉瘤细胞系在裸鼠皮下生长的活性。分析了各种可能影响CPT-11诱导肿瘤生长抑制程度的因素。在等毒性剂量下，CPT-11在每日5次给药方案中比每周2次给药方案更有效，尽管每周2次给药方案中给予的剂量高2倍。由于腹腔注射和静脉注射同样有效，选定的治疗方案是每日腹腔注射20mg/kg，共5次，当肿瘤体积约为150mm³时开始给药。在15种人卵巢癌细胞系中的8种和10种人软组织肉瘤细胞系中的6种中获得了≥75%的生长抑制。在异种移植组织中的拓扑异构酶-I mRNA与对CPT-11的敏感性之间发现了弱相关性。相对拓扑异构酶-I表达在MRI-H-207和WLS-160异种移植中最高，在这些异种移植中CPT-11能够使所有肿瘤治愈。在两组人肿瘤细胞系中的高效表明对其在这些肿瘤类型中的潜在临床活性预测过高。CPT-11在不同物种间疗效的差异可能与药物代谢有关，因为CPT-11在小鼠中更有效地转化为SN-38。此外，小鼠可能对SN-38诱导的副作用不太敏感。基于临床前数据，应考虑频繁给予较低剂量的CPT-11以提高临床反应率。
