Dowlati A, Levitan N, Gordon N H, Hoppel C L, Gosky D M, Remick S C, Ingalls S T, Berger S J, Berger N A
Division of Hematology/Oncology, Case Western Reserve University and University Hospitals of Cleveland, Ohio 44106, USA.
Cancer Chemother Pharmacol. 2001;47(2):141-8. doi: 10.1007/s002800000211.
In vitro and in vivo preclinical models have demonstrated synergistic activity when topoisomerase I and II inhibitors are administered sequentially. Topoisomerase I inhibitors increase topoisomerase II levels and increase cell kill induced by topoisomerase II poisons. We evaluated this hypothesis in a cohort of patients with advanced non-small-cell lung cancer (NSCLC).
A group of 19 patients with advanced NSCLC (70% adenocarcinoma) received topotecan at a dose of 0.85 mg/m2 per day as a continuous 72-h infusion from days 1 to 3. Etoposide was administered orally at a dose of 100 mg twice daily for 3 days on days 7-9 (schedule and dose derived from prior phase I trials). Total and lactone topotecan concentrations were measured at the end of the 72-h infusion. Blood samples were obtained immediately after each 72-h topotecan infusion in order to measure the mutational frequency at the hypoxanthine phosphoribosyl transferase (HPRT) locus in peripheral lymphocytes.
A total of 55 cycles were administered. Toxicity was mainly hematologic with grade 4 neutropenia occurring in 7% of courses. Only one partial response and two stable diseases were observed. The 1-year survival rate was 33%. There was a statistically significant difference between steady-state lactone concentrations between cycle 1 and cycle 2 with decreasing concentrations with cycle 2 (P = 0.02). This was explained by a statistically significant increase in the clearance of topotecan lactone during cycle 2 (P = 0.03). Total but not lactone concentrations correlated with nadir WBC, ANC and platelet levels. Steady-state plasma lactone levels correlated with the mutational frequency at the HPRT locus (P = 0.06). In the one patient with a partial response a sixfold increase in HPRT mutational frequency was observed, which was not seen in patients with progressive disease.
The combination of topotecan and etoposide in this schedule of administration has minimal activity in adenocarcinoma of the lung. This lack of activity may be due to the delay in administration of etoposide after the topotecan as studies have shown that the compensatory increase in topoisomerase II levels after treatment with topoisomerase I inhibitors is shortlived (<24 h). The HPRT mutational frequency results suggest that the lack of clinical response may be associated with failure to achieve sufficient cytotoxic dose as indicated by a lack of increase in mutational frequency in those patients with progressive disease. HPRT mutational frequency may correlate with plasma steady-state topotecan lactone levels. Future studies should be directed toward earlier administration of topoisomerase II inhibitors after topoisomerase I inhibition.
体外和体内临床前模型已证明，当拓扑异构酶I和II抑制剂序贯给药时具有协同活性。拓扑异构酶I抑制剂可提高拓扑异构酶II水平，并增强拓扑异构酶II毒药诱导的细胞杀伤作用。我们在一组晚期非小细胞肺癌（NSCLC）患者中评估了这一假说。
一组19例晚期NSCLC患者（70%为腺癌），从第1天至第3天接受拓扑替康，剂量为0.85mg/m²/天，持续72小时静脉输注。在第7 - 9天口服依托泊苷，剂量为100mg，每日2次，共3天（给药方案和剂量源自先前的I期试验）。在72小时输注结束时测量总拓扑替康和内酯拓扑替康浓度。每次72小时拓扑替康输注后立即采集血样，以测量外周淋巴细胞次黄嘌呤磷酸核糖转移酶（HPRT）基因座的突变频率。
共进行了55个周期的治疗。毒性主要为血液学毒性，4级中性粒细胞减少症发生在7%的疗程中。仅观察到1例部分缓解和2例病情稳定。1年生存率为33%。第1周期和第2周期的稳态内酯浓度之间存在统计学显著差异，第2周期浓度降低（P = 0.02）。这是由于第2周期拓扑替康内酯清除率有统计学显著增加（P = 0.03）。总拓扑替康浓度而非内酯浓度与最低白细胞、中性粒细胞绝对值和血小板水平相关。稳态血浆内酯水平与HPRT基因座的突变频率相关（P = 0.06）。在1例部分缓解的患者中，观察到HPRT突变频率增加了6倍，而疾病进展的患者中未观察到这种情况。
按此给药方案使用拓扑替康和依托泊苷联合治疗在肺腺癌中的活性极小。这种活性缺乏可能是由于拓扑替康给药后依托泊苷给药延迟，因为研究表明，用拓扑异构酶I抑制剂治疗后拓扑异构酶II水平的代偿性增加是短暂的（<24小时）。HPRT突变频率结果表明，临床反应缺乏可能与未能达到足够的细胞毒性剂量有关，如疾病进展患者中突变频率未增加所示。HPRT突变频率可能与血浆稳态拓扑替康内酯水平相关。未来的研究应致力于在拓扑异构酶I抑制后更早地给予拓扑异构酶II抑制剂。
