Robbins K T, Hoffman R M
Department of Surgery, University of California, San Diego, School of Medicine, USA.
Laryngoscope. 1996 Jan;106(1 Pt 1):32-6. doi: 10.1097/00005537-199601000-00007.
There is substantial laboratory and clinical evidence that solid tumors rapidly acquire cellular resistance to cisplatin. Experiments with human carcinoma cell lines and clonogenic assays indicate that resistance is usually mild to moderate and can be circumvented with higher concentrations of drug. The purpose of this investigation was to test this hypothesis with a histoculture assay of human upper aerodigestive tract (UADT) carcinomas. Using a sponge-gel supported histoculture, 43 tumor specimens from patients with squamous cell carcinoma (SCC) of the UADT were grown and exposed to cisplatin. Growth inhibition by the drug, in concentrations equivalent to peak therapeutic doses (1.5 micrograms/mL) and concentrations 10 and 25 times greater (15 and 37.5 micrograms/mL), were measured in specimens from patients with previously untreated and recurrent lesions. In vitro, the overall rate of sensitivity of the tumor samples to cisplatin concentrations of 1.5, 15, and 37.5 micrograms/mL were 22%, 62%, and 83%, respectively. In patients with previously untreated disease, the respective rates were 25.9%, 63.3%, and 79.3%, as compared with 10.0%, 55.6%, and 85.6%, respectively, for patients with recurrent disease. The response difference between cisplatin concentrations of 1.5 and 15 micrograms/mL was statistically significant. The "decadose" effect of cisplatin on growth inhibition was 2.44-fold for untreated lesions and 5.56-fold for recurrent tumors. The results indicate that resistance to standard doses of cisplatin by SCC of the UADT can be substantially overcome with a decadose (standard dose x 10) increase and is more pronounced in tumors from patients with recurrent disease. Progress toward improving survival of patients may be possible by incorporating decadose cisplatin therapy into a multimodality treatment plan.
有大量实验室和临床证据表明实体瘤会迅速获得对顺铂的细胞耐药性。对人癌细胞系进行的实验和克隆形成试验表明，耐药性通常为轻度至中度，且可以通过更高浓度的药物来克服。本研究的目的是通过对人上消化道（UADT）癌的组织培养试验来验证这一假设。使用海绵凝胶支持的组织培养方法，培养了43例UADT鳞状细胞癌（SCC）患者的肿瘤标本，并使其暴露于顺铂。在先前未经治疗和复发病变患者的标本中，测量了相当于峰值治疗剂量（1.5微克/毫升）以及10倍和25倍更高剂量（15和37.5微克/毫升）的药物对生长的抑制作用。在体外，肿瘤样本对1.5、15和37.5微克/毫升顺铂浓度的总体敏感率分别为22%、62%和83%。在先前未经治疗的疾病患者中，相应的比率分别为25.9%、63.3%和79.3%，而在复发性疾病患者中分别为10.0%、55.6%和85.6%。顺铂浓度为1.5和15微克/毫升之间的反应差异具有统计学意义。顺铂对生长抑制的“十剂量”效应在未经治疗的病变中为2.44倍，在复发性肿瘤中为5.56倍。结果表明，UADT的SCC对标准剂量顺铂的耐药性可以通过增加十剂量（标准剂量×10）得到显著克服，并且在复发性疾病患者的肿瘤中更为明显。通过将十剂量顺铂疗法纳入多模式治疗方案，有可能在提高患者生存率方面取得进展。
