Rosell Rafael, Crino Lucio, Danenberg Kathleen, Scagliotti Giorgio, Bepler Gerold, Taron Miquel, Alberola Vicente, Provencio Mariano, Camps Carlos, De Marinis Filippo, Sanchez Jose Javier, Peñas Ramon
Medical Oncology Service, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
Semin Oncol. 2003 Aug;30(4 Suppl 10):19-25. doi: 10.1016/s0093-7754(03)00281-1.
Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and cisplatin are commonly used in the treatment of many solid tumors, although the impact of chemotherapy is limited in metastatic non-small cell lung cancer. However, in clinical practice, there is a minority of patients who can attain long-term survival. Upregulation of mRNA transcripts has been linked to chemoresistance, and in some instances, mRNA expression has been correlated with polymorphisms. Cisplatin resistance is directly linked to the nucleotide excision repair system, specifically to the transcription-coupled nucleotide excision repair pathway that involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. Overexpression of ERCC1 correlates with poor survival in gemcitabine/cisplatin-treated non-small cell lung cancer patients. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; P =.03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biologic redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival and highlight the possibilities of individually tailored chemotherapy.
吉西他滨（健择；礼来公司，印第安纳波利斯，印第安纳州）和顺铂常用于治疗多种实体瘤，尽管化疗对转移性非小细胞肺癌的影响有限。然而，在临床实践中，有少数患者能够获得长期生存。mRNA转录本的上调与化疗耐药有关，在某些情况下，mRNA表达与多态性相关。顺铂耐药直接与核苷酸切除修复系统相关，特别是与转录偶联核苷酸切除修复途径相关，该途径涉及在诸如科凯恩综合征和着色性干皮病等罕见先天性疾病中缺乏的基因。ERCC1的过表达与吉西他滨/顺铂治疗的非小细胞肺癌患者的不良生存相关。在临床前水平，ERCC1和XPD mRNA表达相互关联，XPD的过表达在人肿瘤细胞系中导致选择性顺铂耐药。XPD多态性与较低的DNA修复能力相关。根据我们的经验，吉西他滨/顺铂治疗的Lys751Gln基因型患者的疾病进展时间（9.6个月）显著高于Lys751Lys基因型患者（4.2个月；P = 0.03）。参与平行DNA修复系统的其他多态性很可能提供相同的信息，表明存在高度的生物学冗余。在我们的回顾性评估中，核糖核苷酸还原酶（RRM1）亚基M1的过表达与吉西他滨耐药有关。初步研究结果表明，一小部分吉西他滨/顺铂治疗的ERCC1和RRM1 mRNA水平较低的患者生存期明显更长，这突出了个体化化疗的可能性。
