title: Targeted therapy in combination with gemcitabine in non-small cell lung cancer.
abstract: 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.
authors.affiliation: Medical Oncology Service, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.forename: Lucio
authors.initials: L
authors.lastname: Crino
authors.forename: Kathleen
authors.initials: K
authors.lastname: Danenberg
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scagliotti
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Miquel
authors.initials: M
authors.lastname: Taron
authors.forename: Vicente
authors.initials: V
authors.lastname: Alberola
authors.forename: Mariano
authors.initials: M
authors.lastname: Provencio
authors.forename: Carlos
authors.initials: C
authors.lastname: Camps
authors.forename: Filippo
authors.initials: F
authors.lastname: De Marinis
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Sanchez
authors.forename: Ramon
authors.initials: R
authors.lastname: Peñas
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D004260:DNA Repair / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012264:Ribonucleotide Reductases / Q000235:genetics; D015996:Survival Rate; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D002945:Cisplatin; D000093542:Gemcitabine