title: The promise of pharmacogenomics: gemcitabine and pemetrexed.
abstract: Although no overall differences in survival have been observed between the many chemotherapy combinations in non-small-cell lung cancer, the clinical application of mRNA expression levels of amplified genes may disclose many genetic influences on cytotoxic drug sensitivity and enable clinicians to tailor chemotherapy according to each individual's gene profile. Specifically, the assessment of ribonucleotide reductase subunit M1 and thymidylate synthase mRNA expression levels might select patients who benefit from gemcitabine (Gemzar) or pemetrexed (Alimta) combinations. Until recently, clinical prognostic factors such as performance status, weight loss, and lactate dehydrogenase were the only parameters used to predict chemotherapy response and survival. However, accumulated data indicate that overexpression of genes involved in cancer glycolysis pathways plays an important role, and might be an independent mechanism of chemoresistance. The dysregulation of glycolytic genes is affected by growth signals involving the PI3K/Akt pathway and downstream genes such as hypoxia-inducible factor-1-alpha. One can thus envision that substantial improvements in therapeutic outcome could benefit from the integration of tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotide reductase antisense therapy, and targeted therapy.
authors.affiliation: Medical Oncology Service, Hospital Germans Trias i Pujol, Badalona, Spain. rrosell@ns.hugtip.scs.es
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.forename: Miquel
authors.initials: M
authors.lastname: Taron
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Sanchez
authors.forename: Teresa
authors.initials: T
authors.lastname: Moran
authors.forename: Noemi
authors.initials: N
authors.lastname: Reguart
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.forename: Dolores
authors.initials: D
authors.lastname: Isla
authors.forename: Bartomeu
authors.initials: B
authors.lastname: Massuti
authors.forename: Vicente
authors.initials: V
authors.lastname: Alberola
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Sanchez
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005493:Folic Acid Antagonists / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000008:administration & dosage*; D006147:Guanine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000068437:Pemetrexed; D010597:Pharmacogenetics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine
chemical_list: D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D013940:Thymidylate Synthase; D000093542:Gemcitabine