The promise of pharmacogenomics: gemcitabine and pemetrexed.
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.
Rosell
Rafael
R
Medical Oncology Service, Hospital Germans Trias i Pujol, Badalona, Spain. rrosell@ns.hugtip.scs.es
Taron
Miquel
M
Sanchez
Jose Miguel
JM
Moran
Teresa
T
Reguart
Noemi
N
Besse
Benjamin
B
Isla
Dolores
D
Massuti
Bartomeu
B
Alberola
Vicente
V
Sanchez
Jose Javier
JJ
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
D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D013940:Thymidylate Synthase; D000093542:Gemcitabine