title: Pharmacokinetic and metabolism determinants of fluoropyrimidines and oxaliplatin activity in treatment of colorectal patients.
abstract: Fluoropyrimidines and oxaliplatin continued to be the mainstay of therapeutic regimens in the treatment of colorectal cancer (CRC). For this reason, pharmacokinetic and metabolism of these drugs were analyzed and the identification of accurate and validated predictive, prognostic and toxicity markers became necessary to develop an effective therapy adapted to the patient's molecular profile, while minimizing life-threatening toxicities. In this review, we discuss literature data, defining predictive and prognostic markers actually identified in the treatment of CRC. We analyzed predictive markers of fluoropyrimidines effectiveness, principally for 5-Fluorouracil (5- FU) and also for oral fluoropyrimidines, as thymidylate Synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), methylenetetrahydrofolate reductase (MTHFR), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), microsatellite instability. DPD represent the more studied 5-FU toxicity marker, followed by TS and OPRT. Oxaliplatin effectiveness is principally regulated by nucleotide excision repair (NER) pathway, including excision repair cross-complementation group 1 (ERCC1), X-ray cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XDP). The major oxaliplatin toxicity marker is represented by glutathione S-transferase (GST). All these results are based principally on retrospective studies. The future challenge became to validate molecular markers and their association with clinical outcomes in prospective trials, refining technologic platforms and bioinformatics to accommodate the complexity of the multifaceted molecular map that may determine outcome, and determining CRC patients most likely to benefit from therapeutic interventions tailored specifically for them.
authors.affiliation: Clinical Experimental Oncology Laboratory, National Cancer Institute Giovanni Paolo II, Viale Orazio Flacco, 65 70124 Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gnoni
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Nicola
authors.initials: N
authors.lastname: Silvestris
authors.forename: Evaristo
authors.initials: E
authors.lastname: Maiello
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marech
authors.forename: Gianmauro
authors.initials: G
authors.lastname: Numico
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.forename: Vito
authors.initials: V
authors.lastname: Lorusso
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D011743:Pyrimidines; D000077150:Oxaliplatin