title: Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival.
abstract: Gemcitabine is considered the standard first-line therapy for patients with advanced pancreatic cancer. More recent strategies have focused on improving the efficacy of gemcitabine by either improving the method of delivery or by combining gemcitabine with other non-cross-resistant chemotherapy agents or with small-molecule drugs. However, the clinical benefits, response rates, and duration of responses have been modest. Deoxycytidine kinase (dCK) is the rate-limiting enzyme involved in the metabolism of gemcitabine. The expression of dCK has been postulated to be correlative of gemcitabine resistance. We determined the relationship of dCK immunohistochemical protein expression and/or genetic status of dCK in a panel of human pancreatic cancer tissues and pancreatic cancer cell lines and determined the relationship of these variables to the clinical outcome of patients treated with gemcitabine. We report that dCK protein expression is expressed in the majority of pancreatic cancers analyzed (40 of 44 cases, 91%) and showed a range of labeling intensities ranging from 1+ (labeling weaker in intensity than normal lymphocytes present in same section) to 3+ (labeling greater in intensity than normal lymphocytes present in same section). When labeling intensity was compared with survival, low dCK expression (1+ labeling) was correlated with both overall survival (P < 0.009) and progression-free survival following gemcitabine treatment (P < 0.04). Low dCK labeling intensity was also significantly correlated with patient age (70.3 +/- 8.1 versus 59.8 +/- 7.4 years; P < 0.0006), suggesting that age-related methylation of the dCK gene may account in part for the observed differences. Sequencing of the entire dCK coding sequence in 17 cell lines and 9 patients' cancer tissues with disease progression while on gemcitabine did not identify any mutations, suggesting that genetic alterations of dCK are not a common mechanism of resistance to gemcitabine for this tumor type. Moreover, dCK labeling showed similar patterns and intensities of labeling among matched pretreatment and post-treatment tissues. In summary, pretreatment levels of dCK protein are most correlated with overall survival following gemcitabine treatment and are stable even after resistance to gemcitabine is clinically documented.
authors.affiliation: Department of Pathology, University La Sapienza, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Sebastiani
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.forename: Belen
authors.initials: B
authors.lastname: Rubio-Viqueira
authors.forename: Belen
authors.initials: B
authors.lastname: Rubio-Viquiera
authors.forename: Piotr
authors.initials: P
authors.lastname: Kulesza
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Alison
authors.initials: A
authors.lastname: Klein
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D016019:Survival Analysis; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine