title: Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin.
abstract: OBJECTIVE
  Response rates to fluorouracil (5-FU)-based therapy remain low. As new, active agents are being tested, information regarding specific intratumoral genetic determinants of chemotherapy sensitivity or resistance can be used to plan therapy rationally. Intratumoral thymidylate synthase (TS) quantitation may be among the most important determinants of sensitivity or resistance to 5-FU.
  
  
  METHODS
  Forty-six disseminated colorectal cancer patients had measurable tumor biopsies for polymerase chain reaction (PCR)-based determination of TS mRNA pretreatment. Protracted infusion of 5-FU 200 mg/m2/d for 21 days with weekly intravenous leucovorin 20 mg/m2 each cycle was given. After two cycles, responses were evaluated. Response data were correlated with independently determined intratumoral ratios of TS/beta-actin mRNA for each patient.
  
  
  RESULTS
  TS/beta-actin ratios were successfully obtained for 42 patients (91%). TS/beta-actin ratios ranged from 0.3 x 10(-3) to 18.2 x 10(-3) (median, 3.5 x 10[-3]). Twelve patients (26%) responded to treatment (median TS/beta-actin ratio, 1.7 x 10[+3]). Thirty-four patients did not respond (median TS/beta-actin ratio, 5.6 x 10[-3]). No patient with a TS mRNA level greater than 4.1 x 10(-3) responded. The median TS/beta-actin ratio (3.5 x 10[-3]) significantly segregated responders from nonresponders (P = .001). Median survival for patients with TS/beta-actin ratios < or = 3.5 x 10(-3) was 13.6 months; for patients with TS/beta-actin ratios greater than 3.5 x 10(-3), it was 8.2 months (P = .02).
  
  
  CONCLUSIONS
  For this cohort, the intratumoral TS/beta-actin ratio had a statistically significant association with response and survival. This relationship for other 5-FU schedules remains unknown. Confirmation of these data in a larger patient population could lead to determination of therapy for disseminated colorectal cancer based on a specific intratumoral molecular parameter.
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, USA. cleichma@hsc.usc.edu
authors.forename: C G
authors.initials: CG
authors.lastname: Leichman
authors.forename: H J
authors.initials: HJ
authors.lastname: Lenz
authors.forename: L
authors.initials: L
authors.lastname: Leichman
authors.forename: K
authors.initials: K
authors.lastname: Danenberg
authors.forename: J
authors.initials: J
authors.lastname: Baranda
authors.forename: S
authors.initials: S
authors.lastname: Groshen
authors.forename: W
authors.initials: W
authors.lastname: Boswell
authors.forename: R
authors.initials: R
authors.lastname: Metzger
authors.forename: M
authors.initials: M
authors.lastname: Tan
authors.forename: P V
authors.initials: PV
authors.lastname: Danenberg
mesh_terms: D000199:Actins / Q000032:analysis; D000368:Aged; D000931:Antidotes / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000032:analysis*
chemical_list: D000199:Actins; D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil