title: Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-fluorouracil and weekly leucovorin in disseminated colorectal cancers: preliminary report from an ongoing trial.
abstract: A clinical trial for patients with measurable, disseminated colorectal cancer is being conducted to determine: (1) if intratumoral expression of thymidylate synthase (TS) affects response to protracted-infusion 5-fluorouracil (5FU); and (2) whether intratumoral expression of TS increases when clinical resistance is found after response to 5-FU. Polymerase chain reaction technology is employed to determine TS expression. Using beta-actin as an internal standard, TS expressions for 26 patients range from 0.5 x 10(-3) to 22.6 x 10(-3). Currently, 22 patients are evaluable for response and TS quantitation of their measurable tumour. 8 patients (36%) have had partial responses; 3 responding patients had been previously treated with 5-FU. A strong statistical association between TS expression and resistance to therapy has been found (P = 0.004). No patient with TS expression of 4.0 x 10(-3) or greater has responded. On average, patients previously treated with 5-FU have slightly higher levels of TS expression in their measurable tumours (P = 0.4). Whether responding patients will develop increased expressions of TS upon clinical progression of their cancer remains to be determined. Confirmation of these results in a larger cohort could lead to a scientific rationale for deciding upon specific therapy for patients with disseminated colorectal cancers.
authors.affiliation: Department of Medicine, University of Southern California, USA.
authors.forename: L
authors.initials: L
authors.lastname: Leichman
authors.forename: H J
authors.initials: HJ
authors.lastname: Lenz
authors.forename: C G
authors.initials: CG
authors.lastname: Leichman
authors.forename: S
authors.initials: S
authors.lastname: Groshen
authors.forename: K
authors.initials: K
authors.lastname: Danenberg
authors.forename: J
authors.initials: J
authors.lastname: Baranda
authors.forename: C P
authors.initials: CP
authors.lastname: Spears
authors.forename: W
authors.initials: W
authors.lastname: Boswell
authors.forename: H
authors.initials: H
authors.lastname: Silberman
authors.forename: A
authors.initials: A
authors.lastname: Ortega
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000931:Antidotes / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015870:Gene Expression; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D013940:Thymidylate Synthase / Q000378:metabolism*
chemical_list: D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil