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

• Published in: European journal of cancer (1990) 1995-07, Vol.31 (7), p.1306-1310
• Main Authors: Leichman, L, Lenz, H.-J, Leichman, C.G, Groshen, S, Danenberg, K, Baranda, J, Spears, C.P, Boswell, W, Silberman, H, Ortega, A, Stain, S, Beart, R, Danenberg, P
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antidotes - administration & dosage; Antimetabolites, Antineoplastic - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Base Sequence; Biomarkers, Tumor - metabolism; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Female; Fluorouracil - administration & dosage; Gene Expression; Humans; Leucovorin - administration & dosage; Male; Middle Aged; Molecular Sequence Data; Thymidylate Synthase - metabolism
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/0959-8049(95)00326-E

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 β-actin as an internal standard, TS expressions for 26 patients range from 0.5 × 10 −3 to 22.6 × 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 × 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.