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FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer

Authors' Affiliations: ¹ Medical Oncology, Institut Malalties Hemato-Oncologiques, ² Gastroenterology, ³ Epidemiology, and ⁴ Biochemical Departments, Hospital Clinic Barcelona, Institut d'Investigacions Bimédiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain

Requests for reprints: Joan Maurel, Medical Oncology Department, Institut Malalties Hemato-Oncologiques, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. Phone: 34-93-2275402; Fax: 34-93-2275402; E-mail: jmaurel{at}clinic.ub.es.

Purpose: Oxaliplatin-5-fluorouracil combinations have increased responses in first-line therapy up to 40% in advanced colorectal cancer. Unfortunately, those patients who will respond are unknown and initially sensitive patients become rapidly resistant to current therapies. FAS (CD95) and FAS ligand (FASL; CD95L) have been implicated in chemosensitivity through leading to apoptosis in response to DNA-damaging drugs. Whereas the proapoptotic role of FAS and FASL is well characterized, the function of their soluble forms as predictors of chemosensitivity remains unknown.

Patients and Methods: Blood samples were obtained from 68 patients with advanced colorectal cancer who received oxaliplatin-5-fluorouracil combinations in first-line therapy. Computed tomographic scans were done every 3 months and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression. Ratios between soluble FAS and soluble FASL were established and its values and variations through time were related to treatment responses.

Results: We found a significant increase in soluble FAS levels and a significant decrease in FASL at 3 months compared with baseline (13.2 versus 10.02 ng/mL; P = 0.0001; 0.07 versus 0.14 ng/mL; P = 0.007, respectively). A significant increase in the soluble FASL levels up to 9 months (fourth to fifth extractions; 0.26 ng/mL) of therapy compared with first to third extractions (0.11 ng/mL; P = 0.003) was also found. A random effect regression statistical model determined that >1.2-fold increase in soluble FAS/soluble FASL ratio was a marker of chemosensitivity (P = 0.001).

Conclusions: These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer. On the other hand, a decreased ratio after treatment can be a predictor of chemoresistance despite an initial response.