Investigation of chemotherapy based on enzyme expression and drug sensitivity test in colorectal cancer
Tokunaga, Y.; Ohnishi, T.; Sasaki, H.
Gan to Kagaku Ryoho. Cancer and ChemoTherapy 38(1): 69-73
2011
ISSN/ISBN: 0385-0684 PMID: 21368461 Document Number: 648048
In colorectal cancer (CRC), 5-fluorouracil (5-FU) has been a basic chemotherapeutic agent. Orotate phosphoribosyltransferase (OPRT) and thymidine phosphorylase (TP) are essential enzymes for activation of 5-FU. Dihydropyrimidine dehydrogenase (DPD) is an enzyme for degradation. The feasibility of individualized chemotherapy was studied using the enzyme expression and drug sensitivity test. The study included 160 surgical patients (stage II to IV). OPRT, TP, and DPD expressions, assessed with immunohistochemistry, were evaluated in relation to clinicopathological features and patient survival. We assessed 5-FU sensitivity using the collagen gel droplet. Embedded culture-drug sensitivity test(CDDST). The area under the concentration curve (AUC) and growth inhibition curve (IR) were combined in the AUC-IR curve, according to which the individual AUC(IR₅₀) was calculated. Durations to achieve AUC(IR₅₀) were calculated using AUC(₂₄hr) values in UFT and S-1. TP and DPD expression were positively associated with CRC progression and related with poor prognosis, although OPRT expression was negatively associated with CRC progression and related with better prognosis. Patient survival was best in patients with OPRT (+) DPD (-), and worst in those with OPRT (-) DPD (+). Individual AUC(IR₅₀) ranged from less than 100 mg·hr/mL to more than 10,000 mg·hr/mL. In the chemotherapy with UFT, 55% of patients achieved AUC(IR₅₀) within 6 months, 13% of patients achieved it 6 to 12 months, another 13% of patients in 12 to 24 months, and the other 19% after 24 months of chemotherapy. In the chemotherapy with S-1, 31% of patients achieved AUC(IR₅₀) within 1 course, 15% in 1 to 2 courses, another 23% in 2 to 6 courses and the other 31% of patients achieved AUC(IR₅₀) after 6 courses. The present results suggest that patients' prognosis may be improved with selection of an anti-cancer drug based on the 5-FU metabolizing enzyme expressions and prognostic factors. CD-DST may predict the duration of chemotherapy.