Molecular determinants of folate levels after leucovorin administration in colorectal cancer.
OBJECTIVE
Oral leucovorin (LV) is used with uracil/tegafur (UFT) in the treatment of colorectal cancer (CRC). In order to find the factors related to the efficacy of LV in enhancing the antitumour effect of UFT, we investigated the relationships between the reduced folate levels in the CRC tissue after LV administration and the gene-expression levels of folate-metabolizing enzymes and folate transporters.


METHODS
The subjects were 60 CRC patients, scheduled to undergo surgery. The control group (n = 30) did not receive LV. Three groups (n = 10 for each) received a single dose of oral LV at 25 mg, 4, 12 or 18 h before surgery (LV 4 h, LV 12 h or LV 18 h groups, respectively). The reduced folate levels in plasma and tissues were measured by high-performance liquid chromatography (HPLC) or a thymidylate synthase-FdUMP binding assay, respectively. The intratumoral expression levels of 34 genes were quantitatively evaluated with a real-time polymerase chain reaction (RT-PCR) assay.


RESULTS
The reduced folate levels persisted for a longer period of time in the CRC tissue than in the plasma after LV administration. A multivariate logistic regression analysis revealed that high folylpolyglutamate synthase (FPGS) gene expression, low gamma-glutamyl hydrolase (GGH) gene expression and low ATP-binding cassette sub-family C, number 1 (ABCC1) gene expression in CRC tissues were predictive factors for a high reduced folate level after LV administration.


CONCLUSIONS
The expression level of FPGS, GGH and ABCC1 in CRC tissues could predict the reduced folate level after LV administration, and these factors may determine the efficacy of LV treatment.
Sadahiro
Sotaro
S
Department of Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. sadahiro@is.icc.u-tokai.ac.jp
Suzuki
Toshiyuki
T
Maeda
Yuji
Y
Tanaka
Akira
A
Ogoshi
Kyoji
K
Kamijo
Akemi
A
Murayama
Chieko
C
Tsukioka
Sayaka
S
Sakamoto
Etsuko
E
Fukui
Yousuke
Y
Oka
Toshinori
T
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002851:Chromatography, High Pressure Liquid; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010453:Peptide Synthases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000627:therapeutic use; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics
D005492:Folic Acid; D002955:Leucovorin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010453:Peptide Synthases; D014803:Vitamin B Complex; D011623:gamma-Glutamyl Hydrolase; C023103:folylpolyglutamate synthetase; C421109:multidrug resistance-associated protein 1