The potential clinical value of GML and the p53 gene as a predictor of chemosensitivity for colorectal cancer.
BACKGROUND
Adjuvant chemotherapy with 5-fluorouracil (5-FU) and mitomycin C (MMC) has commonly been used after resection of colorectal cancer. The aim of this study was to determine the predictive value of p53 mutation or the expression of GML, a target of p53, for sensitivity to 5-FU and MMC.


METHODS
We analyzed p53 mutations and the expression of GML in six colorectal cancer cell lines (SW837, DLD-1, RPMI4788, WiDr, HT-29, and HCT116), and examined the correlation between genetic changes and in-vitro chemosensitivity to MMC and 5-FU by measuring the colony-forming ability in these cell lines. We also introduced GML cDNA into a cell line that lacked endogenous GML expression to investigate changes in sensitivity to MMC and 5-FU.


RESULTS
The sensitivity to MMC was highest in HCT116, which had no p53 gene abnormalities and expressed endogenous GML, and lowest in RPMI4788 cells, which had neither p53 gene abnormalities nor expression of endogenous GML. For 5-FU treatment with 24-h exposure, HCT116 showed the highest sensitivity, and SW837, which had p53 mutations without expression of GML, showed the lowest sensitivity. The introduction of GML cDNA to RPMI4788 (RPMI4788-GML) showed that the sensitivity of RPMI4788-GML to MMC was enhanced almost to the level of HCT116 cells. However, when RPMI4788-GML were exposed to 5-FU for 24 h, the sensitivity of RPMI4788-GML was slightly increased compared with that of the parental cells, but was slightly lower than that of HCT116.


CONCLUSIONS
GML expression and p53 mutation in colorectal cancer may be useful predictive genetic markers for sensitivity to MMC and 5-FU, respectively.
Hashimoto
Y
Y
First Department of Surgery, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
Ueda
K
K
Minami
K
K
Watatani
M
M
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D018797:Cell Cycle Proteins; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology*; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis* / Q000096:biosynthesis; D016685:Mitomycin / Q000494:pharmacology*; D009363:Neoplasm Proteins; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; C102519:GML protein, human; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D016685:Mitomycin; D005472:Fluorouracil