IFN gamma-induced up-regulation of PD-ECGF/TP enhances the cytotoxicity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in bladder cancer cells.
BACKGROUND
PD-ECGF/TP is an essential enzyme in converting 5'DFUR and 5FU to their active metabolites and can be up-regulated by some cytokines.


METHODS
PD-ECGF/TP mRNA and protein expressions were determined by RT-PCR and Western blot, respectively. The cytotoxicity of 5FU, 5'DFUR or MMC against RT-4 and T24 cells was evaluated by MTS assay. The PD-ECGF/TP expressions in primary bladder cancers were also analyzed.


RESULTS
Levels of PD-ECGF/TP mRNA and protein were concomitantly elevated in RT-4 and T24 cells after IFN gamma treatment. IFN gamma decreased the IC50 of 5FU and 5'DFUR in both cell lines, while it did not alter the IC50 of MMC, which is not a substrate of PD-ECGF/TP. PD-ECGF/TP expression correlated with tumor stage and grade in primary bladder cancers.


CONCLUSIONS
IFN gamma enhances the cytotoxicity of 5FU and 5'DFUR against human bladder cancer cells through induction of PD-ECGF/TP. The results imply that an IFN gamma/5FU or IFN gamma/5'DFUR combination therapy may be applicable to clinical bladder cancers.
Li
Gang
G
Department of Urology and Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan.
Kawakami
Satoru
S
Kageyama
Yukio
Y
Yan
Chunyin
C
Saito
Kazutaka
K
Kihara
Kazunori
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005467:Floxuridine / Q000493:pharmacokinetics / Q000494:pharmacology*; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008875:Middle Aged; D016685:Mitomycin / Q000493:pharmacokinetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013939:Thymidine Phosphorylase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D005467:Floxuridine; D016685:Mitomycin; D007371:Interferon-gamma; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine