Comparative antitumor activity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in combination with interferon-alpha in renal cell carcinoma cell lines.
OBJECTIVE
Although interferon-alpha (IFNalpha) and interleukin-2 are used in the treatment of advanced renal cell carcinoma (RCC), the rate of efficacy is about 15% and not satisfactory. Therefore, a more effective treatment is being investigated. In this study, we examined the combined effects of IFNalpha and 5-fluorouracil (5-FU) as well as 5-deoxy-5-fluorouridine (5'-DFUR), a produrg of 5-FU, in vitro.


METHODS
Four RCC cell lines (OCUU1, OCUU3, OCUU4, OCUU5) were established at our laboratory from RCC patients. OS-RC-2, RCC10RGB, TUHR14TKB, TUHR4TKB, A498 and Caki-1 were obtained from a commercial source. The sensitivity of the 10 RCC cell lines to 5-FU and 5'-DFUR was evaluated using MTT assay. The IC50 value for the cytostatics was expressed as the concentration at which growth was inhibited by 50% as compared with the control value. Thymidine phosphorylase (TP), the enzyme that converts 5'-DFUR into 5-FU and 5-FU into FdUMP, was estimated by ELISA.


RESULTS
When the 10 RCC cell lines were divided into the low TP expression group and high TP expression group at 2.0 U/ml protein, TP expression was not enhanced by IFNalpha in all 4 cell lines in the low TP expression group. Antitumor effects were not enhanced by IFNalpha in 3 out of 4 cell lines for 5-FU and in all 4 cell lines for 5'-DFUR. On the other hand, in the high TP expression group, TP expression was enhanced by IFNalpha in 5 out of 6 cell lines, and antitumor effects were enhanced by IFNalpha in 5 out of 6 cell lines for 5-FU and in all 6 cell lines for 5'-DFUR. In addition, there was a significant correlation between TP expression and sensitivity to 5-FU and 5'-DFUR in all RCC cell lines.


CONCLUSIONS
These results suggested that TP may be useful as a predictive factor in combination therapy with IFNalpha and 5-FU or 5'-DFUR, which may be a promising treatment for advanced RCC.
Ikemoto
Shinichi
S
Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan. tt-kaaka-iastuko@yahoo.co.jp
Sugimura
Kazunobu
K
Yoshida
Naomasa
N
Kuratsukuri
Katsuyuki
K
Wada
Seiji
S
Nakatani
Tatsuya
T
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D004354:Drug Screening Assays, Antitumor; D005467:Floxuridine / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D016898:Interferon-alpha; D005467:Floxuridine; D005472:Fluorouracil; C025034:doxifluridine