Biochemical modulation of 5-fluorouracil with interferon alpha/beta and gamma on murine renal cell carcinoma.
BACKGROUND
Conventional therapy for renal cell carcinoma (RCC) using interferon (IFN) has shown limited antitumor action. The purpose of the present study was to investigate the synergistic antitumor effects of IFN and 5-fluorouracil (5-FU) and to elucidate the mechanism underlying antitumor effects.


METHODS
The antitumor effects and biochemical modulation of murine IFN and 5-FU were determined using murine renal cell carcinoma (RENCA). The activity of thymidylate synthase, thymidine kinase and the concentration of 5-FU incorporated into RNA was measured using cytosolic extracts of tumors.


RESULTS
Triple combination therapy (5-FU, IFN alpha/beta and IFN gamma) showed a synergistic antitumor effect on RENCA tumors, because triple combination therapy suppressed growth significantly compared to combination therapy (IFN alpha/beta and IFN gamma, P = 0.0258) and 5-FU (P < 0.0001). Total thymidylate synthase was decreased by triple combination therapy (5-FU, IFN alpha/beta and IFN gamma, P = 0.0019) and combination therapy (5-FU and IFN gamma, P = 0.0018) compared to 5-FU alone. Thymidine kinase activity was decreased by triple combination therapy (5-FU, IFN alpha/beta and IFN gamma, P < 0.0001) and combination therapy (5-FU and IFN alpha/beta, P < 0.0001) compared to 5-FU alone. The concentration of 5-FU incorporated into RENCA tumors was increased by triple combination therapy (P = 0.0132) and combination therapy (5-FU and IFN alpha/beta, P = 0.0124) compared to 5-FU alone.


CONCLUSIONS
Interferons alpha/beta and gamma showed different biochemical modulation for 5-FU. Therefore, combination therapy using 5-FU and IFN showed synergistic antitumor effects on murine RCC.
Ishii
Taketsugu
T
Department of Urology, Kawasaki Municipal Kawasaki Hospital, Kanagawa, Japan. taketsugu@kmh.gr.jp
Marumo
Ken
K
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D013937:Thymidine Kinase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
D012334:RNA, Neoplasm; D007372:Interferons; D013940:Thymidylate Synthase; D013937:Thymidine Kinase; D005472:Fluorouracil