Effect of consecutive lower-dose cisplatin in enhancement of 5-fluorouracil cytotoxicity in experimental tumor cells in vivo.
It is known that cisplatin (CDDP) potentiates the cytotoxicity of 5-fluorouracil (5-FU), and that the biochemical mechanism is an increase in the intracellular reduced folate levels in the tumor cells. We investigated the effect of consecutive administration with lower-dose CDDP on intracellular accumulation of reduced folate and the activity of methionine synthase, a key enzyme in intracellular methionine synthesis. When CDDP (1 mg/kg) was administered i.p. to ascitic Yoshida sarcoma-bearing rats for 4 consecutive days, both the reduced folate levels and methionine synthase activity in the cells significantly increased, as the same as a single 5 mg/kg dose of CDDP. Furthermore, when Yoshida sarcoma-bearing rats were pre-treated with 1 mg/kg CDDP for 5 consecutive days, [14C]L-methionine incorporation into the isolated ascitic cells was significantly inhibited as compared to that in non-treated cells, suggesting that consecutive administration of lower-dose CDDP is capable of inducing the intracellular modulation of reduced folate levels and methionine synthase activity via inhibition of cellular uptake of methionine. In addition, 5-day administration of lower-dose (1 mg/kg) CDDP potentiated the antitumor effect of 5 mg/kg S-1, a new oral preparation of tegafur, given for 7 consecutive days, and this combined effect was almost similar to the antitumor effect of a combination of S-1 and a single conventional dose (5 mg/kg) of CDDP. Consecutive lower-dose CDDP also may be concluded to act as an important modulator of the enhancement of 5-FU cytotoxicity in experimental tumors.
Araki
H
H
1st Division of Surgery, Kansai Medical University, 1 Fumizono, Moriguchi-City, 570-8507, Osaka, Japan.
Fukushima
M
M
Kamiyama
Y
Y
Shirasaka
T
T
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity*; D005492:Folic Acid / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000493:pharmacokinetics; D051379:Mice; D009368:Neoplasm Transplantation; D010094:Oxonic Acid / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D012517:Sarcoma, Yoshida / Q000188:drug therapy* / Q000378:metabolism; D005641:Tegafur / Q000008:administration & dosage
D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D005492:Folic Acid; D008715:Methionine; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D002945:Cisplatin; D005472:Fluorouracil