Effect of consecutive lower-dose cisplatin in enhancement of 5-fluorouracil cytotoxicity in experimental tumor cells in vivo

• Published in: Cancer letters Vol. 160; no. 2; pp. 185 - 191
• Main Authors: Araki, Hiroshi, Fukushima, Masakazu, Kamiyama, Yasuo, Shirasaka, Tetsuhiko
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 28.11.2000; Elsevier
• Subjects: 5-Fluorouracil; 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - biosynthesis; 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - metabolism; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - toxicity; Biochemical modulation; Biological and medical sciences; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Cisplatin - pharmacology; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Synergism; Enzyme Induction - drug effects; Fluorouracil - administration & dosage; Fluorouracil - toxicity; Folic Acid - metabolism; Low-dose cisplatin; Male; Medical sciences; Methionine - pharmacokinetics; Methionine synthase; Mice; Neoplasm Transplantation; Oxonic Acid - administration & dosage; Pharmacology. Drug treatments; Pyridines - administration & dosage; Rats; Reduced folate; Sarcoma, Yoshida - drug therapy; Sarcoma, Yoshida - metabolism; Tegafur - administration & dosage; Thymidylate synthase; 5-Fluorouracil; Biochemical modulation; Reduced folate; Low-dose cisplatin; Methionine synthase; Thymidylate synthase; Cisplatin; Antineoplastic agent; O-Acetylhomoserine (thiol)-lyase; Potentiation; Rat; Lyases; Folate; Multiple dose; Enzymatic activity; Mechanism of action; Tumor cell; Fluorouracil; Platinum II Complexes; Drug combination; Sarcoma; Enzyme; Transferases; Low dose; Fluoropyrimidine derivatives; Rodentia; Malignant tumor; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Methyltransferases; Animal; Pyrimidine derivatives; Carbon-oxygen lyases
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(00)00583-8

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.