Antitumour effects of pure diastereoisomers of 5-formyltetrahydrofolate in hepatic transplants of a rodent colon carcinoma model.
The effects of the two diastereoisomers of 5-formyltetrahydrofolate on tumour growth, thymidylate synthase (TS, EC 2.1.1.45) levels, and potentiation of 5-fluorouracil cytotoxicity were studied in an in vivo rat colon carcinoma model, transplanted to liver. The animals were randomized into eight groups, treated with daily i.v. tail vein injections of racemic (d,l)-5-formyltetrahydrofolate (5-CHO-FH4), 15 mg/kg, (1)-5-CHO-FH4 7.5 mg/kg, and (d)-5-CHO-FH4 7.5 mg/kg, 5-fluorouracil (FUra) 30 mg/kg, (d,l)-5-CHO-FH4 15 mg/kg+FUra 30 mg/kg, (l) 5-CHO-FH4 7.5 mg/kg+FUra 30 mg/kg, and (d)-5-CHO-FH4 7.5 mg/kg+FUra 30 mg/kg, and a sham-treated control group. The average tumour size of the groups was equal at the start of treatment. After six days' treatment the average tumour sizes were at laparotomy 3.3 +/- 1.0 g in the (d/l)-5-CHO-FH4 treated group, compared to 2.0 +/- 0.1 g in the FUra treated group and 7.1 +/- 3.1 g in the controls. Natural (l)-5-CHO-FH4 promoted tumour growth (average tumour weight 10.8 +/- 4.0 g), whereas the unnatural (d)-5-CHO-FH4 alone retarded it (average tumour weight 1.2 +/- 0.40 g). (l)-5-CHO-FH4 induced a significant increase in tumour tissue TS levels by [3H]FdUMP radioligand assay (27.5 +/- 8.4 pmol/g tumour tissue) compared to controls (16.8 +/- 6.1 pmol/g tumour tissue). Increases in 5,10-methylenetetrahydrofolate and tetrahydrofolate occurred with FUra alone, with a further statistically significant increase in both folates with the addition of (d)-5-CHO-FH4 to FUra.
Carlsson
G
G
Department of Surgery, Ostra Sjukhuset, Göteborg, Sweden.
Gustavsson
B
B
Frösing
R
R
Odin
E
E
Hafström
L O
LO
Spears
C P
CP
Larsson
P A
PA
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009368:Neoplasm Transplantation; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil