ANTITUMOR 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 pot entiation of 5-fluorouracil cytotoxicity were studied in an in vivo ra t colon carcinoma model, transplanted to liver. The animals were rando mized into eight groups, heated with daily i.v. tail vein injections o f racemic (d,l)-5-formyltetrahydrofolate (5-CHO-FH4), 15 mg/kg, (l)-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, an d a sham-treated control group. The average tumour size of the groups was equal at the start of treatment. After six days' treatment the ave rage tumour sizes were at laparotomy 3.3 +/- 1.0 g in the (d/l)5-CHO-F H4 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 tumo ur growth (average tumour weight 10.8 +/- 4.0 g), whereas the unnatura l (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 l evels by [H-3]FdUMP radioligand assay (27.5 +/- 8.4 pmol/g tumour tiss ue) compared to controls (16.8 +/- 6.1 pmol/g tumour tissue). Increase s 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.