PHASE I-II STUDY OF WEEKLY 5-FLUOROURACIL AND 5,10-METHYLENE-TETRAHYDROFOLATE IN PATIENTS WITH ADVANCED GASTROINTESTINAL AND BREAST-CANCER

Background - 5-fluorouracil (5-FU) modulation with leucovorin offers b etter objective response rates in advanced solid tumors but no signifi cant prolongation of survival. The present clinical study aimed at inv estigating the pharmacokinetics, pharmacodynamic effects and toxicity of 5,10-methylene-tetrahydrofolate (5,10-CH2FH4) as a possible modulat ing agent in 5-fluorouracil (5-FU) treatment of advanced gastrointesti nal and breast carcinomas. Methods - 5,10-methylene-tetrahydrofolate ( 5,10-CH2FH4) was studied as a possible modulating agent in 5-FU treatm ent of advanced gastrointestinal and breast carcinomas. Seventeen pati ents 100 mg and 45 patients 200 mg of 5,10-CH2FH4 plus 5-FU as weekly i.v. bolus injections. Results - Peak plasma concentrations were 18.62 +/-1.22 nmol/ml and 43.3+/-2.6 nmol/ml after injection of 100 and 200 mg of 5,10-CH2FH4 respectively. Dose limiting toxicity (diarrhoea) occ urred in 2/3 of the patients on the highest dose levels. Partial respo nse was observed in 17 patients (29.3%) and time to progression was 16 .5 months and 9.0 months in patients receiving 100 mg and 200 mg of 5, 10-CH2FH4 respectively. Conclusions - 5,10-CH2FH4 is safe in combinati on with 5-FU and warrants further clinical evaluation.