Influence of Dose of [6/?5]Leucovorin on Reduced Folate Pools and 5-Fluorouracil- mediated Thymidylate Synthase Inhibition in Human Colon Adenocarcinoma Xenografts1

Using preclinical models of human colon adenocarcinomas in immunedeprived mice, the influence of dose of [6#5]leucovorin ([6RS]LV, 20 to 1000 mjj/iir) administered by 24-h i.v. infusion was determined on the following parameters: (a) plasma concentrations of the active [6S] and inactive \6R] isomers of [6/?5]LV and the biologically active diastereoisomer of 5-methyltetrahydrolate (5-CH3-H4PteGlu); (b) expansion of intratumor pools of 5,10-methylenetetrahydrofolates (CH2-H4PteGlu„) and tetrahydrofolates (I I4r'te<.hi,,), that may influence the binding of 5fluorodeoxyuridylate to thymidylate synthase; (c) the distribution of polyglutamate forms of CH2-H4PteGlun and H4PteGlu„; and (/f,V|l A, and no significant modulation of FUra-inhibited thymidylate synthase activity was detected, even at 1000 mg/m2 [6RS] LV. CH2-H4PteGlu5 remained similar or decreased as the dose of \6RS] LV was increased, (c) For line HxGC3, pools of CHj-R.PteGlu,, and IU'k-<;iu„increased gradually from 169% of control at 20 mg/m2 \6RS] LV to 233% of control at 1000 mg/m2 |6/i.V|l A, and were intermediate between the expansion observed in 11x1K ', in comparison to I IxKI ,<"> and HxVRCs tumors. CH2-H4PteGlu3_5were elevated at low dose levels of \6RS\L\. A greater extent of retardation of the recovery of thymidylate synthase following FUra administration was observed at a lower dose of [6RS]L\. No relationship was detected between the activity of folylpolyglutamate synthetase and the pattern of modulation of CH2-H4PteGlun specie«in tumors by |6/i,S"]IA . The metabolic characteristics of modu lation by |6/f.S'|l A thus differed among the four colon xenograft lines providing a spectrum from little or no modulation to tumors in which pools could be markedly enhanced.