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

Laboratories for Developmental Therapeutics, Department of Biochemical and Clinical Pharmacology [J. A. H., L. G. W., P. J. C., P. J. H.], and Department of Clinical Pharmacokinetics [I. W. W., P. J.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101

Using preclinical models of human colon adenocarcinomas in immunedeprived mice, the influence of dose of [6RS]leucovorin ([6RS]LV, 20 to 1000 mg/m²) 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 [6RS]LV and the biologically active diastereoisomer of 5-methyltetrahydrolate (5-CH₃-H₄PteGlu); (b) expansion of intratumor pools of 5,10-methylenetetrahydrofolates (CH₂-H₄PteGlu_n) and tetrahydrofolates (H₄PteGlu_n), that may influence the binding of 5-fluorodeoxyuridylate to thymidylate synthase; (c) the distribution of polyglutamate forms of CH₂-H₄PteGlu_n and H₄PteGlu_n; and (d) (5-fluorouracil (FUra)-mediated thymidylate synthase inhibition in HxELC₂, HxGC₃, HxVRC₅, and HxHC₁ tumors. Folylpolyglutamate synthetase activities were also determined in each line. Linear increases in plasma concentrations of [6R]LV, [6S]LV, and 5-CH₃-H₄-PteGlu were determined over the complete range of [6RS]LV doses examined. However, in neoplastic tissues three patterns of biochemical modulation by [6RS]LV were evident. (a) In HxELC₂ and HxVRC₅ tumors, pools of CH₂-H₄PteGlu_n and H₄PteGlu_n were elevated in proportion to the dose of [6RS]LV between dose levels of 50 and 200 mg/m². Subsequent expansion of these pools continued that was disproportionate to the dose of [6RS]LV until no further increase was observed beyond 800 mg/m² [6RS]LV, at which point pools were maximally expanded by 4- to 4.5-fold. The extent of retardation of recovery of thymidylate synthase activity increased as the dose of [6RS]LV was increased in both tumors, when FUra (15 or 50 mg/kg), was administered by i.v. bolus injection 3 h into the 24-h infusion of [6 RS]LV. This was related to the increase in predominance of CH₂-H₄PteGlu_2–5 with increasing dose of [6RS]LV. (b) For HxHC₁ tumors, little expansion of CH₂-H₄PteGlu_n and H₄PteGlu_n pools (maximum, 137% of control) was detected at the highest dose levels of [6RS]LV, 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 CH₂-H₄PteGlu_n and H₄PteGlu_n increased gradually from 169% of control at 20 mg/m² [6RS] LV to 233% of control at 1000 mg/m² [6RS]LV, and were intermediate between the expansion observed in HxHC₁ in comparison to HxELC₂ and HxVRC₅ tumors. CH₂-H₄PteGlu_3–5 were elevated at low dose levels of [6RS]LV. A greater extent of retardation of the recovery of thymidylate synthase following FUra administration was observed at a lower dose of [6RS]LV. No relationship was detected between the activity of folylpolyglutamate synthetase and the pattern of modulation of CH₂-H₄PteGlu_n species in tumors by [6RS]LV. The metabolic characteristics of modulation by [6RS]LV 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.

¹ Supported by National Cancer Institute Awards CA 32613, CA 23099, and Cancer Center Support (CORE) CA 21765 and by the American Lebanese Syrian Associated Charities (ALSAC).

² To whom requests for reprints should be addressed, at Laboratories for Developmental Therapeutics, Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38101.

Received 11/13/89. Revised 3/12/90.

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