Relationship between dose rate of [6RS]Leucovorin administration, plasma concentrations of reduced folates, and pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in human colon adenocarcinoma xenografts.
[6RS]Leucovorin (5-formyltetrahydrofolate; 5-CHO-H4PteGlu) administered in different regimens in combination with 5-fluorouracil (FUra) has increased the response rates to FUra in patients with colon adenocarcinoma. Using preclinical models of human colon adenocarcinomas as xenografts in immune-deprived mice, the effect of the rate of administration of racemic [6RS]leucovorin on the concentration-time profile of reduced folates in plasma, size of intratumor pools of 5,10-methylenetetrahydrofolates (CH2-H4PteGlun) and tetrahydrofolates (H4PteGlun), and the distribution of their polyglutamate species have been examined. Bolus injection i.v., or 4-h or 24-h infusion of [6RS]leucovorin (500 mg/m2) yielded similar concentration profiles of the biologically active [6S] and inactive [6R] isomers of 5-CHO-H4-PteGlu and 5-methyltetrahydrofolate (5-CH3-H4PteGlu) in mouse plasma to those previously reported in humans, but with more rapid elimination half-lives (t1/2 = 11 to 16 min, 23 to 41 min, and 30 to 35 min, respectively). Thus, reduced folates remained elevated in plasma during the period of [6RS]leucovorin administration. In HxELC2 and HxGC3 tumors, pools of CH2-H4PteGlun and H4PteGlun were increased from 350% to 700% of control, but only during [6RS]leucovorin infusion. Intracellular levels subsequently declined rapidly, similar to the loss of reduced folates from plasma. Increasing the rate of [6RS]leucovorin delivery by decreasing the time for administration from a 24-h to a 4-h infusion did not further increase the intratumor pools of CH2-H4PteGlun and H4PteGlun, suggesting saturation in the cellular metabolism of [6RS]leucovorin. In HxGC3 tumors, CH2-H4PteGlu4-5 were elevated more rapidly than in line HxELC2, which accumulated predominantly a shorter chain length species following i.v. bolus injection. During the 4-h infusion schedule, di- and triglutamate species in particular accumulated in both tumors with no elevation in CH2-H4PteGlu5 until the infusion was discontinued, when this species increased as the shorter chain length forms were declining. However, during the 24-h infusion of [6RS]leucovorin, CH2-H4PteGlu3-5 were elevated in tumors. Since these species have been reported to increase the binding affinity of [6-3H]5-fluorodeoxyuridine monophosphate ([6-3H]FdUMP) to thymidylate synthase, and intratumor pools of CH2-H4PteGlun and H4PteGlun were elevated during the 24-h infusion of [6RS]leucovorin, this was considered to be the preferred schedule for administration.(ABSTRACT TRUNCATED AT 400 WORDS)
Houghton
J A
JA
Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101.
Williams
L G
LG
de Graaf
S S
SS
Cheshire
P J
PJ
Rodman
J H
JH
Maneval
D C
DC
Wainer
I W
IW
Jadaud
P
P
Houghton
P J
PJ
D000230:Adenocarcinoma / Q000097:blood / Q000378:metabolism*; D000818:Animals; D003110:Colonic Neoplasms / Q000097:blood / Q000378:metabolism*; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D008808:Mice, Inbred CBA; D013763:Tetrahydrofolates / Q000097:blood*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000097:blood; D013997:Time Factors
D013763:Tetrahydrofolates; D005467:Floxuridine; C013123:5,10-methylenetetrahydrofolic acid; D013940:Thymidylate Synthase; D002955:Leucovorin; C005984:5-methyltetrahydrofolate