Relationship between Dose Rate of [6RS]Leucovorin Administration, Plasma Concentrations of Reduced Folates, and Pools of 5,10-Methylenetetrahydro-folates and Tetrahydrofolates in Human Colon Adenocarcinoma Xenografts

Janet A. Houghton, Larry G. Williams, Pamela J. Cheshire, Peter J Houghton, John H. Rodman, Dan C. Maneval, Irving W. Wainer, Philippe Jadaud, Siebold S.N. de Graaf

Research output: Contribution to journalArticle

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Abstract

[6RS]Leucovorin (5-formyltetrahydrofolate; S-CHO-HUPteGlu) 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 (H4PteGlu,), 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 S-CHO-H4PteGlu and 5-methyl-tetrahydrofolate (5-CH3-H4PteGlu) in mouse plasma to those previously reported in humans, but with more rapid elimination half-lives (Fí = 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 [6 RS]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|Ieucovorin 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. When FUra (6.25 to 25 mg/kg) was administered 3 h into a 24-h infusion of (6RS]leucovorin (500 mg/m2) in tumor-bearing mice, potentiation of thymidylate synthase inhibition in comparison with FUra administered alone was observed. These studies raise important questions regarding the effect of (a) dose of [6RS] leucovorin, (b) frequency of administration, (c) utility of 5-CH3-HiPteGlu, and (d) [6R]5-CHO-H4PteGlu on influencing intratumor pools of CH2-H4PteGlun and H4PteGlun, the inhibition of thymidylate synthase.

Original languageEnglish (US)
Pages (from-to)3493-3502
Number of pages10
JournalCancer Research
Volume50
Issue number12
StatePublished - Jun 15 1990
Externally publishedYes

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Tetrahydrofolates
Leucovorin
Folic Acid
Heterografts
Colon
Adenocarcinoma
Fluorouracil
Thymidylate Synthase
Neoplasms
Appointments and Schedules
Floxuridine
Polyglutamic Acid
Injections

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Relationship between Dose Rate of [6RS]Leucovorin Administration, Plasma Concentrations of Reduced Folates, and Pools of 5,10-Methylenetetrahydro-folates and Tetrahydrofolates in Human Colon Adenocarcinoma Xenografts. / Houghton, Janet A.; Williams, Larry G.; Cheshire, Pamela J.; Houghton, Peter J; Rodman, John H.; Maneval, Dan C.; Wainer, Irving W.; Jadaud, Philippe; de Graaf, Siebold S.N.

In: Cancer Research, Vol. 50, No. 12, 15.06.1990, p. 3493-3502.

Research output: Contribution to journalArticle

Houghton, Janet A. ; Williams, Larry G. ; Cheshire, Pamela J. ; Houghton, Peter J ; Rodman, John H. ; Maneval, Dan C. ; Wainer, Irving W. ; Jadaud, Philippe ; de Graaf, Siebold S.N. / Relationship between Dose Rate of [6RS]Leucovorin Administration, Plasma Concentrations of Reduced Folates, and Pools of 5,10-Methylenetetrahydro-folates and Tetrahydrofolates in Human Colon Adenocarcinoma Xenografts. In: Cancer Research. 1990 ; Vol. 50, No. 12. pp. 3493-3502.
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title = "Relationship between Dose Rate of [6RS]Leucovorin Administration, Plasma Concentrations of Reduced Folates, and Pools of 5,10-Methylenetetrahydro-folates and Tetrahydrofolates in Human Colon Adenocarcinoma Xenografts",
abstract = "[6RS]Leucovorin (5-formyltetrahydrofolate; S-CHO-HUPteGlu) 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 (H4PteGlu,), 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 S-CHO-H4PteGlu and 5-methyl-tetrahydrofolate (5-CH3-H4PteGlu) in mouse plasma to those previously reported in humans, but with more rapid elimination half-lives (F{\'i} = 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 [6 RS]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|Ieucovorin 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. When FUra (6.25 to 25 mg/kg) was administered 3 h into a 24-h infusion of (6RS]leucovorin (500 mg/m2) in tumor-bearing mice, potentiation of thymidylate synthase inhibition in comparison with FUra administered alone was observed. These studies raise important questions regarding the effect of (a) dose of [6RS] leucovorin, (b) frequency of administration, (c) utility of 5-CH3-HiPteGlu, and (d) [6R]5-CHO-H4PteGlu on influencing intratumor pools of CH2-H4PteGlun and H4PteGlun, the inhibition of thymidylate synthase.",
author = "Houghton, {Janet A.} and Williams, {Larry G.} and Cheshire, {Pamela J.} and Houghton, {Peter J} and Rodman, {John H.} and Maneval, {Dan C.} and Wainer, {Irving W.} and Philippe Jadaud and {de Graaf}, {Siebold S.N.}",
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T1 - Relationship between Dose Rate of [6RS]Leucovorin Administration, Plasma Concentrations of Reduced Folates, and Pools of 5,10-Methylenetetrahydro-folates and Tetrahydrofolates in Human Colon Adenocarcinoma Xenografts

AU - Houghton, Janet A.

AU - Williams, Larry G.

AU - Cheshire, Pamela J.

AU - Houghton, Peter J

AU - Rodman, John H.

AU - Maneval, Dan C.

AU - Wainer, Irving W.

AU - Jadaud, Philippe

AU - de Graaf, Siebold S.N.

PY - 1990/6/15

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N2 - [6RS]Leucovorin (5-formyltetrahydrofolate; S-CHO-HUPteGlu) 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 (H4PteGlu,), 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 S-CHO-H4PteGlu and 5-methyl-tetrahydrofolate (5-CH3-H4PteGlu) in mouse plasma to those previously reported in humans, but with more rapid elimination half-lives (Fí = 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 [6 RS]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|Ieucovorin 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. When FUra (6.25 to 25 mg/kg) was administered 3 h into a 24-h infusion of (6RS]leucovorin (500 mg/m2) in tumor-bearing mice, potentiation of thymidylate synthase inhibition in comparison with FUra administered alone was observed. These studies raise important questions regarding the effect of (a) dose of [6RS] leucovorin, (b) frequency of administration, (c) utility of 5-CH3-HiPteGlu, and (d) [6R]5-CHO-H4PteGlu on influencing intratumor pools of CH2-H4PteGlun and H4PteGlun, the inhibition of thymidylate synthase.

AB - [6RS]Leucovorin (5-formyltetrahydrofolate; S-CHO-HUPteGlu) 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 (H4PteGlu,), 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 S-CHO-H4PteGlu and 5-methyl-tetrahydrofolate (5-CH3-H4PteGlu) in mouse plasma to those previously reported in humans, but with more rapid elimination half-lives (Fí = 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 [6 RS]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|Ieucovorin 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. When FUra (6.25 to 25 mg/kg) was administered 3 h into a 24-h infusion of (6RS]leucovorin (500 mg/m2) in tumor-bearing mice, potentiation of thymidylate synthase inhibition in comparison with FUra administered alone was observed. These studies raise important questions regarding the effect of (a) dose of [6RS] leucovorin, (b) frequency of administration, (c) utility of 5-CH3-HiPteGlu, and (d) [6R]5-CHO-H4PteGlu on influencing intratumor pools of CH2-H4PteGlun and H4PteGlun, the inhibition of thymidylate synthase.

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