Factors that influence the therapeutic activity of 5-fluorouracil [6RS]leucovorin combinations in colon adenocarcinoma xenografts

Janet A. Houghton; Larry G. Williams; Susan K. Loftin; Pamela J. Cheshire; Christopher L. Morton; Peter J. Houghton; Alain Dayan; Jacques Jolivet

doi:10.1007/BF00685592

Factors that influence the therapeutic activity of 5-fluorouracil [6RS]leucovorin combinations in colon adenocarcinoma xenografts

Janet A. Houghton, Larry G. Williams, Susan K. Loftin, Pamela J. Cheshire, Christopher L. Morton, Peter J. Houghton, Alain Dayan, Jacques Jolivet

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

The therapeutic activity of FUra alone or combined with [6RS]LV doses ranging from 50 to 1,000 mg/m² was examined in eight colon adenocarcinoma xenografts, of which five were established from adult neoplasms (HxELC₂, HxGC₃, HxVRC₅, HxHC₁, and HxGC₃/c1TK-c3 selected for TK deficiency) and three were derived from adolescent tumors (HxSJC₃A, HxSJC₃B, and HxSJC₂). The growth-inhibitory effects of FUra were potentiated by higher doses of [6RS]LV (500-1,000 mg/m²) in three lines (HxGC₃/c1TK-c3, HxSJC₃A, and HxSJC₃B) and by a low dose of [6RS]LV in only one tumor (HxVRC₅). Expansion of pools of CH₂-H₄PteGlu_n+H₄PteGlu_n (≥2.4-fold) in response to higher doses of [6RS]LV was obtained in all lines except HxHC₁. Metabolism of [6RS]LV was high in HxVRC₅, with high levels of 5-CH₃-H₄PteGlu being detected, but not in HxHC₁, in which levels of 5-CH₃-H₄PteGlu and CH=H₄PteGlu+10-CHO-H₄PteGlu remained relatively low. In the adolescent tumors, levels of CH=H₄PteGlu+10-CHO-H₄PteGlu those of 5-CH₃-H₄PteGlu following [6RS]LV administration. and in HxSJC₃A, in which pools of CH₂-H₄Pte-Glu_n+H₄PteGlu_n were significantly expanded, 5-CH₃-H₄PteGlu concentrations were lower than those observed in the other two lines. The sensitivity of tumors to FUra±[6RS]LV and the characteristics of [6S]LV metabolism did not correlate with the activity of CH=H₄PteGlu synthetase, the enzyme responsible for the initial cellular metabolism of [6S]LV to CH=H₄PteGlu. Thus, no single metabolic phenotype correlated with the [6RS]LV-induced expansion of CH₂-H₄PteGlu_n+H₄PteGlu_n pools. Potentiation of the therapeutic efficacy of FUra by [6RS]LV was observed in HxGC₃c1TK-c3 xenografts but not in parent HxGC₃ tumors, demonstrating the influence of dThd salvage capability in the response to FUra-[6RS]LV combinations. Plasma dThd concentrations in CBA/CaJ mice were high (1.1 μm). The present data therefore demonstrate the importance of (1) higher doses of [6RS]LV, (2) expansion of pools of CH₂-H₄PteGlu_n+H₄PteGlu_n, and (3) dThd salvage capability in potentiation of the therapeutic efficacy of FUra in colon adenocarcinoma xenogafts. The plasma levels of FUra achieved in mice are presented.

Original language	English (US)
Pages (from-to)	423-432
Number of pages	10
Journal	Cancer chemotherapy and pharmacology
Volume	30
Issue number	6
DOIs	https://doi.org/10.1007/BF00685592
State	Published - Nov 1992
Externally published	Yes

ASJC Scopus subject areas

Oncology
Toxicology
Pharmacology
Cancer Research
Pharmacology (medical)

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Factors that influence the therapeutic activity of 5-fluorouracil [6RS]leucovorin combinations in colon adenocarcinoma xenografts. / Houghton, Janet A.; Williams, Larry G.; Loftin, Susan K.; Cheshire, Pamela J.; Morton, Christopher L.; Houghton, Peter J.; Dayan, Alain; Jolivet, Jacques.

In: Cancer chemotherapy and pharmacology, Vol. 30, No. 6, 11.1992, p. 423-432.

Research output: Contribution to journal › Article › peer-review

Houghton, Janet A. ; Williams, Larry G. ; Loftin, Susan K. ; Cheshire, Pamela J. ; Morton, Christopher L. ; Houghton, Peter J. ; Dayan, Alain ; Jolivet, Jacques. / Factors that influence the therapeutic activity of 5-fluorouracil [6RS]leucovorin combinations in colon adenocarcinoma xenografts. In: Cancer chemotherapy and pharmacology. 1992 ; Vol. 30, No. 6. pp. 423-432.

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title = "Factors that influence the therapeutic activity of 5-fluorouracil [6RS]leucovorin combinations in colon adenocarcinoma xenografts",

abstract = "The therapeutic activity of FUra alone or combined with [6RS]LV doses ranging from 50 to 1,000 mg/m2 was examined in eight colon adenocarcinoma xenografts, of which five were established from adult neoplasms (HxELC2, HxGC3, HxVRC5, HxHC1, and HxGC3/c1TK-c3 selected for TK deficiency) and three were derived from adolescent tumors (HxSJC3A, HxSJC3B, and HxSJC2). The growth-inhibitory effects of FUra were potentiated by higher doses of [6RS]LV (500-1,000 mg/m2) in three lines (HxGC3/c1TK-c3, HxSJC3A, and HxSJC3B) and by a low dose of [6RS]LV in only one tumor (HxVRC5). Expansion of pools of CH2-H4PteGlun+H4PteGlun (≥2.4-fold) in response to higher doses of [6RS]LV was obtained in all lines except HxHC1. Metabolism of [6RS]LV was high in HxVRC5, with high levels of 5-CH3-H4PteGlu being detected, but not in HxHC1, in which levels of 5-CH3-H4PteGlu and CH=H4PteGlu+10-CHO-H4PteGlu remained relatively low. In the adolescent tumors, levels of CH=H4PteGlu+10-CHO-H4PteGlu those of 5-CH3-H4PteGlu following [6RS]LV administration. and in HxSJC3A, in which pools of CH2-H4Pte-Glun+H4PteGlun were significantly expanded, 5-CH3-H4PteGlu concentrations were lower than those observed in the other two lines. The sensitivity of tumors to FUra±[6RS]LV and the characteristics of [6S]LV metabolism did not correlate with the activity of CH=H4PteGlu synthetase, the enzyme responsible for the initial cellular metabolism of [6S]LV to CH=H4PteGlu. Thus, no single metabolic phenotype correlated with the [6RS]LV-induced expansion of CH2-H4PteGlun+H4PteGlun pools. Potentiation of the therapeutic efficacy of FUra by [6RS]LV was observed in HxGC3c1TK-c3 xenografts but not in parent HxGC3 tumors, demonstrating the influence of dThd salvage capability in the response to FUra-[6RS]LV combinations. Plasma dThd concentrations in CBA/CaJ mice were high (1.1 μm). The present data therefore demonstrate the importance of (1) higher doses of [6RS]LV, (2) expansion of pools of CH2-H4PteGlun+H4PteGlun, and (3) dThd salvage capability in potentiation of the therapeutic efficacy of FUra in colon adenocarcinoma xenogafts. The plasma levels of FUra achieved in mice are presented.",

author = "Houghton, {Janet A.} and Williams, {Larry G.} and Loftin, {Susan K.} and Cheshire, {Pamela J.} and Morton, {Christopher L.} and Houghton, {Peter J.} and Alain Dayan and Jacques Jolivet",

year = "1992",

month = nov,

doi = "10.1007/BF00685592",

language = "English (US)",

volume = "30",

pages = "423--432",

journal = "Cancer Chemotherapy and Pharmacology",

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TY - JOUR

T1 - Factors that influence the therapeutic activity of 5-fluorouracil [6RS]leucovorin combinations in colon adenocarcinoma xenografts

AU - Houghton, Janet A.

AU - Williams, Larry G.

AU - Loftin, Susan K.

AU - Cheshire, Pamela J.

AU - Morton, Christopher L.

AU - Houghton, Peter J.

AU - Dayan, Alain

AU - Jolivet, Jacques

PY - 1992/11

Y1 - 1992/11

N2 - The therapeutic activity of FUra alone or combined with [6RS]LV doses ranging from 50 to 1,000 mg/m2 was examined in eight colon adenocarcinoma xenografts, of which five were established from adult neoplasms (HxELC2, HxGC3, HxVRC5, HxHC1, and HxGC3/c1TK-c3 selected for TK deficiency) and three were derived from adolescent tumors (HxSJC3A, HxSJC3B, and HxSJC2). The growth-inhibitory effects of FUra were potentiated by higher doses of [6RS]LV (500-1,000 mg/m2) in three lines (HxGC3/c1TK-c3, HxSJC3A, and HxSJC3B) and by a low dose of [6RS]LV in only one tumor (HxVRC5). Expansion of pools of CH2-H4PteGlun+H4PteGlun (≥2.4-fold) in response to higher doses of [6RS]LV was obtained in all lines except HxHC1. Metabolism of [6RS]LV was high in HxVRC5, with high levels of 5-CH3-H4PteGlu being detected, but not in HxHC1, in which levels of 5-CH3-H4PteGlu and CH=H4PteGlu+10-CHO-H4PteGlu remained relatively low. In the adolescent tumors, levels of CH=H4PteGlu+10-CHO-H4PteGlu those of 5-CH3-H4PteGlu following [6RS]LV administration. and in HxSJC3A, in which pools of CH2-H4Pte-Glun+H4PteGlun were significantly expanded, 5-CH3-H4PteGlu concentrations were lower than those observed in the other two lines. The sensitivity of tumors to FUra±[6RS]LV and the characteristics of [6S]LV metabolism did not correlate with the activity of CH=H4PteGlu synthetase, the enzyme responsible for the initial cellular metabolism of [6S]LV to CH=H4PteGlu. Thus, no single metabolic phenotype correlated with the [6RS]LV-induced expansion of CH2-H4PteGlun+H4PteGlun pools. Potentiation of the therapeutic efficacy of FUra by [6RS]LV was observed in HxGC3c1TK-c3 xenografts but not in parent HxGC3 tumors, demonstrating the influence of dThd salvage capability in the response to FUra-[6RS]LV combinations. Plasma dThd concentrations in CBA/CaJ mice were high (1.1 μm). The present data therefore demonstrate the importance of (1) higher doses of [6RS]LV, (2) expansion of pools of CH2-H4PteGlun+H4PteGlun, and (3) dThd salvage capability in potentiation of the therapeutic efficacy of FUra in colon adenocarcinoma xenogafts. The plasma levels of FUra achieved in mice are presented.

AB - The therapeutic activity of FUra alone or combined with [6RS]LV doses ranging from 50 to 1,000 mg/m2 was examined in eight colon adenocarcinoma xenografts, of which five were established from adult neoplasms (HxELC2, HxGC3, HxVRC5, HxHC1, and HxGC3/c1TK-c3 selected for TK deficiency) and three were derived from adolescent tumors (HxSJC3A, HxSJC3B, and HxSJC2). The growth-inhibitory effects of FUra were potentiated by higher doses of [6RS]LV (500-1,000 mg/m2) in three lines (HxGC3/c1TK-c3, HxSJC3A, and HxSJC3B) and by a low dose of [6RS]LV in only one tumor (HxVRC5). Expansion of pools of CH2-H4PteGlun+H4PteGlun (≥2.4-fold) in response to higher doses of [6RS]LV was obtained in all lines except HxHC1. Metabolism of [6RS]LV was high in HxVRC5, with high levels of 5-CH3-H4PteGlu being detected, but not in HxHC1, in which levels of 5-CH3-H4PteGlu and CH=H4PteGlu+10-CHO-H4PteGlu remained relatively low. In the adolescent tumors, levels of CH=H4PteGlu+10-CHO-H4PteGlu those of 5-CH3-H4PteGlu following [6RS]LV administration. and in HxSJC3A, in which pools of CH2-H4Pte-Glun+H4PteGlun were significantly expanded, 5-CH3-H4PteGlu concentrations were lower than those observed in the other two lines. The sensitivity of tumors to FUra±[6RS]LV and the characteristics of [6S]LV metabolism did not correlate with the activity of CH=H4PteGlu synthetase, the enzyme responsible for the initial cellular metabolism of [6S]LV to CH=H4PteGlu. Thus, no single metabolic phenotype correlated with the [6RS]LV-induced expansion of CH2-H4PteGlun+H4PteGlun pools. Potentiation of the therapeutic efficacy of FUra by [6RS]LV was observed in HxGC3c1TK-c3 xenografts but not in parent HxGC3 tumors, demonstrating the influence of dThd salvage capability in the response to FUra-[6RS]LV combinations. Plasma dThd concentrations in CBA/CaJ mice were high (1.1 μm). The present data therefore demonstrate the importance of (1) higher doses of [6RS]LV, (2) expansion of pools of CH2-H4PteGlun+H4PteGlun, and (3) dThd salvage capability in potentiation of the therapeutic efficacy of FUra in colon adenocarcinoma xenogafts. The plasma levels of FUra achieved in mice are presented.

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