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
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
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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U2 - 10.1007/BF00685592
DO - 10.1007/BF00685592
M3 - Article
C2 - 1394798
AN - SCOPUS:0026774481
VL - 30
SP - 423
EP - 432
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 6
ER -