Cancer Chemotherapy and Pharmacology

, Volume 30, Issue 6, pp 423–432 | Cite as

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
Original Articles 5-Fluorouracil [6RS]leucovorin, Xenografts


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.


Adenocarcinoma Cancer Research Plasma Level Therapeutic Efficacy Cellular Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



a mixture of the diastereoisomers of the biologically active [6S] and inactive [6R] forms of [6RS]leucovorin or 5-CHO−H4PteGlu


5-methyltetrahydrofolate 10-CHO−H4PteGlu, 10-formyltetrahydrofolate


5,10-methenyltetrahydrofolate; H2PteGlu, dihydrofolate


folic acid


p-aminobenzoyl glutamic acid


5,10-methylenetetrahydrofolate containing from 1 to 6 glutamate residues


tetrahydrofolate containing from 1 to 6 glutamate residues










thymidine Td2, tumor volume-doubling time


high-performance liquid chromatography


thymidine kinase


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Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Janet A. Houghton
    • 1
  • Larry G. Williams
    • 1
  • Susan K. Loftin
    • 1
  • Pamela J. Cheshire
    • 1
  • Christopher L. Morton
    • 1
  • Peter J. Houghton
    • 1
  • Alain Dayan
    • 2
  • Jacques Jolivet
    • 2
  1. 1.Department of Biochemical and Clinical PharmacologySt. Jude Children's Research HospitalMemphisUSA
  2. 2.Institut du Cancer de MontrealMontrealCanada

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