Summary
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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Abbreviations
- [6RS]LV:
-
a mixture of the diastereoisomers of the biologically active [6S] and inactive [6R] forms of [6RS]leucovorin or 5-CHO−H4PteGlu
- 5-CH3−H4PteGlu:
-
5-methyltetrahydrofolate 10-CHO−H4PteGlu, 10-formyltetrahydrofolate
- CH=H4PteGlu:
-
5,10-methenyltetrahydrofolate; H2PteGlu, dihydrofolate
- PteGlu:
-
folic acid
- PABGlu:
-
p-aminobenzoyl glutamic acid
- CH2−H4PteGlun :
-
5,10-methylenetetrahydrofolate containing from 1 to 6 glutamate residues
- H4PteGlun :
-
tetrahydrofolate containing from 1 to 6 glutamate residues
- FUra:
-
5-fluorouracil
- FUrd:
-
5-fluorouridine
- FdUrd:
-
5-fluoro-2′-deoxyuridine
- FdUMP:
-
5-fluoro-2′-deoxyuridine-5′-monophosphate
- dThd:
-
thymidine Td2, tumor volume-doubling time
- HPLC:
-
high-performance liquid chromatography
- TK:
-
thymidine kinase
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Supported by NCL awards CA 32 613, CA 23 099, and CA 21 765, by the American Lebanese Syrian Associated Charities, and by the Medical Research Council of Canada
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Houghton, J.A., Williams, L.G., Loftin, S.K. et al. Factors that influence the therapeutic activity of 5-fluorouracil [6RS]leucovorin combinations in colon adenocarcinoma xenografts. Cancer Chemother. Pharmacol. 30, 423–432 (1992). https://doi.org/10.1007/BF00685592
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DOI: https://doi.org/10.1007/BF00685592