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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

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.

Keywords

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.

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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References

  1. 1.
    Amicucci G, Guadagni S, Palumbo G, Carlucci G (1991) A simple method for determination of 2′-deoxy-5-fluorouridine and 5-fluorouracil in human serum and ultrafiltrate by HPLC with ultraviolet detection. Reg Cancer Treat 3: 261Google Scholar
  2. 2.
    Bertrand R, Mackenzie RE, Jolivet J (1987) Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates. Biochim Biophys Acta 911: 154Google Scholar
  3. 3.
    Budd GT, Jayaraj A, Grabowski D, Adelstein D, Bauer L, Boyett J, Bukowski J, Murthy S, Weick J (1990) Phase I trial of dipyridamole with 5-fluorouracil and folinic acid. Cancer Res 50: 7206Google Scholar
  4. 4.
    Coustère C, Mentré F, Sommadossi J-P, Diasio RB, Steimer J-L (1991) A mathematical model of the kinetics of 5-fluorouracil and its metabolites in cancer patients. Cancer Chemother Pharmacol 28: 123Google Scholar
  5. 5.
    Doroshow JH, Multhauf P, Leong L, Margolin K, Litchfield T, Akman S, Carr B, Bertrand M, Goldberg D, Blayney D, Odujinrin O, Delap R, Shuster J, Newman E (1990) Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 8: 491Google Scholar
  6. 6.
    Duch DS, Bowers SW, Nichols SA (1983) Analysis of folate cofactor levels in tissues using high-performance liquid chromatography. Anal Biochem 130: 385Google Scholar
  7. 7.
    Ensminger WD, Frei E (1977) The prevention of methotrexate toxiity by thymidine infusions in humans. Cancer Res 37: 1857Google Scholar
  8. 8.
    Erlichman C, Fine S, Wong A, Elhakim T (1988) A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6: 469Google Scholar
  9. 9.
    Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50: 219Google Scholar
  10. 10.
    Heggie GD, Sommadossi J-P, Cross DS, Huster WJ, Diasio RB (1987) Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 47: 2203Google Scholar
  11. 11.
    Houghton JA, Taylor DM (1978) Growth characteristics of human colorectal tumours during serial passage in immune-deprived mice. Br J Cancer 37: 213Google Scholar
  12. 12.
    Houghton JA, Maroda SJ, Phillips JO, Houghton PJ (1981) Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in human colorectal adenocarcinoma xenografts. Cancer Res 41: 144Google Scholar
  13. 13.
    Houghton JA, Williams LG, Radparvar S, Houghton PJ (1988) Characterization of the pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in xenografts of human colon adenocarcinomas. Cancer Res 48: 3062Google Scholar
  14. 14.
    Houghton PJ, Houghton JA, Myers L, Cheshire P, Howbert JJ, Grindey GB (1989) Evaluation ofN-(5-indanylsulfonyl)-N′-(4-chlorophenyl)-urea against xenografts of pediatric rhabdomyosarcoma. Cancer Chemother Pharmacol 25: 84Google Scholar
  15. 15.
    Houghton JA, Williams LG, Graaf SSN de, Cheshire PJ, Rodman JH, Maneval DC, Wainer IW, Jadaud P, Houghton PJ (1990) Relationship between dose rate of [6RS]leucovorin administration, plasma concentrations of reduced folates, and pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in human colon adenocarcinoma xenografts. Cancer Res 50: 3493Google Scholar
  16. 16.
    Houghton JA, Williams LG, Cheshire PJ, Wainer IW, Jadaud P, Houghton PJ (1990) Influence of dose of [6RS]LV on reduced folate pools and 5-fluorouracil-mediated thymidylate synthase inhibition in human colon adenocarcinoma xenografts. Cancer Res 50: 3940Google Scholar
  17. 17.
    Houghton JA, Adkins DA, Rahman A, Houghton PJ (1991) Interaction between 5-fluorouracil, [6RS]leucovorin and recombinant human interferon-α2a in cultured colon adenocarcinoma cells. Cancer Commun 3: 225Google Scholar
  18. 18.
    Howell SB, Ensminger WD, Krishan A, Frei E (1978) Thymidine rescue of high-dose methotrexate in humans. Cancer Res 38: 325Google Scholar
  19. 19.
    Howell SB, Mansfield SJ, Taetle R (1981) Thymidine and hypoxanthine requirements of normal and malignant human cells for protection against methotrexate cytotoxicity. Cancer Res 41: 945Google Scholar
  20. 20.
    Hughes WL, Christine M, Stollar BD (1973) A radioimmunoassay for measurement of serum thymidine. Anal Biochem 55: 468Google Scholar
  21. 21.
    Khym JX (1975) An analytical system for rapid separation of tissue nucleotides at low pressures on conventional anion exchangers. Clin Chem 21: 1245Google Scholar
  22. 22.
    Lynch G, Kemeny N, Chun H, Martin D, Young C (1985) Phase I evaluation and pharmacokinetic study of weekly i. v. thymidine and 5-FU in patients with advanced colorectal carcinoma. Cancer Treat Rep 69: 179Google Scholar
  23. 23.
    Petrelli N, Herrera L, Rustum Y, Burke P, Creaven P, Stulc J, Emrich LJ, Mittelman A (1987) A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5: 1559Google Scholar
  24. 24.
    Petrelli N, Douglass HO, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, Megibow A, Greenwald ES, Bukowski RM, Harris J, Levin B, Gaynor E, Loutfi A, Kalser MH, Barkin JS, Benedetto P, Woolley PV, Nauta R, Weaver DW, Leichman LP (1989) The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol 7: 1419Google Scholar
  25. 25.
    Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Weisenfeld M (1989) Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7: 1407Google Scholar
  26. 26.
    Radparvar S, Houghton PJ, Houghton JA (1989) Effect of polyglutamylation of 5,10-methylenetetrahydrofolate on the binding of 5-fluoro-2′-deoxyuridylate to thymidylate synthase purified from a human colon adenocarcinoma xenograft. Biochem Pharmacol 38: 335Google Scholar
  27. 27.
    Radparvar S, Houghton PJ, Germain G, Pennington J, Rahman A, Houghton JA (1990) Cellular pharmacology of 5-fluorouracil in a human colon adenocarcinoma cell line selected for thymidine kinase deficiency. Biochem Pharmacol 39: 1759Google Scholar
  28. 28.
    Semon JH, Grindey GB (1978) Potentiation of the antitumor activity of methotrexate by concurrent infusion of thymidine. Cancer Res 38: 2905Google Scholar
  29. 29.
    Tsavaris N, Zinelis A, Karvounis N, Beldecos D, Mylonacis N, Zamanis N, Bacoyannis C, Valilis P, Antonopoulos A, Kosmidis P (1990) Multimodal biochemical modulation of 5-fluorouracil activity in advanced colorectal cancer with allopurinol, folinic acid and dipyridamole. J Chemother 2: 123Google Scholar
  30. 30.
    Wadler S, Wiernik PH (1990) Clinical update on the role of fluorouracil and recombinant interferon alpha-2a in the treatment of colorectal carcinoma. Semin Oncol 17: 16Google Scholar
  31. 31.
    Wadler S, Lembersky B, Atkins M, Kirkwood J, Petrelli N (1991) Phase II trial of fluorouracil and recombinant interferon alpha-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 9: 1806Google Scholar
  32. 32.
    Winer BJ, Brown DR, Michels KM (1991) Statistical principles in experimental design, 3rd edn. McGraw-Hill New York, p 182Google Scholar

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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