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January 18, 1995, Vol 273, No. 3 >
ARTICLE | January 18, 1995

New Therapeutic Strategies for Patients With Gastrointestinal Malignancies Using Biochemical Modulation of Fluorouracil FREE

Carmen J. Allegra, MD
[+] Author Affiliations

Reprint requests to the National Cancer Institute— Navy Medical Oncology Branch, National Naval Medical Center, 8901 Wisconsin Ave, Bldg 8, Room 5101, Bethesda, MD 20889-5105 (Dr Allegra).

Grand Rounds at the Clinical Center of the National Institutes of Health section editors: John I. Gallin, MD, the Clinical Center of the National Institutes of Health, Bethesda, Md; David S. Cooper, MD, Contributing Editor, JAMA.


JAMA. 1995;273(3):236-239. doi:10.1001/jama.1995.03520270070034
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Article
References

SELECTED CASE  A 53-year-old man was evaluated for a several-month history of generalized fatigue and vague lower abdominal cramping. A barium enema revealed an encircling lesion in the distal sigmoid colon, and computed tomographic scanning of the abdomen revealed multiple hepatic defects consistent with metastatic disease. The patient underwent an exploratory laparotomy with resection of the sigmoid colon and a needle biopsy of one of the hepatic masses. The pathology demonstrated a moderately to poorly differentiated adenocarcinoma arising in the sigmoid colon with metastatic spread to the liver. The patient was referred to the National Cancer Institute and enrolled in a clinical trial using a combination of fluorouracil, leucovorin, and interferon alfa. After 3 months of therapy, the patient's repeat computed tomographic examination of the liver demonstrated regression of his metastatic disease by greater than 50%. In addition, his serum carcinoembryonic antigen level had fallen to 7.3 μg/L from a

REFERENCES

1 +
Boring CC, Squires TS, Tong T, Montgomery S.  Cancer statistics, 1994. CA Cancer J Clin . 1994;; 44:7-26.
2 +
Moertel CG, Fleming TR, MacDonald JS, et al.  Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med . 1990;; 322:352-358.
3 +
Wolmark N, Rockette H, Fisher B, et al.  The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol . 1993;;11:1879-1887.
4 +
Johnston PG, Drake JC, Trepel J, Allegra CJ.  Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and resistant human cancer cell lines. Cancer Res . 1992;;52:4306-4312.
5 +
SwainSM, Lippman ME, Egan EF, Drake JC, Steinberg SM, Allegra CJ.  5-Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol . 1989;;7:890-899.
6 +
Petrelli N, Herrera L, Rustum Y, et al.  A 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 . 1990;;8: 491-501.
7 +
Piedbois P, Buyse M, Rustum Y, et al.  Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol . 1992;;10:896-903.
8 +
Danenberg PV, Danenberg KD.  Effect of 5, 10-methylenetetrahydrofolate on the dissociation of 5-fluoro-2-deoxyuridylate from thymidylate synthase: evidence for an ordered mechanism. Biochemistry . 1978;;17:4018-4024.
9 +
Ullman B, Lee M, Martin DW Jr, Santi DV.  Cytotoxicity of 5-fluoro-2-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci U S A . 1978;; 75:980-983.
10 +
Evans RM, Laskin JD, Hakala MT.  Effect of excess of folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res . 1981;;41:3288-3295.
11 +
Sotos GA, Grogan L, Allegra CJ.  Preclinical and clinical aspects of biomodulation of 5-fluorouracil. Cancer Treat Rev . 1994;;20:11-49.
12 +
Poon MA, O'Connell MJ, Wieand HS, et al.  Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol . 1991;;9:1967-1972.
13 +
Bobbio-Pallavicini E, Porta C, Moroni M, Spaghi A, Casagranda I, Nastasi G.  Folinic acid does improve 5-fluorouracil activity in vivo: results of a phase III study comparing 5-fluorouracil to 5-fluorouracil and folinic acid in advanced colon cancer patients. J Chemother . 1993;;5:52-55.
14 +
Chu E, Zinn S, Boarman D, Allegra CJ.  The interaction of gamma interferon and 5-fluorouracil in the H630 human colon carcinoma cell line. Cancer Res . 1990;;50:5834-5840.
15 +
Keyomarsi K, Moran RG.  Mechanism of the cytotoxic synergism of fluoropyrimidines and folinic acid in mouse leukemic cells. J Biol Chem . 1988;;263:14402-14409.
16 +
Chu E, Voeller D, Koeller DM, et al.  Identification of an RNA binding site for human thymidylate synthase. Proc Natl Acad Sci U S A . 1993;;90:517-521.
17 +
Chu E, Koeller DM, Casey JL, et al.  Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. Proc Natl Acad Sci U S A . 1991;;88:8977-8981.
18 +
Houghton JA, Morton CL, Adkins DA, Rahman A.  Locus of the interaction among 5-fluorouracil, leucovorin, and interferon-α2a in colon carcinoma cells. Cancer Res . 1993;;53:4243-4250.
19 +
Schwartz EL, Hoffman M, O'Connor CJ, Wadler S.  Stimulation of 5-fluorouracil metabolic activation by interferon alpha in human colon carcinoma cells. Biochem Biophys Res Commun . 1992;;182: 1232-1239.
20 +
Wadler S, Wiernik PH.  Clinical update on the role of fluorouracil and recombinant interferon alfa-2a in the treatment of colorectal carcinoma. Semin Oncol . 1990;;17:16-21.
21 +
Kemeny N, Younes A, Seiter K, et al.  Interferon alpha-2a and 5-fluorouracil for advanced colorectal carcinoma: assessment of activity and toxicity. Cancer . 1990;;66:2470-2475.
22 +
Pazdur R, Ajani J, Patt Y, et al.  Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. J Clin Oncol . 1990;;8:2027-2031.
23 +
Grem JL, McAtee N, Murphy RF, et al.  A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma. J Clin Oncol . 1991;;9:1811-1820.
24 +
Grem JL, Jordan E, Robson ME, et al.  Phase II study of 5-fluorouracil, leucovorin and interferon alfa-2a in metastatic colorectal carcinoma. J Clin Oncol . 1993;;11:1737-1745.
25 +
Calvert AH, Harland SJ, Robinson BA, et al.  A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid, CB3717. J Clin Oncol . 1986;;4:1245-1252.
26 +
Jackman AL, Taylor GA, O'Connor BM, et al.  Activity of the thymidylate synthase inhibitor 2-desamino-N10-propargyl-5,8-dideazafolic acid and related compounds in murine (L1210) and human (WIL2) systems and in L1210 in vivo. Cancer Res . 1990;;50:5212-5218.
27 +
Sorensen JM, Jordan E, Grem JL, et al.  Phase I trial of ZD1694, a pure thymidylate synthase inhibitor. Proc Am Soc Clin Oncol . 1993;;12:158.
28 +
Clarke SJ, Ward J, de Boer M, et al.  Phase I study of the new thymidylate synthase inhibitor Tomudex (ZD1694) in patients with advanced malignancy. Ann Oncol . 1994;;5( (suppl 5) ):5. Abstract.
29 +
Smith IE, Spielmann M, Bonneterre J, et al.  Tomudex (ZD1694), a new thymidylate synthase inhibitor with antitumour activity in breast cancer. Ann Oncol . 1994;;5( (suppl 5) ):5. Abstract.
30 +
Zalcberg J, Cunningham D, Van Cutsem E, et al.  Good antitumour activity of the new thymidylate synthase inhibitor Tomudex (ZD1694) in colorectal cancer. Ann Oncol . 1994;;5( (suppl 5) ):5. Abstract.
31 +
Johnston PG, Liang C-M, Henry S, Chabner BA, Allegra CJ.  The production and characterization of monoclonal antibodies that localize human thymidylate synthase in the cytoplasm of human cells and tissue. Cancer Res . 1991;;51:6668-6676.
32 +
Johnston PG, Drake JC, Steinberg SM, Allegra CJ.  Quantitation of thymidylate synthase in human tumors using an ultrasensitive enzyme-linked immunoassay. Biochem Pharmacol . 1993;;45:2483-2486.
33 +
Johnston PG, Fisher E, Rockette HE, Fisher B, Wolmark N, Allegra CJ.  Thymidylate synthase expression is an independent predictor of survival/ disease free survival in patients with rectal cancer. Proc Am Soc Clin Oncol . 1993;;12:202. Abstract.
34 +
Lenz HJ, Leichman C, Danenberg P, et al.  Thymidylate synthase (TS) gene expression predicts response of primary gastric cancer (GC) to 5-fluorouracil (5FU)-leucovorin (LV)-cisplatin (DDP). Proc Am Soc Clin Oncol . 1993;;12:199. Abstract.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Boring CC, Squires TS, Tong T, Montgomery S.  Cancer statistics, 1994. CA Cancer J Clin . 1994;; 44:7-26.
2 +
Moertel CG, Fleming TR, MacDonald JS, et al.  Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med . 1990;; 322:352-358.
3 +
Wolmark N, Rockette H, Fisher B, et al.  The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol . 1993;;11:1879-1887.
4 +
Johnston PG, Drake JC, Trepel J, Allegra CJ.  Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and resistant human cancer cell lines. Cancer Res . 1992;;52:4306-4312.
5 +
SwainSM, Lippman ME, Egan EF, Drake JC, Steinberg SM, Allegra CJ.  5-Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol . 1989;;7:890-899.
6 +
Petrelli N, Herrera L, Rustum Y, et al.  A 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 . 1990;;8: 491-501.
7 +
Piedbois P, Buyse M, Rustum Y, et al.  Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol . 1992;;10:896-903.
8 +
Danenberg PV, Danenberg KD.  Effect of 5, 10-methylenetetrahydrofolate on the dissociation of 5-fluoro-2-deoxyuridylate from thymidylate synthase: evidence for an ordered mechanism. Biochemistry . 1978;;17:4018-4024.
9 +
Ullman B, Lee M, Martin DW Jr, Santi DV.  Cytotoxicity of 5-fluoro-2-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci U S A . 1978;; 75:980-983.
10 +
Evans RM, Laskin JD, Hakala MT.  Effect of excess of folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res . 1981;;41:3288-3295.
11 +
Sotos GA, Grogan L, Allegra CJ.  Preclinical and clinical aspects of biomodulation of 5-fluorouracil. Cancer Treat Rev . 1994;;20:11-49.
12 +
Poon MA, O'Connell MJ, Wieand HS, et al.  Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol . 1991;;9:1967-1972.
13 +
Bobbio-Pallavicini E, Porta C, Moroni M, Spaghi A, Casagranda I, Nastasi G.  Folinic acid does improve 5-fluorouracil activity in vivo: results of a phase III study comparing 5-fluorouracil to 5-fluorouracil and folinic acid in advanced colon cancer patients. J Chemother . 1993;;5:52-55.
14 +
Chu E, Zinn S, Boarman D, Allegra CJ.  The interaction of gamma interferon and 5-fluorouracil in the H630 human colon carcinoma cell line. Cancer Res . 1990;;50:5834-5840.
15 +
Keyomarsi K, Moran RG.  Mechanism of the cytotoxic synergism of fluoropyrimidines and folinic acid in mouse leukemic cells. J Biol Chem . 1988;;263:14402-14409.
16 +
Chu E, Voeller D, Koeller DM, et al.  Identification of an RNA binding site for human thymidylate synthase. Proc Natl Acad Sci U S A . 1993;;90:517-521.
17 +
Chu E, Koeller DM, Casey JL, et al.  Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. Proc Natl Acad Sci U S A . 1991;;88:8977-8981.
18 +
Houghton JA, Morton CL, Adkins DA, Rahman A.  Locus of the interaction among 5-fluorouracil, leucovorin, and interferon-α2a in colon carcinoma cells. Cancer Res . 1993;;53:4243-4250.
19 +
Schwartz EL, Hoffman M, O'Connor CJ, Wadler S.  Stimulation of 5-fluorouracil metabolic activation by interferon alpha in human colon carcinoma cells. Biochem Biophys Res Commun . 1992;;182: 1232-1239.
20 +
Wadler S, Wiernik PH.  Clinical update on the role of fluorouracil and recombinant interferon alfa-2a in the treatment of colorectal carcinoma. Semin Oncol . 1990;;17:16-21.
21 +
Kemeny N, Younes A, Seiter K, et al.  Interferon alpha-2a and 5-fluorouracil for advanced colorectal carcinoma: assessment of activity and toxicity. Cancer . 1990;;66:2470-2475.
22 +
Pazdur R, Ajani J, Patt Y, et al.  Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. J Clin Oncol . 1990;;8:2027-2031.
23 +
Grem JL, McAtee N, Murphy RF, et al.  A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma. J Clin Oncol . 1991;;9:1811-1820.
24 +
Grem JL, Jordan E, Robson ME, et al.  Phase II study of 5-fluorouracil, leucovorin and interferon alfa-2a in metastatic colorectal carcinoma. J Clin Oncol . 1993;;11:1737-1745.
25 +
Calvert AH, Harland SJ, Robinson BA, et al.  A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid, CB3717. J Clin Oncol . 1986;;4:1245-1252.
26 +
Jackman AL, Taylor GA, O'Connor BM, et al.  Activity of the thymidylate synthase inhibitor 2-desamino-N10-propargyl-5,8-dideazafolic acid and related compounds in murine (L1210) and human (WIL2) systems and in L1210 in vivo. Cancer Res . 1990;;50:5212-5218.
27 +
Sorensen JM, Jordan E, Grem JL, et al.  Phase I trial of ZD1694, a pure thymidylate synthase inhibitor. Proc Am Soc Clin Oncol . 1993;;12:158.
28 +
Clarke SJ, Ward J, de Boer M, et al.  Phase I study of the new thymidylate synthase inhibitor Tomudex (ZD1694) in patients with advanced malignancy. Ann Oncol . 1994;;5( (suppl 5) ):5. Abstract.
29 +
Smith IE, Spielmann M, Bonneterre J, et al.  Tomudex (ZD1694), a new thymidylate synthase inhibitor with antitumour activity in breast cancer. Ann Oncol . 1994;;5( (suppl 5) ):5. Abstract.
30 +
Zalcberg J, Cunningham D, Van Cutsem E, et al.  Good antitumour activity of the new thymidylate synthase inhibitor Tomudex (ZD1694) in colorectal cancer. Ann Oncol . 1994;;5( (suppl 5) ):5. Abstract.
31 +
Johnston PG, Liang C-M, Henry S, Chabner BA, Allegra CJ.  The production and characterization of monoclonal antibodies that localize human thymidylate synthase in the cytoplasm of human cells and tissue. Cancer Res . 1991;;51:6668-6676.
32 +
Johnston PG, Drake JC, Steinberg SM, Allegra CJ.  Quantitation of thymidylate synthase in human tumors using an ultrasensitive enzyme-linked immunoassay. Biochem Pharmacol . 1993;;45:2483-2486.
33 +
Johnston PG, Fisher E, Rockette HE, Fisher B, Wolmark N, Allegra CJ.  Thymidylate synthase expression is an independent predictor of survival/ disease free survival in patients with rectal cancer. Proc Am Soc Clin Oncol . 1993;;12:202. Abstract.
34 +
Lenz HJ, Leichman C, Danenberg P, et al.  Thymidylate synthase (TS) gene expression predicts response of primary gastric cancer (GC) to 5-fluorouracil (5FU)-leucovorin (LV)-cisplatin (DDP). Proc Am Soc Clin Oncol . 1993;;12:199. Abstract.

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