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Angiogenesis
Published in: Angiogenesis 2/2012

Open Access 01-06-2012 | Original Paper

Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers

Authors: Giacomo Allegrini, Teresa Di Desidero, Maria Teresa Barletta, Anna Fioravanti, Paola Orlandi, Bastianina Canu, Silvio Chericoni, Fotios Loupakis, Antonello Di Paolo, Gianluca Masi, Andrea Fontana, Sara Lucchesi, Giada Arrighi, Mario Giusiani, Andrea Ciarlo, Giovanni Brandi, Romano Danesi, Robert S. Kerbel, Alfredo Falcone, Guido Bocci

Published in: Angiogenesis | Issue 2/2012

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Abstract

Aims

To evaluate UFT and cyclophosphamide (CTX) based metronomic chemotherapy plus celecoxib (CXB) for the treatment of patients with heavily pre-treated advanced gastrointestinal malignancies.

Methods

Thirty-eight patients received 500 mg/mq2 CTX i.v bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 100 mg/twice a day UFT p.o. and 200 mg/twice a day CXB p.o. Tegafur, 5-FU, 5-FUH2, GHB and uracil pharmacokinetics were assessed. Plasma vascular endothelial growth factor (VEGF), soluble VE-cadherin (sVE-C) and thrombospondin-1 (TSP-1) levels were detected by ELISA and real-time PCR of CD133 gene expression on peripheral blood mononuclear cell was also performed.

Results

Seventeen patients (45%) obtained stable disease (SD) with a median duration of 5.8 ms (range, 4.2–7.4). Median progression free survival (PFS) and overall survival (OS) were 2.7 ms (95% CI, 1.6–3.9 ms) and 7.1 ms (95% CI, 4.3–9.9 ms), respectively. No toxicities of grade >1 were observed. Pharmacokinetics of 27 patients (13/14, SD/progressive disease, PD) after the first treatment of UFT revealed that 5-FU AUC and Cmax values greater than 1.313 h × μg/ml and 0.501 μg/ml, respectively, were statistically correlated with stabilization of disease and prolonged PFS/OS. VEGF and sVE-C plasma levels were greater in the PD group when compared to SD group. CD133 expression increased only in the PD patients.

Conclusion

Metronomic UFT and CTX with CXB in heavily pre-treated gastrointestinal patients were well tolerated and associated with interesting activity. Potential predictive pharmacokinetic parameters and pharmacodynamic biomarkers have been found.
Literature
1.
Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4(6):423–436PubMedCrossRef
2.
Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, Del Tacca M (2005) Cyclophosphamide-methotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol 16(8):1243–1252PubMedCrossRef
3.
Fioravanti A, Canu B, Ali G, Orlandi P, Allegrini G, Di Desidero T, Emmenegger U, Fontanini G, Danesi R, Del Tacca M, Falcone A, Bocci G (2009) Metronomic 5-fluorouracil, oxaliplatin and irinotecan in colorectal cancer. Eur J Pharmacol 619(1–3):8–14PubMedCrossRef
4.
Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Hewitt SM, Shoemaker RH, Melillo G (2004) Schedule-dependent inhibition of hypoxia-inducible factor-1 protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 64(19):6845–6848PubMedCrossRef
5.
Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL (2009) Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci 106(7):2353–2358PubMedCrossRef
6.
7.
Allegrini G, Falcone A, Fioravanti A, Barletta MT, Orlandi P, Loupakis F, Cerri E, Masi G, Di Paolo A, Kerbel RS, Danesi R, Del Tacca M, Bocci G (2008) A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients. Br J Cancer 98(8):1312–1319PubMedCrossRef
8.
Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60(7):1878–1886PubMed
9.
Blansfield JA, Caragacianu D, Alexander HR III, Tangrea MA, Morita SY, Lorang D, Schafer P, Muller G, Stirling D, Royal RE, Libutti SK (2008) Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy. Clin Cancer Res 14(1):270–280PubMedCrossRef
10.
Young SD, Whissell M, Noble JC, Cano PO, Lopez PG, Germond CJ (2006) Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors. Clin Cancer Res 12(10):3092–3098PubMedCrossRef
11.
Leahy KM, Ornberg RL, Wang Y, Zweifel BS, Koki AT, Masferrer JL (2002) Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 62(3):625–631PubMed
12.
Wu YL, Fu SL, Zhang YP, Qiao MM, Chen Y (2005) Cyclooxygenase-2 inhibitors suppress angiogenesis and growth of gastric cancer xenografts. Biomed Pharmacother 59(Suppl 2):S289–S292PubMed
13.
Tanaka F (2007) UFT (tegafur and uracil) as postoperative adjuvant chemotherapy for solid tumors (carcinoma of the lung, stomach, colon/rectum, and breast): clinical evidence, mechanism of action, and future direction. Surg Today 37(11):923–943PubMedCrossRef
14.
Bennouna J, Saunders M, Douillard JY (2009) The role of UFT in metastatic colorectal cancer. Oncology 76(5):301–310PubMedCrossRef
15.
Nakayama T, Noguchi S (2010) Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan. Oncologist 15(1):26–36PubMedCrossRef
16.
Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N (2004) A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350(17):1713–1721PubMedCrossRef
17.
Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y (2009) Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, Fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for breast cancer 01 trial. J Clin Oncol 27(9):1368–1374PubMedCrossRef
18.
Basaki Y, Chikahisa L, Aoyagi K, Miyadera K, Yonekura K, Hashimoto A, Okabe S, Wierzba K, Yamada Y (2001) Gamma-hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor. Angiogenesis 4(3):163–173PubMedCrossRef
19.
Munoz R, Man S, Shaked Y, Lee CR, Wong J, Francia G, Kerbel RS (2006) Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy. Cancer Res 66(7):3386–3391PubMedCrossRef
20.
Nio Y, Iguchi C, Kodama H, Itakura M, Hashimoto K, Koike M, Toga T, Maruyama R, Fukushima M (2007) Cyclophosphamide augments the anti-tumor efficacy of uracil and tegafur by inhibiting dihydropyrimidine dehydrogenase. Oncol Rep 17(1):153–159PubMed
21.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216PubMedCrossRef
22.
Wu AT, Au JL, Sadee W (1978) Hydroxylated metabolies of R, S-1-(tetrahydro-2-furanyl)-5-fluorouracil (Ftorafur) in rats and rabbits. Cancer Res 38(1):210–214PubMed
23.
Bocci G, Barbara C, Vannozzi F, Di Paolo A, Melosi A, Barsanti G, Allegrini G, Falcone A, Del Tacca M, Danesi R (2006) A pharmacokinetic-based test to prevent severe 5-fluorouracil toxicity. Clin Pharmacol Ther 80(4):384–395PubMedCrossRef
24.
Villain M, Cirimele V, Ludes B, Kintz P (2003) Ultra-rapid procedure to test for gamma-hydroxybutyric acid in blood and urine by gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 792(1):83–87PubMedCrossRef
25.
Bocci G, Fioravanti A, Orlandi P, Bernardini N, Collecchi P, Del Tacca M, Danesi R (2005) Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells. Br J Cancer 93(3):319–330PubMedCrossRef
26.
Scartozzi M, Falcone A, Pucci F, Braconi C, Pierantoni C, Cavanna L, Franciosi V, Berardi R, Beretta G, Masi G, Allegrini G, Zaniboni A, Labianca R, Cascinu S (2006) Capecitabine and mitomycin C may be an effective treatment option for third-line chemotherapy in advanced colorectal cancer. Tumori 92(5):384–388PubMed
27.
Chen HX, Mooney M, Boron M, Vena D, Mosby K, Grochow L, Jaffe C, Rubinstein L, Zwiebel J, Kaplan RS (2006) Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol 24(21):3354–3360PubMedCrossRef
28.
McCollum AD, Wu B, Clark JW, Kulke MH, Enzinger PC, Ryan DP, Earle CC, Michelini A, Fuchs CS (2006) The combination of capecitabine and thalidomide in previously treated, refractory metastatic colorectal cancer. Am J Clin Oncol 29(1):40–44PubMedCrossRef
29.
Glode LM, Barqawi A, Crighton F, Crawford ED, Kerbel R (2003) Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer 98(8):1643–1648PubMedCrossRef
30.
Fontana A, Galli L, Fioravanti A, Orlandi P, Galli C, Landi L, Bursi S, Allegrini G, Fontana E, Di Marsico R, Antonuzzo A, D’Arcangelo M, Danesi R, Del Tacca M, Falcone A, Bocci G (2009) Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res 15(15):4954–4962PubMedCrossRef
31.
Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nole F, Viale G, Goldhirsch A (2006) Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol 17(2):232–238PubMedCrossRef
32.
Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, Shaked Y, Mancuso P, Goldhirsch A, Rocca A, Pietri E, Colleoni M (2008) Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 26(30):4899–4905PubMedCrossRef
33.
Garcia-Saenz JA, Martin M, Calles A, Bueno C, Rodriguez L, Bobokova J, Custodio A, Casado A, Diaz-Rubio E (2008) Bevacizumab in combination with metronomic chemotherapy in patients with anthracycline- and taxane-refractory breast cancer. J Chemother 20(5):632–639PubMed
34.
Lin EH, Curley SA, Crane CC, Feig B, Skibber J, Delcos M, Vadhan SR, Morris J, Ayers GD, Ross A, Brown T, Rodriguez-Bigas MA, Janjan N (2006) Retrospective study of capecitabine and celecoxib in metastatic colorectal cancer: potential benefits and COX-2 as the common mediator in pain, toxicities and survival? Am J Clin Oncol 29(3):232–239PubMedCrossRef
35.
Penel N, Clisant S, Dansin E, Desauw C, Degardin M, Mortier L, Vanhuyse M, Bonodeau F, Fournier C, Cazin JL, Adenis A (2010) Megestrol acetate versus metronomic cyclophosphamide in patients having exhausted all effective therapies under standard care. Br J Cancer 102(8):1207–1212PubMedCrossRef
36.
Hoff PM (2000) The tegafur-based dihydropyrimidine dehydrogenase inhibitory fluoropyrimidines, UFT/leucovorin (ORZEL) and S-1: a review of their clinical development and therapeutic potential. Invest New Drugs 18(4):331–342PubMedCrossRef
37.
Shirao K, Hoff PM, Ohtsu A, Loehrer PJ, Hyodo I, Wadler S, Wadleigh RG, O’Dwyer PJ, Muro K, Yamada Y, Boku N, Nagashima F, Abbruzzese JL (2004) Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV. J Clin Oncol 22(17):3466–3474PubMedCrossRef
38.
Tang TC, Man S, Lee CR, Xu P, Kerbel RS (2010) Impact of metronomic UFT/cyclophosphamide chemotherapy and antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopic hepatocellular carcinoma. Neoplasia 12(3):264–274PubMed
39.
Ogawa Y, Ishikawa T, Chung SH, Ikeda K, Takashima T, Onoda N, Nakata B, Nishiguchi Y, Hirakawa K (2003) Oral UFT and cyclophosphamide combination chemotherapy for metastatic breast cancer. Anticancer Res 23(4):3453–3457PubMed
40.
Zweig MH, Campbell G (1993) Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 39(4):561–577PubMed
41.
Bocci G, Danesi R, Di Paolo AD, Innocenti F, Allegrini G, Falcone A, Melosi A, Battistoni M, Barsanti G, Conte PF, Del Tacca M (2000) Comparative pharmacokinetic analysis of 5-fluorouracil and its major metabolite 5-fluoro-5,6-dihydrouracil after conventional and reduced test dose in cancer patients. Clin Cancer Res 6(8):3032–3037PubMed
42.
Yonekura K, Basaki Y, Chikahisa L, Okabe S, Hashimoto A, Miyadera K, Wierzba K, Yamada Y (1999) UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res 5(8):2185–2191PubMed
43.
Basaki Y, Yonekura K, Chikahisa L, Okabe S, Hashimoto A, Miyadera K, Aoyagi K, Yamada Y (2000) Anti-angiogenic activities of UFT and its metabolites, GHB and GBL, in the dorsal air sac (DAS) model in mice. Gan To Kagaku Ryoho 27(1):93–98PubMed
44.
Emi Y, Sumiyoshi Y, Oki E, Kakeji Y, Fukui Y, Maehara Y (2007) Pharmacokinetics of gamma-hydroxybutylic acid (GHB) and gamma-butyrolactone (GBL), the anti-angiogenic metabolites of oral fluoropyrimidine UFT, in patients with gastric cancer. Fukuoka Igaku Zasshi 98(12):418–424PubMed
45.
Kania G, Corbeil D, Fuchs J, Tarasov KV, Blyszczuk P, Huttner WB, Boheler KR, Wobus AM (2005) Somatic stem cell marker prominin-1/CD133 is expressed in embryonic stem cell-derived progenitors. Stem Cells 23(6):791–804PubMedCrossRef
46.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115PubMedCrossRef
47.
O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110PubMedCrossRef
48.
Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, Kerbel RS (2003) Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63(15):4342–4346PubMed
49.
Shaked Y, Emmenegger U, Man S, Cervi D, Bertolini F, Ben-David Y, Kerbel RS (2005) Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106(9):3058–3061PubMedCrossRef
50.
Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G, Samuel S II, Kim MP, Lim SJ, Ellis LM (2009) Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res 69(5):1951–1957PubMedCrossRef
51.
Dejana E, Orsenigo F, Lampugnani MG (2008) The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 121(Pt 13):2115–2122PubMedCrossRef
52.
Rabascio C, Muratori E, Mancuso P, Calleri A, Raia V, Foutz T, Cinieri S, Veronesi G, Pruneri G, Lampertico P, Iavarone M, Martinelli G, Goldhirsch A, Bertolini F (2004) Assessing tumor angiogenesis: increased circulating VE-cadherin RNA in patients with cancer indicates viability of circulating endothelial cells. Cancer Res 64(12):4373–4377PubMedCrossRef
53.
Bocci G, Francia G, Man S, Lawler J, Kerbel RS (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA 100(22):12917–12922PubMedCrossRef
Metadata
Title
Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers
Authors
Giacomo Allegrini
Teresa Di Desidero
Maria Teresa Barletta
Anna Fioravanti
Paola Orlandi
Bastianina Canu
Silvio Chericoni
Fotios Loupakis
Antonello Di Paolo
Gianluca Masi
Andrea Fontana
Sara Lucchesi
Giada Arrighi
Mario Giusiani
Andrea Ciarlo
Giovanni Brandi
Romano Danesi
Robert S. Kerbel
Alfredo Falcone
Guido Bocci
Publication date
01-06-2012
Publisher
Springer Netherlands
Published in
Angiogenesis / Issue 2/2012
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-012-9260-6

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