Hydroxyurea: A key player in cancer chemotherapy

Expert Review of Anticancer Therapy

Volumn 12, Issue 1, 2012, Pages 19-29

  Madaan, Kapish ^a   Kaushik, Darpan ^a   VerM A , Tarawanti ^a  

^a RITS   (India)

Author keywords

carcino M.A.; chemotherapy; hydroxyurea; ribonucleotide reductase

Indexed keywords

ACETYLSALICYLIC ACID; ALPHA INTERFERON; ALPHAN1 INTERFERON; BEVACIZUMAB; CETUXIMAB; CISPLATIN; CYTARABINE; DOCETAXEL; DOXORUBICIN; ETOPOSIDE; FLUOROURACIL; FOLINIC ACID; GEMCITABINE; HOMOHARRINGTONINE; HYDROXYUREA; IMATINIB; IRINOTECAN; MITOXANTRONE; PACLITAXEL; PEGINTERFERON ALPHA2A; POMALIDOMIDE; RECOMBINANT ALPHA2A INTERFERON; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; VANDETANIB; VERAPAMIL;

ALLOGENEIC STEM CELL TRANSPLANTATION; ALLOGENIC BONE MARROW TRANSPLANTATION; ALOPECIA; ARTICLE; BLOOD TOXICITY; BONE MARROW DEPRESSION; BONE MARROW SUPPRESSION; CANCER CHEMOTHERAPY; CHEMORADIOTHERAPY; CHRONIC MYELOID LEUKEMIA; COLORECTAL CANCER; COMBINATION CHEMOTHERAPY; CONTINUOUS INFUSION; DERMATOMYOSITIS; DIARRHEA; DIGESTIVE SYSTEM CANCER; DOSE RESPONSE; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG DOSE COMPARISON; DRUG DOSE SEQUENCE; DRUG EFFICACY; DRUG EXCRETION; DRUG HALF LIFE; DRUG MECHANISM; DRUG MEGADOSE; DRUG METABOLISM; DRUG POTENTIATION; DRUG RESPONSE; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG WITHDRAWAL; ERYTHEMA; ESOPHAGUS CANCER; FEVER; FOOT EDEMA; GASTROINTESTINAL SYMPTOM; GLIOBLASTOMA; HAND EDEMA; HEAD AND NECK CANCER; HEMOLYTIC ANEMIA; HEPATITIS; HUMAN; HYPERBILIRUBINEMIA; HYPERPIGMENTATION; LEUKOPENIA; LOW DRUG DOSE; LUNG NON SMALL CELL CANCER; MAXIMUM PLASMA CONCENTRATION; MENINGIOMA; MONOTHERAPY; MUCOSA INFLAMMATION; MYELOPROLIFERATIVE DISORDER; OROPHARYNX CANCER; PANCREAS CANCER; PAPULE; PHARMACODYNAMICS; POLYCYTHEMIA VERA; SKIN ATROPHY; SQUAMOUS CELL CARCINOMA; STOMACH CANCER; STOMATITIS; THROMBOCYTHEMIA; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT; UTERINE CERVIX CANCER; UTERINE CERVIX CARCINOMA;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CLINICAL TRIALS AS TOPIC; DRUG EVALUATION, PRECLINICAL; HUMANS; HYDROXYUREA; MYELOPROLIFERATIVE DISORDERS; NEOPLASMS;

EID: 83455217893     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/era.11.175     Document Type: Article

References (105)

1. Cantwell BMJ, Veale D, Rivette C, Ghani S, Harris AL. Cisplatin with high-dose infusions of hydroxyurea to inhibit DNA repair, a Phase II study in non-small-cell lung cancer. Cancer Chemother. Pharmacol. 23, 252-254 (1989).
2. Finch RA, Liu MC, Grill SP et al. Triapine (3-aminopyridine-2- carboxaldehyde-thiosemicarbazone): a potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem. Pharmacol. 59, 983-991 (2000).
3. Smith DC, Vaughan WP, Gwilt PR, Trump DL. A Phase I trial of high-dose continuous-infusion hydroxyurea. Cancer Chemother. Pharmacol. 33, 139-143 (1993).
4. Ford SS, Shackney SC. Lethal and sublethal effects of hydroxyurea in relation to drug comcentration and duration of drug exposure in sarcoma 180 in vitro. Cancer Res. 37, 2628-2637 (1977).
5. Moran RE, Straus MJ. Cytokinetic analysis of L1210 leukemia after continuous infusion of hydroxyurea in vivo. Cancer Res. 39, 1616-1622 (1979).
6. Heeney MM, Whorton MR, Howard TA, Johnson CA, Ware RE. Chemical and functional analysis of hydroxyurea oral solutions. J. Pediatr. Hematol. Oncol. 26, 179-184 (2004).
7. Dresler WFC, Stein R. Ueber den hydroxylharnstoff. Justus Leibigs Ann. Chem. Pharmacol. 150, 242-252 (1869).
8. Saban N, Bujak M. Hydroxyurea and hydroxamic acid derivatives as antitumor drugs. Cancer Chemother. Pharmacol. 64, 213-221 (2009).
9. Mutschler E, Derendorf H. Drug Actions, Basic Principles and Therapeutic Aspects. Medpharm Scientific Publishers, CRC Press, Stuttgart, Germany (1995).
10. Charache S, Dover GJ, Moyer MA. Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia. Blood 69, 109-116 (1987).
11. Charache S, Terrin ML, Moore RD et al. Effect of hydroxyurea on frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N. Engl. J. Med. 332, 1317-1322 (1995).
12. Schechter AN, Rodgers GP. Sickle cell anemia: basic research reaches the clinic. N. Engl. J. Med. 332, 1372-1374 (1995).
13. Gao WY, Cara A, Gallo RC, Lori F. Low levels of deoxynucleotides in peripheral blood lymphocytes: a stratergy to inhibit human immunodeficiency virus type 1 replication. Proc. Natl Acad. Sci. USA 90, 8925-8928 (1993).
14. Cortellazo S, Finazzi G, Ruggeri M et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N. Engl. J. Med. 332, 1132-1136 (1995).
15. Rosten M. Hydroxyurea: a new antimetabolite in the treatment of psoriasis. Br. J. Dermatol. 85, 177-181 (1971).
16. Donovan PB, Kaplan ME, Goldberg JD et al. Treatment of polycythemia vera with hydroxyurea. Am. J. Hematology 17, 329-334 (2006).
17. Chabner BA, Ryan DP, Paz-Ares L, Garcia-Carbonero R, Calabrasi P. Antineoplastic agents. In: Goodman and Gilman's the Pharmacological Basis of Therapeutics (10th Edition). McGraw-Hill, NY, USA, 1435-1436 (2001).
18. Chou JT, Beck WT, Khwaja T, Mayer K, Lein EJ. Synthesis and anticancer activity of novel cyclic N-hydroxyureas. J. Pharm. Sci. 66, 1556-1561 (1977).
19. Kennedy BJ. Hydroxyurea therapy in chronic myelogenous leukemia. Cancer 29, 1052-1056 (1972).
20. Piver MS, Howes AE, Suit HD, Marshall N. Effect of hydroxyurea on the radiation response of C3H mouse mammory tumors. Cancer 29, 407-412 (1972).
21. Latagliata R, Spadea A, Cedrone M et al. Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome negative myeloproliferative neoplasms. Cancer doi:10.1002/cncr.26194 (2011) (Epub ahead of print).
22. Mesa RA. How I treat symptomatic splenomegaly in patients with myelofibrosis. Blood 113, 5394-5400 (2009).
23. Burnett AK, Milligan D, Prentice AG et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 109, 1114-1124 (2007).
24. Garcia SM, Svarch E, Llanes OA et al. Treatment with moderate doses of hydroxyurea in drepanocytosis. Rev. Cubana Hematol. Immunol. Hemoter. 24 (2008).
25. Ariel IM. Therapeutic effects of hydroxyurea experience with 118 patients with inoperable solid tumors. Cancer 25, 705-714 (1970).
26. Borenfreund E, Karim M, Bendlich A. Chromosomal aberrations induced by hyponitrite and hydroxylamine derivatives. J. Nat. Cancer Inst. 32, 667-669 (1964).
27. Weinlich G, Fritsch P. Leg ulcers in patients treated with hydroxyurea for myeloproliferative disorders: what is the trigger? Br. J. Dermatol. 141, 171-172 (1999).
28. Veale D, Cantwell BMJ, Kerr N, Upfold A, Harris AL. Phase I study of high-dose hydroxyurea in lung cancer. Cancer Chemother. Pharmacol. 21, 53-56 (1988).
29. Fishbein WN, Carbone PP. Hydroxyurea -mechanism of action. Science 142, 1069-1070 (1963).
30. Frenkel EP, Skinner WN, Smiley JD. Studies on a metabolic defect induced by hydroxyurea (NSC-32065). Cancer Chemother. Rep. 40, 19-22 (1964).
31. Krakoff IH, Brown NC, Reichard P. Inhibition of ribonucleoside diphosphate reductase by hydroxyurea. Cancer Res. 28, 1559-1565 (1968).
32. Lassmann G, Thelander L, Graslund A. EPR stopped-flow studies of the reaction of the tyrosyl radical of protein R2 from ribonucleotide reductase with hydroxyurea. Biochem. Biophys. Res. Commun. 188, 879-887 (1992).
33. Sato K, Akaike T, Sawa T et al. Nitric oxide generation from hydroxyurea via copper-catalyzed peroxidation and implications for pharmacological actions of hydroxyurea. Jpn. J. Cancer Res. 88, 1199-1204 (1997).
34. Wawra E, Wintersbeger E. Does hydroxyurea inhibit DNA replication in mouse cells by more than one mechanism? Mol. Cell Biol. 3, 297-304 (1983).
35. Young CW, Schochetman G, Karnofski DA. Hydroxyurea-induced inhibition of deoxyribonucleotide synthesis: studies in intact cells. Cancer Res. 27, 526-529 (1967).
36. Vogl SE, Camacho F, Kaplan BH, Lerner H, Cinberg J. Hydroxyurea fails to improve the results of MBD chemotherapy in cancer of the head and neck, but reduces toxicity. Cancer 52, 2011-2016 (1983).
37. Sinclair WK. The combined effect of Hydroxyurea and x-rays on Chinese hamster cells in vitro. Cancer Res. 28, 198-206 (1968).
38. Tracewell WG, Trump DL, Vaughan WP, Smith DC, Gwilt PR. Population pharmacokinetics of hydroxyurea in cancer patients. Cancer Chemother. Pharmacol. 35, 417-422 (1995).
39. Budavari S. The Merck Index (12th Edition). Merck & Co. Inc., NJ, USA, 833 (1996).
40. Neil MJO, Heckleman PE, Koch CB, Roman KJ. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals (14th Edition). Merck Research Laboratories Division of Merck & Co. Inc., NJ, USA, 4848 (2006).
41. Martindale W, Reynolds JEF, Prasad AB. Martindale The Extra Pharmacopoeia (28th Edition). Reynolds JEF (Ed.). Published by Direction of the Council of The Pharmaceutical Society of Great Britain, UK, 212 (1982).
42. Children's Oncology Group. Pharmacology Manual. Cartwright J, Sinsabaugh D, Henry D (Eds). March revision, 87 (2003).
43. Miller S, Murphy P. The use of hydroxyurea as adjunct treatment for human immunodeficiency virus. J. Pediatr. Pharm. Pract. 4, 107-109 (1999).
44. WHO International Agency for Research on Cancer. Hydroxyurea, International Agency for Research on Cancer (IARC) Monographs on the Evaluation of Carcinogenic Risk to Humans. IARC Press, Lyon, France (2000).
45. Rodriguez GI, Kuhn JG, Weiss GR et al. A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea. Blood 91, 1533-1541(1998).
46. Belt RJ, Haas CD, Kennedy J, Taylor S. Studies of hydroxyurea administered by continuous infusion: toxicity, pharmacokinetics, and cell synchronization. Cancer 46, 455-462 (1980).
47. Newman EM, Carroll M, Akman SA et al. Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 39, 254-258 (1997).
48. Hydroxyurea. British Columbia Cancer Agency (BCCA), Cancer Drug Manual, BC Canada (2006).
49. Andrae U. Evidence for the involvement of cytochrome P-450-dependent monooxygenase(s) in the formation of genotoxic metabolites from N-hydroxyurea. Biochem. Biophys. Res. Commun. 118, 409-415 (1984).
50. DeSesso JM, Scialli AR, Goeringer GC. d-mannitol, a specific hydroxyl free radical scavenger, reduces the developmental toxicity of hydroxyurea in rabbits. Teratology, 49, 248-259 (1994).
51. King SB. N-hydroxyurea and acyl nitroso compounds as nitroxyl (HNO) and nitric oxide (NO) donors. Curr. Top. Med. Chem. 5, 665-673 (2005).
52. Kovacic P. Hydroxyurea (therapeutics and mechanism): metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signalling and clinical applications. Med. Hypothesis. 76, 24-31 (2011).
53. Donehower RC. An overview of the clinical experience with hydroxyurea. Semin. Oncol. 19(Suppl. 9), 11-19 (1992).
54. Burkitt MJ, Raafat A. Nitric oxide generation from hydroxyurea: significance and implications for leukemogenesis in the management of myeloproliferative disorders. Blood 107, 2219-2222 (2006).
55. Beitler JJ, Smith RV, Haynes H et al. A Phase I clinical trial of prolonged infusion of hydroxyurea in combination with hyperfractionated, accelerated, external radiation therapy in patients with advanced squamous cell cancer of the head and neck. Invest. New Drugs 16, 161-169 (1998).
56. Brockstein B, Haraf DJ, Stenson K et al. A Phase I-II study of concomitant chemoradiotherapy with paclitaxel (one hour infusion), 5-fluorouracil and hydroxyurea with granulocyte colony stimulating factor support for patients with poor prognosis head and neck cancer. Ann. Oncol. 11 (6), 721-728 (2000).
57. Beitler JJ, Anderson P, Haynes H et al. Phase I clinical trial of parenteral hydroxyurea in combination with pelvic and para-aortic external radiation and brachytherapy for patients with advanced squamous cell cancer of the uterine cervix. Int. J. Radiat. Oncol. Biol. Phys. 52, 637-642 (2002).
58. Seiwert TY, Haraf DJ, Cohen EEW et al. Phase I study of bevacizumab added to fluorouracil-and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. J. Clin. Oncol. 26, 1732-1741 (2008).
59. Salama JK, Haraf DJ, Stenson KM et al. A randomized Phase II study of 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy compared with bevacizumab plus 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy for intermediate-stage and T4N0-1 head and neck cancers. Ann. Oncol. 22(10), 2304-2309 (2011).
60. Haraf DJ, Kies M, Rademaker AW et al. Radiation therapy with concomitant hydroxyurea and fluorouracil in stage II and III head and neck cancer. J. Clin. Oncol. 17, 638-644 (1999).
61. Spencer SA, Harris J, Wheeler RH et al. RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck. Int. J. Radiat. Oncol. Biol. Phys. 51, 1299-1304 (2001).
62. Salama JK, Haraf DJ, Stenson K, Milano MT, Witt ME, Vokes EE. Phase I study of concomitant chemoradiotherapy with irinotecan, 5-FU, and hydroxyurea for patients with advanced and/or recurrent head and neck cancer. Cancer J. 11, 140-146 (2005).
63. Brockstein B, Haraf DJ, Stenson K et al. Phase I study of concomitant chemoradiotherapy with paclitaxel, fluorouracil, and hydroxyurea with granulocyte colony-stimulating factor support for patients with poor-prognosis cancer of the head and neck. J. Clin. Oncol. 16, 735-744 (1998).
64. Kao J, Genden EM, Gupta V et al. Phase 2 trial of concurrent 5-fluorouracil, hydroxyurea, cetuximab, and hyperfractionated intensity-modulated radiation therapy for locally advanced head and neck cancer. Cancer 117, 318-326 (2011).
65. Kies MS, Haraf DJ, Rosen F et al. Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer. J. Clin. Oncol. 19, 1961-1969 (2001).
66. Rosen FR, Haraf DJ, Kies MS et al. Multicenter randomized Phase II study of paclitaxel (1-hour infusion), fluorouracil, hydroxyurea, and concomitant twice daily radiation with or without erythropoietin for advanced head and neck cancer. Clin. Cancer Res. 9, 1689-1697 (2003).
67. Vokes EE, Stupp R, Haraf D et al. Hydroxyurea with continuous infusion paclitaxel, 5-fluorouracil, and concomitant radiotherapy for poor-prognosis head and neck cancer. Semin. Oncol. 22(3 Suppl. 6), 47-52 (1995).
68. Argiris A, Haraf DJ, Kies MS, Vokes EE. Intensive concurrent chemoradiotherapy for head and neck cancer with 5-fluorouracil-and hydroxyurea-based regimens: reversing a pattern of failure. Oncologist 8, 350-360 (2003).
69. Rose PG, Ali S, Watkins E et al. Longterm follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a necologic oncology group study. J. Clin. Oncol. 25, 2804-2810 (2007).
70. Mabro M, Louvet C, André T et al. Bimonthly leucovorin, infusion 5-fluorouracil, hydroxyurea, and irinotecan (FOLFIRI-2) for pretreated metastatic colorectal cancer. Am. J. Clin. Oncol. 26, 254-258 (2003).
71. Jakobsen A, Pfeiffer P, Hansen F, Sandberg E, Aabo K. Dual modulation of UFT with leucovorin and hydroxyurea in metastatic colorectal cancer. Acta Oncol. 40, 63-66 (2001).
72. Di Costanzo F, Gasperoni S, Malacarne P et al. High-dose folinic acid and 5-fluorouracil alone or combined with hydroxyurea in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for clinical research. Am. J. Clin. Oncol. 21, 369-375 (1998).
73. Di Costanzo F, el-Taani H, Parriani D et al. Hydroxyurea may increase the activity of fluorouracil plus folinic acid in advanced gastrointestinal cancer: Phase II study. Cancer Invest. 14, 234-238 (1996).
74. Wadler S, Brain C, Catalano P, Einzig Al, Cella D, Benson AB. Randomized Phase II trial of either fluorouracil, parenteral hydroxyurea, IFN-a-2a, and filgrastim or doxorubicin/docetaxel in patients with advanced gastric cancer with quality-of-life assessment: Eastern Cooperative Oncology Group study E6296. Cancer J. 8, 282-286 (2002).
75. Yen Y, Chow W, Leong L et al. Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: a California cancer consortium trial. Cancer Chemother. Pharmacol. 50, 353-359 (2002).
76. Taieb J, Artru P, Baujat B et al. Optimisation of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of hydroxyurea, leucovorin, 5-FU and cisplatin (HLFP regimen) for metastatic oesophageal cancer. Eur. J. Cancer, 38, 661-666 (2002).
77. Stewart DJ, Tomiak EM, Goss G et al. Paclitaxel plus hydroxyurea as second line therapy for non-small cell lung cancer. Lung Cancer 15, 115-123 (1996).
78. Blumenreich MS, Kellihan MJ, Joseph UG et al. Long-term intravenous hydroxyurea infusions in patients with advanced cancer. A Phase I trial. Cancer 71, 2828-2832 (1993).
79. Raschko JW, Akman SA, Leong LA et al. Phase I study of 5-day continuous infusion fluorodeoxyuridine and high-dose folinic acid with oral hydroxyurea. Cancer Chemother. Pharmacol. 35, 161-164 (1994).
80. Sharon R, Tatarsky I, Ben-Arieh Y. Treatment of polycythemia vera with hydroxyurea. Cancer 57, 718-720 (1986).
81. Kannedy BJ, Smith LR, Goltz RW. Skin changes secondary to hydroxyurea therapy. Arch. Dermatol. 111, 183-187 (1975).
82. Brincker H, Christensen BE. Acute mucocutaneous toxicity following high dose hydroxyurea. Cancer Chemother. Pharmacol. 32, 496-497 (1993).
83. Jackson GH, Wallis J, Ledingham J, Lennard A, Proctor SJ. Hydroxyurea-induced acute alveolitis in a patient with chronic myeloid leukaemia. Cancer Chemother. Pharmacol. 27, 168-169 (1990).
84. Jabr FI, Ali S, Ali T. Hydroxyurea-induced hemolytic anemia in a patient with essential thrombocythemia. Am. J. Hematol. 77, 374-376 (2004).
85. Tauscher J, Siegel J, Petrides PE. Hydroxyurea induced oscillations in twelve patients with polycythemia vera. Haematologica 95, 1227-1229 (2010).
86. Hydroxyurea (hydroxyurea) -Description and Clinical Pharmacology. www.druglib.com/druginfo/hydroxyurea/description pharmacology
87. National Cancer Institute (US FDA approved drugs). http://dtp.nci.nih. gov/timeline/flash/FDA.htm
88. ClinicalTrials.gov. Ph I Zactima + Imatinib Mesylate & Hydroxyurea for Pts w Recurrent MG. http://clinicaltrials.gov/ct2/show/NCT00613054?term= hydroxyurea+as+anti+cancer&rank=4
89. ClinicalTrials.gov. Combination of Hydroxyurea and Verapamil for Refractory Meningiomas. http://clinicaltrials.gov/ct2/show/NCT00706810?term= hydroxyurea+as+anti+cancer&rank=6
90. ClinicalTrials.gov. Primary Thrombocythaemia 1 Trial (PT-1). http://clinicaltrials.gov/ct2/show/study/NCT00175838?term=hydroxyurea+as+ant i+cancer&rank=7
91. ClinicalTrials.gov. Combination Chemotherapy Plus Interferon Alfa Followed by Filgrastim in Treating Patients With Gastrointestinal Tract Cancer. http://clinicaltrials.gov/ct2/show/NCT00 019474?term= hydroxyurea+as+anti+cancer&rank=8
92. ClinicalTrials.gov. Homoharringtonine Compared With Hydroxyurea for Chronic Myelogenous Leukemia That Has Not Responded to Interferon Alfa. http://clinicaltrials.gov/ct2/show/NCT00004933?term= hydroxyurea+as+anti+cancer&rank=10
93. ClinicalTrials.gov. Combination Chemotherapy and Interferon Alfa Followed by Surgery and/or Radiation Therapy in Treating Patients with Stage I, Stage II, or Stage III Esophageal Cancer. http://clinicaltrials.gov/ct2/show/NCT00 004897?term=hydroxyurea+as+anti+cancer&rank=12
94. ClinicalTrials.gov. Chemotherapy and Biological Therapy With or Without Bone Marrow or Peripheral Stem Cell Transplant in Treating Patients with Chronic Myelogenous Leukemia. http://clinicaltrials.gov/ct2/show/NCT00 025402?term=hydroxyurea+as+anti+cancer&rank=13
95. ClinicalTrials.gov. Intensive Compared With Nonintensive Chemotherapy in Treating Older Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome. http://clinicaltrials.gov/ct2/show/NCT00005823?term= hydroxyurea+as+anti+cancer&rank=15
96. ClinicalTrials.gov. Interferon Alfa in Treating Patients With Newly Diagnosed Chronic Myelogenous Leukemia. http://clinicaltrials.gov/ct2/show/ NCT00002869?term=hydroxyurea+as+anti+cancer&rank=17
97. ClinicalTrials.gov. Randomized Trial of Pegylated Interferon Alfa-2a versus Hydroxyurea in Polycythemia Vera (PV) and Essential Thrombocythemia (ET). http://clinicaltrials.gov/ct2/show/NCT01259856?term= hydroxyurea+as+anti+cancer&rank=18
98. ClinicalTrials.gov. Pegylated Interferon Alfa-2a Salvage Therapy in High Risk Polycythemia Vera (PV) or Essential Thrombocythemia (ET). http://clinicaltrials.gov/ct2/show/NCT01259817?term= hydroxyurea+as+anti+cancer&rank=19
99. ClinicalTrials.gov. Imatinib Mesylate With or Without Interferon Alfa or Cytarabine Compared With Interferon Alfa Followed by Donor Stem Cell Transplant in Treating Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia. http://clinicaltrials.gov/ct2/show/NCT00 055874?term= hydroxyurea+as+anti+cancer &rank=20
100. ClinicalTrials.gov. Chemotherapy, Interferon, and Bone Marrow Transplantation in Treating Patients with Chronic Myelogenous Leukemia. http://clinicaltrials.gov/ct2/show/NCT00002771?term= hydroxyurea+as+anti+cancer&rank=21
101. ClinicalTrials.gov. Pomalidomide in Patients with Myeloproliferative Neoplasms in Fibrotic Stage. http://clinicaltrials.gov/ct2/show/NCT00949364? term=hydroxyurea+as+anti+cancer&rank=22
102. ClinicalTrials.gov. Comparison of Combination Chemotherapy Regimens in Treating Patients With Advanced Stomach Cancer. http://clinicaltrials.gov/ct2/ show/NCT00?term=hydroxyurea+as+anti+cancer&rank=11
103. ClinicalTrials.gov. Combination Chemotherapy Followed by Peripheral Stem Cell Transplantation in Treating Patients with Chronic Myelogenous Leukemia. http://clinicaltrials.gov/ct2/show/NCT00002674?term= hydroxyurea+as+anti+cancer&rank=14
104. ClinicalTrials.gov. Interferon-Alfa With or Without Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients with Newly Diagnosed Chronic Myelogenous Leukemia. http://clinicaltrials.gov/ct2/show/NCT00002868? term=hydroxyurea+as+anti+cancer&rank=16
105. ClinicalTrials.gov. Phase II Imatinib Mesylate + Hydroxyurea in Treatment for Patients with Recurrent/Progressive Meningioma. http://clinicaltrials.gov/ ct2/show/NCT00611234?term=hydroxyurea+as+anti+cancer&rank=3