Targeted drug delivery via folate receptors in recurrent ovarian cancer: A review

OncoTargets and Therapy

Volumn 7, Issue , 2014, Pages 1223-1236

  Marchetti, Claudia ^a   Palaia, Innocenza ^a   Giorgini, Margherita ^a   De Medici, Caterina ^a   Iadarola, Roberta ^a   Vertechy, Laura ^a   Domenici, Lavinia ^a   Di Donato, Violante ^a   Tomao, Federica ^a   Muzii, Ludovico ^a   Panici, Pierluigi Benedetti ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Antifolate; Farletuzumab; Folate receptor; Ovarian cancer; Targeted therapies; Vintafolide

Indexed keywords

ANGIOGENESIS INHIBITOR; ANTINEOPLASTIC AGENT; BEVACIZUMAB; BMS 753493; CARBOPLATIN; DOCETAXEL; DOXORUBICIN; EC 0225; EC 17; EC 90; EPOFOLATE; EPOTHILONE A; ETARFOLATIDE; FARLETUZUMAB; FOLATE CONJUGATED VACCINE; FOLATE IMMUNE; FOLATE RECEPTOR; FOLIC ACID; GP 0100; IMMUNOLOGICAL ADJUVANT; MEMBRANE RECEPTOR; MITOMYCIN; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; PACLITAXEL; PLACEBO; PLATINUM; TAXANE DERIVATIVE; TUMOR ANTIGEN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VACCINE; VINCA ALKALOID; VINTAFOLIDE;

ABDOMINAL PAIN; ABSENCE OF SIDE EFFECTS; ADVANCED CANCER; ALLERGIC REACTION; ANEMIA; CANCER CHEMOTHERAPY; CANCER MORTALITY; CANCER RECURRENCE; CANCER SURVIVAL; CAUSE OF DEATH; CHILL; CONSTIPATION; DIARRHEA; DRUG ACTIVITY; DRUG DELIVERY SYSTEM; DRUG DOSE ESCALATION; DRUG HALF LIFE; DRUG TARGETING; FATIGUE; FEBRILE NEUTROPENIA; FEVER; HAND FOOT SYNDROME; HUMAN; HYPERGLYCEMIA; ILEUS; INTESTINE OBSTRUCTION; LEUKOPENIA; LUNG ADENOCARCINOMA; LYMPHOMA; METASTASIS; MOLECULARLY TARGETED THERAPY; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUROPATHY; NEUTROPENIA; NONHUMAN; OVARY CANCER; PERITONEUM CANCER; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; RECOMMENDED DRUG DOSE; REPEATED DRUG DOSE; REVIEW; STOMATITIS; THROMBOCYTOPENIA; TREATMENT RESPONSE; UROSEPSIS; UTERINE TUBE CARCINOMA;

EID: 84904291201     PISSN: None     EISSN: 11786930     Source Type: Journal    
DOI: 10.2147/ott.s40947     Document Type: Review

References (91)

1. National Cancer Institute. Ovarian cancer [homepage on the Internet]. Bethesda, MD: National Cancer Institute; 2014. Available from: http://www.cancer.gov/cancertopics/types/ovarian. Accessed April 26, 2014.
2. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46(4): 765-781.
3. Vaughan S, Coward JI, Bast RC Jr, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011;11(10): 719-725.
4. Burke T W, Morris M. Secondary cytoreductive surgery for ovarian cancer. Obstet Gynecol Clin North Am. 1994;21(1):167-178.
5. Naumann RW, Coleman RL. Management strategies for recurrent platinum-resistant ovarian cancer. Drugs. 2011;71(11):1397-1412.
6. Armstrong DK, Bundy B, Wenzel L, et al; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34-43.
7. Chatelut E, Delord J P, Canal P. Toxicity patterns of cytotoxic drugs. Invest New Drugs. 2003;21(2):141-148.
8. Carroll AR, Coleman RL, Sood AK. Therapeutic advances in women's cancers. Front Biosci (Schol Ed). 2011;3:82-97.
9. Walters CL, Arend RC, Armstrong DK, Naumann RW, Alvarez RD. Folate and folate receptor alpha antagonists mechanism of action in ovarian cancer. Gynecol Oncol. 2013;131(2):493-498.
10. Armstrong DK, White AJ, Weil SC, Phillips M, Coleman RL. Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed platinumsensitive ovarian cancer. Gynecol Oncol. 2013;129(3):452-458.
11. Kelemen LE, Goodman MT, McGuire V, et al; Australian Cancer Study (Ovarian Cancer) Study Group; Australian Ovarian Cancer Study Group; Ovarian Cancer Association Consortium. Genetic variation in TYMS in the one-carbon transfer pathway is associated with ovarian carcinoma types in the Ovarian Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev. 2010;19(7):1822-1830.
12. Choi S W, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr. 2000;130(2):129-132.
13. Stokstad, ELR. Historical perspective on key advances in the biochemistry and physiology of folates. In: Picciano MF, Stokstad ELR, Gregory J.F, editors. Folic Acid Metabolism in Health and Disease. New York: John Wiley & Sons, Incorporated; 1990:1-21.
14. Zhao R, Matherly LH, Goldman ID. Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med. 2009;11:e4.
15. Gonen N, Assaraf YG. Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012;15(4): 183-210.
16. Matherly LH, Hou Z, Deng Y. Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer Metastasis Rev. 2007;26(1):111-128.
17. Whetstine JR, Flatley RM, Matherly LH. The human reduced folate carrier gene is ubiquitously and differentially expressed in normal human tissues: identifcation of seven non-coding exons and characterization of a novel promoter. Biochem J. 2002;367(Pt 3):629-640.
18. Kelemen LE. The role of folate receptor alpha in cancer development, progression and treatment: cause, consequence or innocent bystander? Int J Cancer. 2006;119(2):243-250.
19. Shen F, Wang H, Zheng X, Ratnam M. Expression levels of functional folate receptors alpha and beta are related to the number of Nglycosylated sites. Biochem J. 1997;327 (Pt 3):759-764.
20. Shen F, Ross JF, Wang X, Ratnam M. Identifcation of a novel folate receptor, a truncated receptor, and receptor type beta in hematopoietic cells: cDNA cloning, expression, immunoreactivity, and tissue specifcity, Biochemistry. 1994;33(5):1209-1215.
21. Shen F, Wu M, Ross JF, Miller D, Ratnam M. Folate receptor type gamma is primarily a secretory protein due to lack of an effcient signal for glycosylphosphatidylinositol modifcation: protein characterization and cell type specifcity. Biochemistry. 1995;34(16):5660-5665.
22. Wang H, Ross J F, Ratnam M. Structure and regulation of a polymorphic gene encoding folate receptor type gamma/gamma'. Nucleic Acids Res. 1998;26(9):2132-2142.
23. Rijnboutt S, Jansen G, Posthuma G, Hynes JB, Schornagel JH, Strous GJ. Endocytosis of GPI-linked membrane folate receptor-alpha. J Cell Biol. 1996;132(1-2):35-47.
24. Ramamoorthy K, Potala S, Verma RS. Insilco analysis of functionally important residues in folate receptors. Bioinformation. 2007;2(4): 157-162.
25. Yuan Y, Nymoen DA, Dong H P, et al. Expression of the folate receptor genes FOLR1 and FOLR3 differentiates ovarian carcinoma from breast carcinoma and malignant mesothelioma in serous effusions. Hum Pathol. 2009;40(10):1453-1460.
26. Spiegelstein O, Eudy JD, Finnell RH. Identifcation of two putative novel folate receptor genes in humans and mouse. Gene. 2000;258(1-2): 117-125.
27. Ragoussis J, Senger G, Trowsdale J, Campbell IG. Genomic organization of the human folate receptor genes on chromosome 11q13. Genomics. 1992;14(2):423-430.
28. Wang X, Shen F, Freisheim JH, Gentry LE, Ratnam M. Differential stereospecifcities and affnities of folate receptor isoforms for folate compounds and antifolates. Biochem Pharmacol. 1992;44(9):1898-1901.
29. Miotti S, Canevari S, Ménard S, et al. Characterization of human ovarian carcinoma-associated antigens defned by novel monoclonal antibodies with tumor-restricted specifcity. Int J Cancer. 1987;39(3):297-303.
30. Kalofonos H P, Karamouzis M V, Epenetos AA. Radioimmunoscintigraphy in patients with ovarian cancer. Acta Oncol. 2001;40(5):549-557.
31. Melani C, Figini M, Nicosia D, et al. Targeting of interleukin 2 to human ovarian carcinoma by fusion with a single-chain Fv of antifolate receptor antibody. Cancer Res. 1998;58(18):4146-4154.
32. Toffoli G, Cernigoi C, Russo A, Gallo A, Bagnoli M, Boiocchi M. Overexpression of folate binding protein in ovarian cancers. Int J Cancer. 1997;74(2):193-198.
33. Elnakat H, Ratnam M. Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev. 2004;56(8):1067-1084.
34. Chancy CD, Kekuda R, Huang W, et al. Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor alpha in mammalian retinal pigment epithelium. J Biol Chem. 2000;275(27):20676-20684.
35. Weitman SD, Frazier KM, Kamen BA. The folate receptor in central nervous system malignancies of childhood. J Neurooncol. 1994;21(2):107-112.
36. Garin-Chesa P, Campbell I, Saigo PE, Lewis JL Jr, Old LJ, Rettig W.J. Trophoblast and ovarian cancer antigen LK26. Sensitivity and specifcity in immunopathology and molecular identifcation as a folate-binding protein. Am J Pathol. 1993;142(2):557-567.
37. Toffoli G, Russo A, Gallo A, et al. Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer. Int J Cancer. 1998;79(2):121-126.
38. Lorusso PM, Edelman MJ, Bever SL, et al. Phase I study of folate conjugate EC145 (Vintafolide) in patients with refractory solid tumors. J Clin Oncol. 2012;30(32):4011-4016.
39. Bellati F, Napoletano C, Gasparri ML, et al. Monoclonal antibodies in gynecological cancer: a critical point of view. Clin Dev Immunol. 2011;2011:890758.
40. Hartmann LC, Keeney GL, Lingle WL, et al. Folate receptor overexpression is associated with poor outcome in breast cancer. Int J Cancer. 2007;121(5):938-942.
41. Kalli KR, Oberg AL, Keeney GL, et al. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008;108(3): 619-626.
42. Brown Jones M, Neuper C, Clayton A, et al. Rationale for folate receptor alpha targeted therapy in "high risk" endometrial carcinomas. Int J Cancer. 2008;123(7):1699-1703.
43. Wu M, Gunning W, Ratnam M. Expression of folate receptor type alpha in relation to cell type, malignancy, and differentiation in ovary, uterus, and cervix. Cancer Epidemiol Biomarkers Prev. 1999;8(9):775-782.
44. Naumann RW, Coleman RL, Burger RA, et al. PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2013;31(35):4400-4406.
45. Ratnam M, Marquardt H, Duhring JL, Freisheim JH. Homologous membrane folate binding proteins in human placenta: cloning and sequence of a cDNA. Biochemistry. 1989;28(20);8249-8254.
46. Ross JF, Chaudhuri PK, Ratnam M. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer. 1994;73(9):2432-2443.
47. Salazar MD, Ratnam M. The folate receptor: what does it promise in tissuetargeted therapeutics? Cancer Metastasis Rev. 2007;26(1):141-152.
48. Puig-Kröger A, Sierra-Filardi E, Domínguez-Soto A, et al. Folate receptor beta is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-infammatory/regulatory macrophages. Cancer Res. 2009;69(24):9395-9403.
49. Ross J F, Wang H, Behm FG, et al. Folate receptor type beta is a neutrophilic lineage marker and is differentially expressed in myeloid leukemia. Cancer. 1999;85(2):348-357.
50. Zhao X, Li H, Lee RJ. Targeted drug delivery via folate receptors. Expert Opin Drug Deliv. 2008;5(3):309-319.
51. Sadasivan E, da Costa M, Rothenberg SP, Brink L. Purification, properties, and immunological characterization of folate-binding proteins from human leukemia cells. Biochim Biophys Acta. 1987;925(1):36-47.
52. Sadasivan E, Rothenberg S P, da Costa M, Brink L. Characterization of multiple forms of folate-binding protein from human leukemia cells. Biochim Biophys Acta. 1986;882(3):311-321.
53. Wang H, Zheng X, Behm FG, Ratnam M. Differentiation-independent retinoid induction of folate receptor type beta, a potential tumor target in myeloid leukemia. Blood. 2000;96(10):3529-3536.
54. Paulos CM, Turk MJ, Breur GJ, Low PS. Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis. Adv Drug Deliv Rev. 2004;56(8): 1205-1217.
55. Pan XQ, Zheng X, Shi G, Wang H, Ratnam M, Lee RJ. Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. Blood. 2002;100(2):594-602.
56. Morphotek. Safety, tolerability and pharmacokinetics of MORAb-003 in subjects with advanced ovarian cancer. In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2 013 [updated November 5, 2 013]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00428766.NLMidentifier:NCT00428766. Accessed April 26, 2014.
57. Ebel W, Routhier EL, Foley B, et al. Preclinical evaluation of MORAb-003, a humanized monoclonal antibody antagonizing folate receptor-alpha. Cancer Immun. 2007;7:6.
58. Kamen BA, Smith AK. Farletuzumab, an anti-folate receptor α antibody, does not block binding of folate or anti-folates to receptor nor does it alter the potency of anti-folates in vitro. Cancer Chemother Pharmacol. 2012;70(1):113-120.
59. Armstrong D. Farletuzumab (MORAb-003) in platinum-sensitive ovarian cancer patients experiencing a frst relapse. Community Oncol. 2010;7(2)Suppl 1:1-4.
60. Konner JA, Bell-McGuinn KM, Sabbatini P, et al. Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer: a phase I study. Clin Cancer Res. 2010;16(21): 5288-5295.
61. Coleman RL, Armstrong DK, White AJ, et al. A novel monoclonal antibody against folate receptor-alpha, exhibits clinical effcacy in platinum-sensitive 1st relapse of ovarian cancer subjects. Proc Eur Soc Gynecol Oncol. 2009;Abstract 90.
62. Kim KH, Jelovac D, Armstong DK, et al. Phase I safety study of farletuzumab, carboplatin, and pegylated liposomal doxorubicin (PLD) in patients with platinum-sensitive epithelial ovarian cancer (EOC). American Society of Clinical Oncology 4 8th Annual Meeting; June 1-5, 2012; Chicago, IL. J Clin Oncol. 2012;30(Suppl 18): abstract 5062.
63. Rustin GJ. Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol. 2003;21(10 Suppl):187s-193s.
64. Markman M, Markman J, Webster K, et al. Duration of response to second-line, platinum-based chemotherapy for ovarian cancer: implications for patient management and clinical trial design. J Clin Oncol. 2004;22(15):3120-3125.
65. Morphotek. Efficacy and safety of MORAb-003 in subjects with platinum-sensitive ovarian cancer in first relapse. In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2013 [updated November 18, 2013]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00849667.NLMidentifier:NCT00849667. Accessed April 26, 2014.
66. PRNewswire. Morphotek announces top-line results of a phase III study of farletuzumab in patients with relapsed platinum-sensitive epithelial ovarian cancer [press release]. Exton, PA: Morphotek Inc.; 2013 [Jan 10]. Available from: http://www.prnewswire.com/news-releases/morphotek-announces-top-line-results-of-a-phase-iii-study-of-farletuzumab-in-patients-with-relapsed-platinum-sensitive-epithelial-ovariancancer-186384621.html. Accessed April 26, 2014.
67. Vergote I, Armstrong D, Scambia G, et al. Phase 3 double-blind, placebo-controlled study of weekly farletuzumab with carboplatin/ taxane in subjects with platinum-sensitive ovarian cancer in frst relapse. European Society of Gynaecological Oncology 18th International Meeting; October 19-22, 2013; Liverpool, UK. Int J Gynecol Cancer. 2013;23(8 Suppl 1):11.
68. Morphotek. An efficacy and safety study of MORAb-003 in platinum-resistant or refractory relapsed ovarian cancer (FAR-122). In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2013 [updated November 18, 2013]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00738699.NLMidentifier:NCT00738699. Accessed April 26, 2014.
69. Morphotek. Safety Study of farletuzumab, carboplatin and pegylated liposomal doxorubicin (PLD) to treat platinum-sensitive ovarian cancer. In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2013 [updated November 5, 2013]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01004380.NLM identifier:NCT01004380. Accessed April 26, 2014.
70. Zwicke GL, Mansoori GA, Jeffery CJ. Utilizing the folate receptor for active targeting of cancer nanotherapeutics. Nano Rev. 2012;3.
71. Aronov O, Horowitz AT, Gabizon A, Gibson D. Folate-targeted PEG as a potential carrier for carboplatin analogs. Synthesis and in vitro studies. Bioconjug Chem. 2003;14(3):563-574.
72. Liu J, Kolar C, Lawson TA, Gmeiner WH. Targeted drug delivery to chemoresistant cells: folic acid derivatization of FdUMP[10] enhances cytotoxicity toward 5 -FU-resistant human colorectal tumor cells. J Org Chem. 2001;66(17):5655-5663.
73. Majoros IJ, Myc A, Thomas T, Mehta CB, Baker JR. PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality. Biomacromolecules. 2006;7(2): 572-579.
74. Ladino CA, Chari RV, Bourret LA, Kedersha NL, Goldmacher VS. Folate-maytansinoids: target-selective drugs of low molecular weight. Int J Cancer. 1997;73(6):859-864.
75. Suzuki T, Hisakawa S, Itoh Y, et al. Design, synthesis, and biological activity of folate receptor-targeted prodrugs of thiolate histone deacetylase inhibitors. Bioorg Med Chem Lett. 2007;17(15):4208-4212.
76. Vlahov IR, Santhapuram HK, Kleindl PJ, Howard SJ, Stanford KM, Leamon CP. Design and regioselective synthesis of a new generation of targeted chemotherapeutics. Part 1: EC145, a folic acid conjugate of desacetylvinblastine monohydrazide. Bioorg Med Chem Lett. 2006;16(19):5093-5096.
77. Weitman SD, Lark RH, Coney LR, et al. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res. 1992;52(12):3396-3401.
78. Vlahov IR, Leamon C P. Engineering folate-drug conjugates to target cancer: from chemistry to clinic. Bioconjug Chem. 2012;23(7):1357-1369.
79. Li J, Sausville EA, Klein PJ, et al. Clinical pharmacokinetics and exposure-toxicity relationship of a folate-Vinca alkaloid conjugate EC145 in cancer patients. J Clin Pharmacol. 2009;49(12):1467-1476.
80. Fisher RE, Siegel BA, Edell SL, et al. Exploratory study of 99mTcEC20 imaging for identifying patients with folate receptor-positive solid tumors. J Nucl Med. 2008;49(6):899-906.
81. Matteson EL, Lowe VJ, Prendergast FG, et al. Assessment of disease activity in rheumatoid arthritis using a novel folate targeted radiopharmaceutical Folatescan. Clin Exp Rheumatol. 2009;27(2):253-259.
82. Reddy JA, Dorton R, Westrick E, et al. Preclinical evaluation of EC145, a folate-vinca alkaloid conjugate. Cancer Res. 2007;67(9):4434-4442.
83. Sausville E, LoRusso P, Quinn M, et al. A phase I study of EC145 administered weeks 1 and 3 of a 4-week cycle in patients with refractory solid tumors. American Society of Clinical Oncology 4 3rd Annual Meeting; June 1-5, 2007; Chicago, IL. J Clin Oncol. 2007;25(18 Suppl): abstract 2577.
84. Naumann RW, Morris R, Harb W, et al. Protocol EC-FV-02: A phase II study of EC145 in patients with advanced ovarian cancer. European Society of Gynaecological Oncology 16th International Meeting; October 11-14, 2009; Belgrade, Serbia. Int J Gynecol Cancer. 2009;19(Suppl 2): abstract 1181.
85. Merck Sharp and Dohme Corp. Study of EC145 in patients with advanced ovarian and endometrial cancers. In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2013 [updated September 1 9, 2 013]. Available from: http://clinicaltrials.gov/show/NCT00507741.NLMidentifier:NCT00507741. Accessed April 26, 2014.
86. Merck Sharp and Dohme Corp. Study for women with platinum resistant ovarian cancer evaluating EC145 in combination with Doxil® (PROCEED). In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2014 [updated April 17, 2014]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01170650.NLMidentifier:NCT01170650. Accessed April 26, 2014.
87. Amato RJ, Engel J, Lu J, Low P, Naveed F. Phase I Trial of EC90 (keyhole-limpet hemocyanin fuorescein isothiocyanate conjugate) with GPI-0100 adjuvant followed by EC 1 7 (folate-fuorescein isothiocyanate conjugate) in patients with metastatic renal cell carcinoma and ovarian cancer. American Society of Clinical Oncology 40th Annual Meeting; June 5-8, 2004; New Orleans, LA. J Clin Oncol. 2004;22(Suppl 14): abstract 4754.
88. Endocyte. Study of EC0225 for the treatment of refractory or metastatic tumors. In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2012 [updated March 8, 2012]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00441870.NLMidentifier:NCT00441870. Accessed April 26, 2014.
89. Bristol-Myers Squibb. A phase 1/2 study of epofolate (BMS-753493) in subjects with advanced cancer (schedule 1). In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2011 [updated January 24, 2011]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00546247.NLMidentifier:NCT00546247. Accessed April 26, 2014.
90. Bristol-Myers Squibb. A phase 1/2 study of epofolate (BMS-753493) in subjects with advanced cancer (schedule 2). In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2011 [updated January 24, 2011]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00550017.NLMidentifier:NCT00550017. Accessed April 26, 2014.
91. Endocyte. Study of EC0489 for the treatment of refractory or metastatic tumors. In: ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US National Library of Medicine; 2012 [updated August 7, 2012]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00852189. NLM identifier: NCT00852189. Accessed April 26, 2014.