Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis

Biochimica et Biophysica Acta - Proteins and Proteomics

Volumn 1697, Issue 1-2, 2004, Pages 17-27

  Manley, Paul William ^a   Bold, Guido ^a   Brüggen, Josef ^a   Fendrich, Gabrielle ^a   Furet, Pascal ^a   Mestan, Jürgen ^a   Schnell, Christian ^a   Stolz, Barbara ^a   Meyer, Thomas ^a   Meyhack, Bernd ^a   Stark, Wilhelm ^a   Strauss, Andre ^a   Wood, Jeanette ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

AAL993 ZK260255; Abl related gene tyrosine kinase; Anti angiogenesis; Arg; AUC24h; C Abl; Cellular protein encoded by Abelson gene (tyrosine kinase); Crystal structure; Protein kinase inhibitor; Tumor metastasis; VEGF receptor

Indexed keywords

2,4 DIMETHYL 5 (2 OXO 1H INDOL 3 YLMETHYLENE) 3 PYRROLEPROPIONIC ACID; AAL 993; ANGIOZYME; ANTHRANILIC ACID DERIVATIVE; BEVACIZUMAB; CREMOPHOR; DORAMAPIMOD; FLUOROURACIL; FOLINIC ACID; IRINOTECAN; PACLITAXEL; SEMAXANIB; SUNITINIB; UNCLASSIFIED DRUG; VANDETANIB; VASCULOTROPIN INHIBITOR; VATALANIB;

ACNE; ANGIOGENESIS; ASTHENIA; BLEEDING; BREAST METASTASIS; CANCER GROWTH; CLINICAL TRIAL; CONFERENCE PAPER; CRYSTAL STRUCTURE; DIARRHEA; DIGESTIVE SYSTEM PERFORATION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CONFORMATION; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG DOSE REGIMEN; DRUG EFFICACY; DRUG ERUPTION; DRUG HALF LIFE; DRUG PROTEIN BINDING; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG TOLERABILITY; FATIGUE; HUMAN; HYPERTENSION; IC 50; KIDNEY CARCINOMA; LUNG NON SMALL CELL CANCER; METASTASIS INHIBITION; NAUSEA; PAIN; PRIORITY JOURNAL; PROTEINURIA; SURVIVAL RATE; THROMBOEMBOLISM; VOMITING; X RAY CRYSTALLOGRAPHY;

ANGIOGENESIS INHIBITORS; ANIMALS; CLINICAL TRIALS; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; MODELS, MOLECULAR; NEOVASCULARIZATION, PATHOLOGIC; PROTEIN BINDING; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR;

EID: 12144290647     PISSN: 15709639     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bbapap.2003.11.010     Document Type: Conference Paper

References (61)

1. Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am. J. Physiol., Cell Physiol. 246:2001;C1358-C1366.
2. Bergers G., Benjamin L.E. Tumorigenesis and the angiogenic switch. Nat. Rev., Cancer. 3:2003;401-410.
3. Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat. Rev., Cancer. 3:2003;422-433.
4. Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285:1971;1182-1186.
5. Kerbel R., Folkman J. Clinical translation of angiogenesis inhibitors. Nat. Rev., Cancer. 2:2002;727.
6. Miller K.D., Sweeney C.J., Sledge G.W. The snark is a boojum: the continuing problem of drug resistance in the antiangiogenic era. Ann. Oncol. 14:2003;20-28.
7. Manley P.W., Martiny-Baron G., Schlaeppi J.-M., Wood J.M. Anti-VEGF therapy. Expert Opin. Biol. Ther. 11:2002;1715-1736.
8. Leung D.W., Cachianes D., Kuang W.J., Goeddel D.V., Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 246:1989;1306-1309.
9. Tischer E., Gospodarowicz D., Mitchell R., Silva M., Schilling J., Lau K., Crisp T., Fiddes J.C., Abraham J.A. Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem. Biophys. Res. Commun. 165:1989;1198-1206.
10. Autiero M., Waltenberger J., Communi D., Kranz A., Moons L., Lambrechts D., Kroll J., Plaisance S., De Mol M., Bono F., Kliche S., Fellbrich G., Ballmer-Hofer K., Maglione D., Mayr-Beyrle U., Dewerchin M., Dombrowski S., Stanimirovic D., Van Hummelen P., Dehio C., Hicklin D.J., Persico G., Herbert J.-M., Communi D., Shibuya M., Collen D., Conway E.M., Carmeliet P. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat. Med. 9:2003;936-943.
11. Fernando N.H., Hurwitz H.I. Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer. Semin. Oncol. 30:2003;S39-S50.
12. Hollash J., Davis S., Papadopoulos N., Croll S.D., Ho L., Russell M., Boland P., Leidich R., Hylton D., Burova E., Ioffe E., Huang T., Radziejewski C., Bailey K., Fandl J.P., Daly T., Wiegand S.J., Yancopoulos G.D., Rudge J.S. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Natl. Acad. Sci. U. S. A. 99:2002;11393-11398.
13. Yang J.C., Haworth L., Sherry R.M., Hwu P., Schwartzentruber D.J., Topalian S.L., Steinberg S.M., Chen H.X., Rosenberg S.A. A randomized trial of bevacizumab, an anti-vascular endothelial growth fact antibody for metastatic renal cancer. N. Engl. J. Med. 349:2003;427-434.
14. Muang M. Capecitabine/bevacizumab compared to capecitabine alone in pretreated metastatic breast cancer: results of a phase III study. Clin. Breast Cancer. 3:2003;375-377.
15. Burstein H.J., Parker L.M., Savoie J., Younger J., Kuter I., Ryan P.D., Garber J.E., Campos S.M., Shulman L.N., Harris L.N., Gelman R., Winer E.P. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res. Treat. 76:2002;S115.
16. DeVorre R.F., Fehrenbacher L., Herbst R.S., Langer C.J., Kelly K., Gaudreault J., Holmgren E., Novotny W.F., Kabbinavar F. A randomized phase II trial comparing rhuMab VEGF (recombinant humanized monoclonal antibody to vascular endothelial growth factor) plus carboplatin/paclitaxel (CP) to CP alone in patients with stage IIIB/IV NSCLC. Proc.-Am. Soc. Clin. Oncol., Meet. 19:2000;485a. (Abstr. 1896).
17. Kabbinavar F.F., Johnson D., Langmuir V.K., Holmgren E., Bergsland E. Patterns of tumor progression during therapy with bevacizumab (BV) and chemotherapy (CT) for metastatic colorectal cancer (MCRC) and advanced non-small cell lung cancer (NSCLC). Proc.-Am. Soc. Clin. Oncol., Meet. 20:2001;277a. (Abstr. 1105).
18. Kabbinavar F., Hurwitz H.I., Fehrenbacher L., Meropol N.J., Novotny W.F., Lieberman G., Griffing S., Bergsland E. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J. Clin. Oncol. 21:2003;60-65.
19. Hurwitz H., Fehrenbacher L., Cartwright T., Hainsworth J., Heim W., Berlin J., Griffing S., Novotny W., Holmgren E., Kabbinavar F. Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC. Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;. http://www.asco.org/hurwitz_no3646 (Abstr. 3646).
20. Venook A., Hurwitz H., Cunningham C., Burris H.A., Aitchison R., Radka S., Pavco P., Capra W., Wolin M., Usman N. Relationship of clinical outcome in metastatic colorectal carcinoma to levels of soluble VEGFR-1: results of a phase II trial of a ribozyme targeting the pre-mRNA of VEGFR-1 (angiozyme), in combination with chemotherapy. Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;256. (Abstr. 1025).
21. Mendel D.B., Laird A.D., Smolich B.D., Blake R.A., Liang C., Hannah A.L., Shaheen R.M., Ellis L.M., Weitman S., Shawver L.K., Cherrington J.M. Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent. Anti-cancer Drug Des. 15:2000;29-41.
22. Manley P.W., Furet P., Bold G., Brüggen J., Mestan J., Meyer T., Schnell C.R., Wood J., Haberey M., Huth A., Krüger M., Menrad A., Ottow E., Seidelmann D., Siemeister G., Thierauch K.H. Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors. J. Med. Chem. 45:2002;5687-5693.
23. Kuenen B.C., Rosen L., Smit E.F., Parson M.R.N., Levi M., Ruijter R., Huisman H., Keddy M.A., Noordhuis P., van der Vijgh W.J.F., Peters G.J., Cropp G.C., Scigalla P., Hoekman K., Pinedo H.M., Giaccone G. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J. Clin. Oncol. 20:2002;1657-1667.
24. Kuenen B.C., Tabernero J., Baselga J., Cavalli F., Pfanner E., Conte P.C., Seeber S., Madhusudan S., Deplanque G., Huisman H., Scigalla P., Hoekman K., Harris A.L. Efficacy and toxicity of the angiogenesis inhibitor SU5416 as a single agent in patients with advanced renal cell carcinoma, melanoma, and soft tissue sarcoma. Clin. Cancer Res. 9:2003;1648-1655.
25. Stopek A., Sheldon M., Vahedian M., Cropp G., Gosalia R., Hannah A. Results of a phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Clin. Cancer Res. 8:2002;2798-2805.
26. Fabbro D., Manley P.W. SU-6668, SUGEN. Curr. Opin. Investig. Drugs. 2:2001;1142-1148.
27. Rosen L.S., Rosen P.J., Kabbinavar F., Mulay M., Mickey J., Hernandez L., Brown J.M., Alexander J., Bello C., Cropp G., Kelsey S., Scigalla P. Phase I experience with SU6668, a novel multiple receptor tyrosine kinase inhibitor in patients with advanced malignancies. Proc.-Am. Soc. Clin. Oncol., Meet. 20:2001;97a. (Abstr. 383).
28. Buchdunger E., Matter A., Druker B.J. Bcr-Abl inhibition as a modality of CML therapeutics. Biochim. Biophys. Acta. 1551:2001;M11-M18.
29. Sun L., Liang C., Shirazian S., Zhou Y., Miller T., Cui J., Fukuda J.F., Chu J.-Y., Nematalla A., Wany X., Chen H., Sistla A., Luu T.C., Tang F., Wei J., Tang C. Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J. Med. Chem. 46:2003;1116-1119.
30. Mendel D.B., Laird A.D., Xin X., Louie S.G., Christensen J.G., Li G., Schreck R.E., Abrams T.J., Ngai T.J., Lee L.B., Murray L.J., Carver J., Chan E., Moss K.G., Haznedar J.O., Sukbuntherng J., Blake R.A., Sun L., Tang C., Miller T., Shirazian S., McMahon G., Cherrington J.M. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9:2003;327-337.
31. Rosen L., Mulay M., Long J., Wittner J., Brown J., Martino A.-M., Bello C.L., Walter S., Scigalla P., Zhu J. Phase I trial of SU011248, a novel tyrosine kinase inhibitor in advanced solid tumors. Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;191. (Abstr. 765).
32. Demetri G.D., George S., Heinrich M.C., Fletcher J.A., Fletcher C.D.M., Desai J., Cohen D.P., Scigalla P., Cherrington J.M., Van Den Abbeele A.D. Clinical activity and tolerability of the multi-targeted tyrosine kinase inhibitor SU11248 in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) refractory to imatinib mesylate. Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;814. (Abstr. 3273).
33. Raymond E., Faivre S., Vera K., Delbaldo C., Robert C., Spatz A., Bello C., Brega N., Scigalla P., Armand J.P. Final results of a phase I and pharmacokinetic study of SU11248, a novel multi-target tyrosine kinase inhibitor, in patients with advanced cancers. Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;192. (Abstr. 769).
34. Hennequin L.F., Stokes E.S.E., Thomas A.P., Johnstone C., Ple P.A., Ogilvie D.J., Dukes M., Wedge S.R., Kendrew J., Curwen J.O. Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. J. Med. Chem. 45:2002;1300-1312.
35. Wedge S.R., Ogilvie D.J., Dukes M., Kendrew J., Chester R., Jackson J.A., Boffey S.J., Valentine P.J., Curwen J.O., Musgrove H.L., Graham G.A., Hughes G.D., Thomas A.P., Stokes E.S.E., Curry B., Richmond G.H.P., Wadsworth P.F., Bigley A.L., Hennequin L.F. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 62:2002;4645-4655.
36. Ciardiello F., Caputo R., Damiano V., Caputo R., Troiani T., Vitagliano D., Carlomagno F., Veneziani B.M., Fontanini G., Bianco A.F., Tortora G. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin. Cancer Res. 9:2003;1546-1556.
37. Hurwitz H.I., Eckhardt S.G., Holden S.N.et al. A phase I study of ZD6474, an oral VEGF receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin. Cancer Res. 7:2001;36545. (Suppl., Abstr. 5).
38. Minami H., Ebi H., Tahara M., Sasaki Y., Yamamoto N., Yamada Y., Tamura T., Saijo N. A phase I study of an oral VEGF receptor tyrosine kinase inhibitor ZD6474, in Japanese patients with solid tumors. Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;197. (Abstr. 778).
39. Dancey J., Sausville E.A. Issues and progress with protein kinase inhibitors for cancer treatment. Nat. Rev., Drug Discov. 2:2003;296-313.
40. Bold G., Altmann K.-H., Frei J., Lang M., Manley P.W., Traxler P., Wietfeld B., Buchdunger E., Cozens R., Ferrari S., Furet P., Hofmann F., Martiny-Baron G., Mestan J., Rösel J., Sills M., Stover D., Acemoglu F., Boss E., Emmenegger R., Lässer L., Masso E., Roth R., Schlachter C., Vetterli W., Wyss D., Wood J.M. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J. Med. Chem. 43:2000;2310-2323.
41. Bold G., Frei J., Furet P., Manley P.W., Brüggen J., Cozens R., Ferrari S., Hofmann F., Martiny-Baron G., Mestan J., Meyer T., Wood J.M. CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Future. 27:2002;43-55.
42. Wood J.M., Bold G., Buchdunger E., Cozens R., Ferrari S., Frei J., Hofmann F., Mestan J., Mett H., O'Reilly T., Persohn E., Rösel J., Schnell C., Stover D., Theuer A., Towbin H., Wenger F., Woods-Cook K., Menrad A., Siemeister G., Schirner M., Thierauch K.-H., Schneider M.R., Drevs J., Martiny-Baron G., Totzke F., Marmé D. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 60:2000;2178-2189.
43. Drevs J., Mross K., Fuxius S., Müller M., Dugan M., Peng B., Chong J., Henry A., Laurent D., Putz B., Marmé D., Unger C. A Phase-1 dose-escalating and pharmacokinetic (PK) study of the VEGF-receptor-inhibitor PTK787/ZK222584 (PTK/ZK) in patients with liver metastasis of advanced cancer. Proc.-Am. Soc. Clin. Oncol., Meet. 20:2001;100a. (Abstr. 398).
44. George D., Michaelson D., Oh W.K., Reitsma D., Laurent D., Mietlowski W., Wang Y., Dugan M., Kaelin W.G., Kantoff P. A Phase I study of PTK787/ZK 222584 (PTK/ZK) in metastatic renal cell carcinoma. Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;385. (Abstr. 1548).
45. Reardon D., Friedman H.S., Yung W.K.A., Brada M., Conrad C., Provenzale J., Jackson E.F., Serajuddin H., Laurent D., Reitsma D. A phase I trial of PTK787/ZK 222584 (PTK/ZK), an oral VEGF tyrosine kinase inhibitor, in combination with either temozolomide or lomustine for patients with recurrent glioblastoma multiforme (GBM). Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;103. (Abstr. 412).
46. Steward W.P., Thomas A.L., Morgan B., Wiedenmann B., Bartel C., Vanhoefer U., Trarbach T., Riedel U., Laurent D., Reitsma D. Extended phase I study of the oral vascular endothelial growth factor (VEGF) receptor inhibitor PTK787/ZK 222584 in combination with oxaliplatin/5-fluorouracil (5-FU)/leucovorin as first line treatment for metastatic colorectal cancer. Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;274. (Abstr. 1098).
47. Trarbach T., Schleucher N., Riedel U., Tewes M., Suppart C., Reitsma D., Seeber S., Laurent D., Vanhoefer U. Phase I study of the oral vascular endothelial growth factor (VEGF) receptor inhibitor PTK787/ZK 222584 (PTK/ZK) in combination with irinotecan/5-fluorouracil/leucovorin in patients with metastatic colorectal cancer. Proc.-Am. Soc. Clin. Oncol., Meet. 22:2003;285. (Abstr. 1144).
48. Thomas A.L., Morgan B., Drevs J., Unger C., Weidenmann B., Vanhoefer U., Laurent D., Dugan M., Steward W.P. Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. Semin. Oncol. 30:2003;32-38.
49. Drevs J., Muller-Driver R., Wittig C., Fuxius S., Esser N., Hugenschmidt H., Konerding M.A., Allegrini P.R., Wood J., Hennig J., Unger C., Marmé D. PTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging. Cancer Res. 62:2002;4015-4022.
50. Morgan B., Thomas A.L., Drevs J., Hennig J., Buchert M., Jivan A., Horsfield M.A., Mross K., Ball H.A., Lee L., Mietlowski W., Fuxius S., Unger C., O'Byrne K., Henry A., Cherryman G.R., Laurent D., Dugan M., Marmé D., Steward W.P. Dynamic contrast enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 21:2003;3955-3964.
51. Manning G., Whyte D.B., Martinez R., Hunter T., Sudarsanam S. The protein kinase complement of the human genome. Science. 298:2002;1912-1916.
52. Manley P., Furet P. Prospects for anti-angiogenic therapies based upon VEGF inhibition, in anticancer agents: frontiers in cancer chemotherapy. Ojima I., Vite G., Altmann K. ACS Symposium Series. vol. 796:2001;282-298 American Chemical Society, Washington, DC.
53. Furet P., Bold G., Hofmann F., Manley P., Meyer T., Altman K.-H. Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching. Bioorg. Med. Chem. Lett. 13:2003;2967-2971.
54. Kort W.J., Zondervan P.E., Hulsman L.O., Wiejma I.M., Westbroek D.L. Light-dark shift stress, with special reference to spontaneous tumour incidence in female rats. J. Natl. Cancer Inst. 76:1986;439-446.
55. Hendrix M.J.C., Seftor E.A., Hess A.R., Seftor R.E.B. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat. Rev., Cancer. 3:2003;411-421.
56. McTigue M.A., Wickersham J.A., Pinko C., Shoewalter R.E., Parast C.V., Tempczyk-Russell A., Gehring M.R., Mroczkowski B., Chen-Chen K., Villafranca J.E., Krzysztof A. Crystal structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis. Structure. 7:1999;319-330.
57. Hubbard S.R., Wei L., Ellis L., Hendrikson W.A. Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature. 372:1994;746-754.
58. Huse M., Kuriyan J. The conformational plasticity of protein kinases. Cell. 109:2002;275-282.
59. Nagar B., Bornmann W.G., Pellicena P., Schindler T., Veach D.R., Miller W.T., Clarkson B., Kuriyan J. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). J. Cancer Res. 62:2002;4236-4243.
60. Pargellis C., Tong L., Churchill L., Cirillo P.F., Gilmore T., Graham A.G., Grob P.M., Hickey E.R., Moss N., Pav S., Regan J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat. Struct. Biol. 9:2002;268-272.
61. Klement G., Baruchel S., Rak J., Man S., Clark K., Hicklin D.J., Bohlen P., Kerbel R.S. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105:2000;R15-R24.