In recent years, it has become increasingly apparent that proteins regulated by activated oncogenes or mutated tumor suppressor genes are responsible for the transformation of normal cells to malignant cells as well as for malignant characteristics such as uncontrolled cellular proliferation and the development of metastases. These proteins may be soluble factors, receptors on cell surfaces, or intracellular enzymes that produce signals that stimulate cellular development or proliferation. This process is called signal transduction.In many cases, increased amounts of these proteins have been demonstrated in cancer cells (over normal cells) and have been found to carry prognostic significance. New approaches in cancer treatment are being designed to block such proteins; this approach is termed signal transduction inhibition. !Specific protein targets that anticancer therapies have been developed to inhibit include epidermal growth factor receptors, tyrosine kinase, farnesyl transferase, and various promoters of angiogenesis.
Waksal HW. Role of an anti-epidermal growth factor receptor in treating cancer. Cancer Metastasis Rev. 1999;18:427-436.
2.
Schlessinger J.Cell signaling by receptor tyrosine kinases. Cell. 2000;103:211-225.
3.
Simon MA. Receptor tyrosine kinases: specific outcomes from general signals. Cell. 2000;103:13-15.
4.
Salomon DS, Brandt R, Ciardiello F, Normanno N.Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183-232.
5.
Coffey RJ, McCutchen CM, Graves-Deal R, Polk WH. Transforming growth factors and related peptides in gastrointestinal neoplasia. J Cell Biochem. 1992;16(suppl):111-118.
6.
Tahara E.Growth factors and oncogenes in human gastrointestinal carcinomas. J Cancer Res Clin Oncol. 1990;116:121-131.
7.
Aaronson SA. Growth factors and cancer. Science. 1991;254: 1146-1153.
8.
Mayer A, Takimoto M, Fritz E, Schellander G, et al. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer. 1993;71:2454-2460.
9.
Karameris A, Kanavaros P, Aninos D, et al. Expression of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) in gastric and colorectal carcinomas: an immunohistological study of 63 cases. Pathol Res Pract. 1993;189:133-137.
10.
Mendelsohn J.Epidermal growth factor receptor as a target for therapy with antireceptor monoclonal antibodies. J Natl Cancer Inst Monogr. 1992;13:125-131.
11.
Ennis BW, Lippman ME, Dickson RB. The EGF receptor system as a target for antitumor therapy. Cancer Invest. 1991;9:553-562.
Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J.Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in human tumor xenograft model. Clin Cancer Res. 1995;1:1311-1318.
14.
Prewett M, Rockwell P, Rose C, Zuklys K, Goldstein NI. Altered cell cycle distribution and cyclin-CDK protein expression in A431 epidermoid carcinoma cells treated with doxorubicin and a chimeric monoclonal antibody to the epidermal growth factor receptor. Mol Cell Differ. 1996;4:167-186.
15.
Prewett M, Rockwell, Rose C, Goldstein NI. Antitumor and cell cycle responses in KB cells treated with a chimeric anti-EGFR monoclonal antibody in combination with cisplatin. Int J Oncol. 1996;9:217-224.
16.
Ciardiello F, Bianco R, Damiano V, et al. Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res. 1999;5:909-916.
17.
Kim YB, Perrotte P, Matsumoto T, Tsan R, Dinney CPN, Radinski R.Immunochemotherapy of human transitional cell carcinoma (TCC) with anti-EGF-R monoclonal antibody (Mab) C225 and the anti-cancer drugs, Taxol® and cisplatinum [abstract]. Proc Am Assoc Cancer Res. 1998;39:64.
18.
Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 1999;59:1935-1940.
19.
Bruns CJ, Portera CA, Tsan R, Hicklin DJ, Radinsky R.Regression of human pancreatic carcinoma growth orthotopically in athymic nude mice by blockade of epidermal growth factor receptor (EGF-R) signaling in combination with gemcitabine [abstract]. Proc Am Assoc Cancer Res. 1999;40:23.
20.
Fan Z, Baselga J, Masui H, Mendelsohn J.Antitumor effects of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res. 1993;53:4637-4642.
21.
Fisher-Colbrie J, Witt A, Hinzl H, et al. EGFR and steroid receptors in ovarian carcinoma: comparison with prognostic parameters and outcome of patients. Anticancer Res. 1997;17:613-620.
22.
Prewett M, Hooper A, Bassi R, Ellis LM, Waksal H, Hicklin DJ. Growth inhibition of human colorectal carcinoma xenografts by anti-EGF receptor monoclonal antibody IMC-C225 in combination with irinotecan. Proc Am Assoc Cancer Res. 2001:42a.
23.
Ciardiello F, Damiano V, Bianco C, Fontanini G, et al. Antitumour activity of combined blockade of epidermal growth factor receptor and protein kinase A. J Natl Cancer Inst. 1996; 88:1170-1176.
24.
Petit AMV, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and erbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo. Am J Pathol. 1997;151:1523-1530.
25.
Perrotte P, Matsumoto T, Inoue K, et al. Antiepidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 1999;5:257-265.
26.
Bruns CJ, Hargison MT, Davis DW, et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res. 2000;6:1936-1948.
27.
Milas L, Mason K, Hunter N, et al. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res. 2000;6:701-708.
28.
Rubin MS, Shin DM, Pasmantier M, et al. Monoclonal antibody (MoAb) IMC-C225, an anti-epidermal growth factor receptor (EGFr), for patients (pts) with EGFr-positive tumors refractory to or in relapse from previous therapeutic regimens. Proc Am Soc Clin Oncol. 2000;19:474a.
29.
Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol. 2001;20.
30.
Mendelsohn J, Shin DM, Donato N, et al. A phase I study of chimerized anti-epidermal growth factor receptor (EGFr) monoclonal antibody, C225 in combination with cisplatin (CDDP) in patients (pts) with recurrent head and neck squamous cell carcinoma (SCC). Proc Am Soc Clin Oncol. 1999;18:389a.
31.
Robert F, Ezekiel MP, Spenser SA, et al. Phase I study of antiepidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol. 2001;19:3234-3243.
32.
Cohen RB, Falceyh JW, Paulter V, Fetzer KM, Waksal HW. Safety profile of the monoclonal antibody (MoAb) IMC-C225, an antiepidermal growth factor receptor (EGFr) used in the treatment of EGFr-positive tumors. Proc Am Soc Clin Oncol. 2000;19;474a.
33.
Figlin RA, Belldegrun A, Lohner ME. ABX-EGF: a fully humanized anti-EGF receptor antibody in patients with advanced cancer [abstract]. Proc Am Soc Clin Oncol. 2001;20:276a.
34.
Pfister DG, Lipton A, Belt R, et al. A phase I trial of the epidermal growth factor receptor (EGFR)-directed bispecific antibody (BsAB) MDX-447 in patients with solid tumors [abstract]. Proc Am Soc Clin Oncol. 1999;18:433.
35.
Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily. Drugs2000;59:753-767.
Klohs WD, Fry DW, Kraker AJ. Inhibitors of tyrosine kinase. Curr Opin Oncol. 1997;9:562-568.
38.
Ciardiello F, Caputo R, Bianco R, et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 2000;6:2053-2063.
39.
Ciardiello F, Caputo R, Bianco R, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD 1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res. 2001;7:1459-1465.
40.
Sirotnak F, Zakowsky M, Miller V.Potentiation of cytotoxic agents against human tumors in mice by ZD 1839 (Iressa™, an inhibitor of EGFR tyrosine kinase, does not require high levels of expression of EGFR [abstract]. Proc Am Soc Cancer Res. 2000;41:482.
41.
Nakagawa K, Yamamoto N, Kudoh S, et al. A phase I intermittent dose-escalation trial of ZD1839 (Iressa) in Japanese patients with solid malignant tumours [Abstract]. Proc Am Soc Clin Oncol. 2000;19:183a.
42.
Negoro S, Nakagawa K, Fukouka M, et al. Final results of a phase I intermittent dose-escalation trial of ZD1839 (‘Iressa’) in Japanese patients with various solid tumours [abstract]. Proc Am Soc Clin Oncol. 2001;20:324a.
43.
Ferry D, Hammond L, Ranson M, et al. Intermittent oral AD 1839 (Iressa), a novel oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), shows evidence of good tolerability and activity: final results from a phase I study. Proc Am Soc Clin Oncol. 2000;19:3a.
44.
Baselga J, Herbst R, LoRusso P, et al. Continuous administration of ZD1839 (Iressa), a novel oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected tumor types: evidence of activity and good tolerability [abstract]. Proc Am Soc Clin Oncol. 2000;19:177A.
45.
Pollack V, Savage D, Baker D, et al. Therapy of human carcinomas in athymic mice by inhibition of EGF receptor-mediated signal transduction with CP-358774: dynamics of receptor inhibition and anti-tumor effects [abstract]. Proc Am Assoc Cancer Res. 1997;38:633.
46.
Hammond LA, Denis LJ, Salman UA, et al. 18FDG-PET evaluation of patients treated with the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor, CP-358,774 [abstract]. Clin Cancer Res. 2000;6(suppl):4543s.
47.
Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001;19:3267-3279.
48.
Perez-Soler R, Chachoua A, Huberman M, et al. A phase II trial of the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients with advanced, EGFR-expressing, non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol. 2001;20:310.
49.
Finkler N, Gordon A, Crozier M, et al. Phase 2 evaluation of OSI-774, a potent oral antagonist of the EGFR-TK in patients with advanced ovarian cancer [abstract]. Proc Am Soc Clin Oncol. 2001;20:208.
50.
Senzer NN, Soulieres D, Siu L, et al. Phase 2 evaluation of OSI-774, a potent oral antagonist of the EGFR-TK in patients with advanced squamous cell carcinoma of the head and neck [abstract]. Proc Am Soc Clin Oncol. 20:2.
51.
Kohl NE, Wilson FR, Mosser SD, et al. Protein farnesyl transferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci U S A. 1994;91:9141-9145.
52.
Gibbs JB, Oliff A.The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Ann Rev Pharmacol Toxicol. 1997;37:143-166.
53.
Cooper MR. Novel noncytotoxic anticancer agents: signal transduction inhibitors. In: Perry MC, ed. American Society of Clinical Oncology Educational Book 1998. Alexandria, Va: Am Soc Clin Oncol. 1998;118-125.
54.
Moasser MM, Sepp-Lorenzino, Kohl NE, et al. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to Taxol and epothilones. Proc Natl Acad Sci U S A1998;95:1369-1374.
55.
Schellens JHM, de Klerk G, Swart M, et al. Phase I and pharmacologic study with the novel farnesyltransferase inhibitor (FTI) R115777 [abstract]. Proc Am Soc Clin Oncol. 2000;19:184a. Abstract 715.
56.
Johnston SR, Ellis PA, Houston S, et al. A phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced breast cancer [abstract]. Proc Am Soc Clin Oncol. 2000 Abstract 19:83a.
57.
Patnaik A, Eckhardt SG, Izbicka E, et al. A phase I and pharmacokinetic (PK) study of the farnesyltransferase inhibitor, R115777 in combination with gemcitabine [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:5a.
58.
Piccart-Gebhart M, Branle F, de Valeriola D, et al. A phase I, clinical and pharmacokinetic (PK) trial of farnesyl transferase inhibitor (FTI) R115777 + docetaxel: a promising combination in patients (PTS) with solid tumors [abstract]. Proc Am Soc Clin Oncol. 2001;20:80a.
59.
Liebes L, Hochster H, Speyer J, et al. Enhanced myelo-suppression of topotecan when combined with the farnesyl transferase inhibitor, R115777: a phase I &pharmacodynamic study [abstract]. Proc Am Soc Clin Oncol. 2001;20:81a.
60.
Lancet JE, Rosenblatt JD, Liesveld JL, et al. Use of a farnesyl transferase inhibitor R115777 in relapsed and refractory acute leukemias: preliminary results of a phase I trial [abstract]. Proc Am Soc Clin Oncol. 2000;14:3a. Abstract 5B.
61.
Sonnichsen D, Damle B, Manning J, et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of the farnesyltransferase (FT) inhibitor BMS-214662 in patients with advanced solid tumors [abstract]. Proc Am Soc Clin Oncol. 2000;19:178a. Abstract 691.
62.
Kim KB, Shin DM, Summey C, et al. Phase I study of farnesyl transferase inhibitor, BMS-214662 in solid tumors [abstract]. Proc Am Soc Clin Oncol. 2001;20:79a.
63.
Ryan DP, Eder JP, Supko JG, et al. Phase I clinical trial of the farnesyltransferase (FT) inhibitor BMS-214662 in patients with advanced solid tumors [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:185a.
64.
Morgan DO. Principles of Cdk regulation. Nature. 1995;374:131-134.
65.
Senderowicz AM, Messmann R, Arbuck S, et al. A phase I trial of 1 hour infusion of flavopiridol (FLA), a novel cyclin-dependent kinase inhibitor, in patients with advanced neoplasms [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:204a.
66.
Dees EC, O’Reilly S, Figg WD, et al. A phase I and pharmacologic study of UCN-01, a protein kinase C inhibitor [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:205a.
67.
Crooke ST, Lebleu B.Antisense Research and Applications. Boca Raton, Fla: CRC Press; 1993.
68.
Helene C.Control of oncogene expression by antisense nucleic acids. Eur J Cancer. 1994;30A:1721-1726.
69.
Waters JS, Webb A, Cunningham D, et al. Phase I clinical and pharmacokinetic study of Bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2000;18:1812-1823.
70.
O’Dwyer PJ, Stevenson JP, Gallagher M, et al. C-raf-1 depletion and tumor responses in patients treated with the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A). Clin Cancer Res. 1999;5:3977-3982.
71.
Stevenson JP, DeMaria D, Reilly D, et al. Phase I/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule. Cancer Chemother Pharmacol. 1999;44: 228-234.
72.
Nemunaitis H, Holmlund JT, Kraynak M, et al. Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer. J Clin Oncol. 1999;17:3586-3595.
73.
Bishop MR, Iversen PL, Bayever E, et al. Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies. J Clin Oncol. 1996;14:1320-1326.
74.
Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994;124:1-6.
75.
Kitada S, Miyashita T, Tanaka S, et al. Investigations of antisense oligonucleotides targeted against bcl-2 RNAs. Antisense Res Dev. 993;3:157-169.
76.
Yuen A, Advani R, Fisher G, et al. A phase I/II trial of ISIS 3521, an antisense inhibitor of protein kinase C alpha combined with carboplatin and paclitaxel in patients with non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:459a.
77.
Yuen A, Halsey J, Fisher G, et al. Phase I/II trial of ISIS 3521, an antisense inhibitor of PKC-alpha, with carboplatin and paclitaxel in non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol. 2001;20:309a.
78.
Chen HX, Marshall JL, Trocky N, et al. A phase I study of BCL-2 antisense G3139 (GENTA) and weekly docetaxel in patients with advanced breast cancer and other solid tumors [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:178a.
79.
Scher HI, Morris MJ, Tong WP, et al. A phase I trial of G3139 (Genta, Inc), a BCL2 antisense drug, by continuous infusion (CI) as a single agent and with weekly Taxol (T) [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:199a.
80.
Chi KN, Gleave ME, Klasa R, et al. A phase I trial of an antisense oligonucleotide to BCL-2 (G3139, Genta) and mitoxantrone in patients with metastatic hormone refractory prostate cancer (HRPC) [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:330a.
81.
Folkman J.What is the evidence that tumours are angiogenesis dependent?J Natl Cancer Inst. 1990;82:4-6.
82.
Tannock IF. The relationship between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer. 1968;22:258-273.
83.
Weidner N.Current pathological methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breast Cancer Res Treat. 1996;36:169-180.
84.
Horak ER, Leek R, Klenk N, et al. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastasis and survival in breast cancer. Lancet. 1992;340:1120-1124.
85.
Brawer MK, Deering RE, Brown M, et al. Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer. 1994;73:678-687.
86.
Lindmark G, Gerdin B, Sundberg C, et al. Prognostic significance of the microvascular count in colorectal cancer. J Clin Oncol. 1996;14:461-466.
87.
Macchiarini P, Fontanini G, Dulment E, et al. Relation of neovascularisation to metastasis of non-small cell lung cancer. Lancet. 1992;340:145-146.
88.
Li VW, Folkerth RD, Watanabe H.Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumours. Lancet1994;344:82-86.
89.
Hayes AJ, Li LY, Lippman ME. Antivascular therapy: a new approach to cancer treatment. BMJ. 1999;318:853-856.
90.
Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes the accumulation of ascites fluid. Science. 1983;219:983-985.
91.
Senger DR, Perruzzi CA, Feder J, Dvorak HS. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986;46:5629-5632.
92.
Nguyen M, Watanabe H, Budson AE, et al. Elevated levels of an angiogenic peptide, basic fibroblasts growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst. 1994;86:356-361.
93.
Harris AL. Antiangiogenesis for cancer therapy. Lancet. 1997;349(suppl II):13-15.
94.
Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994;79:185-188.
95.
Parangi S, O’Reilly M, Christofori G, et al. Antiangiogenic therapy of transgenic mice impairs de-novo tumor-growth. Proc Natl Acad SciUSA. 1996;93:2002-2007.
96.
Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis supresses tumour growth in vivo. Nature. 1993;362:841-844.
97.
Czubayko F, Liaudet-Coopman ED, Aigner A, Tuverson AT, Berchem GH, Wellstein A.A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. Nature Med. 1997;3:1137-1140.
98.
Rosen LS, Kabbinavar F, Rosen P, et al. Phase I trial of SU5416 a novel angiogenesis inhibitor in patients with advanced malignancies [abstract]. Proc Am Soc Clin Oncol. 1998;17:843.
99.
Gordon MS, Talpaz M, Margolin E, et al. Phase I trial of recombinant humanized anti vascular endothelial growth factor in patients with metastatic cancer [abstract]. Proc Am Soc Clin Oncol. 1998;17:908.
100.
Sledge G, Miller K, Novotny W, et al. A phase II trial of single-agent Rhumab VEGF (recombinant humanized monoclonal antibody to vascular endothelial growth factor) in patients with relapsed metastatic breast cancer [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:3a.
101.
Bergsland E, Hurwitz H, Fehrenbacher L, et al. A randomized phase II trial comparing rhuMAb VEGF (recombinant humanized monoclonal antibody to vascular endothelial cell growth factor) plus 5-fluorouracil/leucovorin (FU/LV) to FU/LV alone in patients with metastatic colorectal cancer [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:242a.
102.
DeVore RF, Fehrenbacher L, Herbst RS, et al. A randomized phase II trial comparing Rhumab VEGF (recombinant humanized monoclonal antibody to vascular endothelial cell growth factor) plus carboplatin/paclitaxel (CP) to CP alone in patients with stage IIIB/IV NSCLC [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:485a.
103.
Stopeck A.Results of a phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 802.
104.
O’Donnell AE, Trigo JM, Udai B, et al. A phase I trial of the VEGF inhibitor SU5416, incorporating dynamic contrast MRI assessment of vascular permeability [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:177a.
105.
Miles, S, Arasteh K, Gill P, et al. A multicenter dose-escalating study of SU5416 in AIDS-related Kaposi’s sarcoma [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:176a.
106.
Rosen PJ, Amado R, Hecht JR, et al. A phase I/II study of SU5416 in combination with 5-FU/leucovorin in patients with metastatic colorectal cancer [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:3a.
107.
O’Reilly MS, Holmgren L, Chen C, Folkman J.Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med. 1996;2:689-692.
108.
O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997; 88:277-285.
109.
Boehm T, Folkman J, Browder T, et al. Antiangiogenic therapy of experimental cancer does not induce drug resistance. Nature. 1997;390:404-407.
110.
Kuska M, Sudo K, Matsutani E, et al. Cytostatic inhibition of endothelial cell growth by the angiogenesis inhibitor TNP-470 (AG-1470). Br J Cancer. 1994;69:212-216.
111.
Bhargava P, Rizvi N, Baidas S, et al. Phase I study and assessment of bioactivity of 120-hour infusion of TNP-470 in patients with advanced cancer [abstract]. Proc Am Soc Clin Oncol. 2000; Abstract 19:176a.
112.
Dezube BJ, von Roenn JH, Holden-Wiltase J, et al. Fumagillin analog in the treatment of Kaposi’s sarcoma: a phase I AIDS Clinical Trial Group study-AIDS Clinical Trial Group No. 215 Team. J Clin Oncol. 1998;16:1444-1449.
113.
Kudelka AP, Levy T, Verschraegen CF, et al. A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix. Clin Cancer Res. 1997;3:1501-1505.
114.
Bhargava P, Marshall J, Rizvi N, et al. A study of TNP-470 in patients with advanced cancer [abstract]. Proc Am Assoc Cancer Res. 1997;38:1489.
115.
Stadler WM, Kuzel T, Shapiro CL, et al. Multi-institutional study of the angiogenesis inhibitor TNP-470 in metastatic renal cell carcinoma. J Clin Oncol. 1999;17:2541-2545.
116.
Fontanini G, DeLaurentiis M, Vignati S, et al. Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. Clin Cancer Res. 1998;4:241-249.
117.
Fujino S, Enokibori T, Tezuka N, et al. A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-small cell lung cancer. Eur J Cancer. 1996;32:2070-2074.
118.
Klijn JG, Berns PM, Schmitz PI, et al. The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients. Endocr Rev. 1992;13:3-17.
119.
Walker RA, Dearing SJ. Expression of epidermal growth factor receptor mRNA and protein in primary breast carcinomas. Breast Cancer Res Treat. 1999;53:167-176.
120.
Beckman MW, Niederacher D, Massenkeil G, et al. Expression analyses of epidermal growth factor receptor and HER-2/neu: no advantage of prediction of recurrence or survival in breast cancer patients. Oncology. 1996;53:441-447.
121.
Bucci B, D’Angnano I, Botti C, et al. EGF-R expression in ductal breast cancer: proliferation and prognostic implications. Anticancer Res. 1997;17:769-774.
122.
Grandis JR, Melhem MF, Barnes EL, et al. Quantitative immunohistochemical analysis of transforming growth factor α and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer. 1996; 78:1284-1292.
123.
Messa C, Russo F, Caruso MG, et al. EGF, TGF α, and EGF-R in human colorectal adenocarcinoma. Acta Oncol. 1998; 37:285-289.
124.
Bartlett JM, Langdon SP, Simpson BJ, et al. The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer. Br J Cancer. 1996;73:301-306.
