Epidermal growth factor in clinical practice - A review of its biological actions, clinical indications and safety implications

International Wound Journal

Volumn 6, Issue 5, 2009, Pages 331-346

  Berlanga Acosta, Jorge ^a   Gavilondo Cowley, Jorge ^a   López Saura, Pedro ^b   González López, Tania ^b   Castro Santana, María D ^a   López Mola, Ernesto ^a   Guillén Nieto, Gerardo ^a   Herrera Martinez, Luis ^a  

^a CENTER FOR GENETIC ENGINEERING AND BIOTECHNOLOGY   (Cuba)

^b Center for Biological Research Cuba   (Cuba)

Author keywords

Cancer; EGF; Malignant; Ulcers; Wounds

Indexed keywords

AMPHIREGULIN; BETACELLULIN; EPIDERMAL GROWTH FACTOR; EPIREGULIN; FIBROBLAST GROWTH FACTOR; GROWTH FACTOR; SULFADIAZINE SILVER; TRANSFORMING GROWTH FACTOR; TRANSFORMING GROWTH FACTOR BETA;

BIOLOGICAL ACTIVITY; BURN; BURN PATIENT; CANCER GROWTH; CANCER INCIDENCE; CARCINOGENESIS; CELL DIFFERENTIATION; CLINICAL PRACTICE; CLINICAL TRIAL; CONTINUOUS INFUSION; CUBA; DIABETIC FOOT; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG EXPOSURE; DRUG INDICATION; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; DUODENUM ULCER; FOLLOW UP; GASTROINTESTINAL DISEASE; HEMORRHAGIC CYSTITIS; HUMAN; HYPERPLASIA; INCIDENCE; INTESTINE ISCHEMIA; LONG TERM CARE; MEDLINE; MICROVILLOUS ATROPHY; NECROTIZING ENTEROCOLITIS; NEOPLASM; NONHUMAN; PATIENT SELECTION; PHENOTYPE; PHYSICAL DISABILITY; PRIORITY JOURNAL; REVIEW; RISK BENEFIT ANALYSIS; SHORT BOWEL SYNDROME; SOCIAL DISABILITY; STOMACH ULCER; STOMATITIS; TISSUE REPAIR; ULCER; WOUND; WOUND HEALING; ZOLLINGER ELLISON SYNDROME;

ANIMALS; CARCINOGENICITY TESTS; DISEASE MODELS, ANIMAL; EPIDERMAL GROWTH FACTOR; HUMANS; RECEPTOR, EPIDERMAL GROWTH FACTOR; WOUND HEALING;

EID: 73349135952     PISSN: 17424801     EISSN: 1742481X     Source Type: Journal    
DOI: 10.1111/j.1742-481X.2009.00622.x     Document Type: Review

References (114)

1. Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the newborn animal. J Biol Chem 1962 237 : 1555 1562.
2. Scott J, Urdea MS, Quiroga M, Sánchez-Pescador R, Fong N, Selby M, Rutter WJ, Bell GI. Structure of a mouse submaxillary messenger RNA encoding epidermal growth factor and seven related proteins. Science 1983 221 : 236 240.
3. Bennet N, Schultz G. Growth factors and wound healing: biochemical properties of growth factors and their receptors. Am J Surg 1993 165 : 728 737. (Pubitemid 23281403)
4. Pusztai L, Lewis CE, Lorenzen J, McGee JOD. Review article-Growth factors: regulation of normal and neoplastic growth. J Pathol 1993 169 : 191 201.
5. Tannock IF, Rotin D. Acidic pH in tumors and its potential for therapeutic exploitation. Cancer Res 1989 49 : 4373 4384.
6. Davis MD, Weed B, Felty CL, Rooke T. Treatment of recalcitrant lower extremity ulcers with topical becaplermin. J Am Acad Dermatol 2004 50 : 981 982.
7. Embil JM, Papp K, Sibbald G, Tousignant J, Smiell JM, Wong B, Lau CY. Recombinant human platelet-derived growth factor-BB (becaplermin) for healing chronic lower extremity diabetic ulcers: an open-label clinical evaluation of efficacy. Wound Repair Regen 2000 8 : 162 168.
8. Takehara K. Growth regulation of skin fibroblasts. J Dermatol Sci 2000 24 (Suppl 1 S70 7.
9. Mast BA, Schultz GS. Interactions of cytokines, growth factors and proteases in acute and chronic wounds. Wound Repair Regen 1996 4 : 411 420.
10. Lerman OZ, Galiano RD, Armour M, Levine JP, Gurtner GC. Cellular dysfunction in the diabetic fibroblast. Impairment in migration, vascular endothelial growth factor production, and response to hypoxia. Am J Pathol 2003 162 : 303 312.
11. Doxey DL, Ng MC, Dill RE, Iacopino AM. Platelet-derived growth factor levels in wounds of diabetic rats. Life Sci 1995 57 : 1111 1123.
12. Werner S, Breeden M, Hubner G, Greenhalgh DG, Longaker MT. Induction of keratinocyte growth factor expression is reduced and delayed during wound healing in the genetically diabetic mouse. J Invest Dermatol 1994 103 : 469 473.
13. Mansbridge JN, Liu K, Pinney RE, Patch R, Ratcliffe A, Naughton GK. Growth factors secreted by fibroblasts: role in healing diabetic foot ulcers. Diabetes Obes Metab 1999 1 : 265 279.
14. Portero-Otín M, Pamplona R, Bellmunt MJ, Ruiz MC, Prat J, Salvayre R, Nègre-Salvayre A. Advanced glycation end product precursors impair epidermal growth factor receptor signaling. Diabetes 2002 51 : 1535 1542.
15. Berlanga J, Cibrian D, Guillen I, Freyre F, Alba JS, Lopez-Saura P, Merino N, Aldama A, Quintela AM, Ajamieh H, Urquiza D, Ahmed N, Thornalley P. Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds. Clin Sci (Lond) 2005 109 : 83 95.
16. Hansen SL, Young DM, Boudreau NJ. HoxD3 expression and collagen synthesis in diabetic fibroblasts. Wound Repair Regen 2003 11 : 474 480.
17. Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity ulcers. Plast Reconstr Surg 2006 117 (suppl 7 143S 9S.
18. Tsang MW, Wong WK, Hung CS, Lai KM, Tang W, Cheung EY, Kam G, Leung L, Chan CW, Chu CM, Lam EK. Human epidermal growth factor enhances healing of diabetic foot ulcers. Diabetes Care 2003 26 (6 1856 1861.
19. Hong JP, Jung HD, Kim YW. Recombinant human epidermal growth factor (EGF) to enhance healing for diabetic foot ulcers. Ann Plast Surg 2006 56 : 394 398.
20. Hanft JR, Pollak RA, Barbul A, van Gils C, Kwon PS, Gray SM, Lynch CJ, Semba CP, Breen TJ. Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers. J Wound Care 2008 17 : 30 2, 34 7.
21. Driver VR, Hanft J, Fylling CP, Beriou JM, Autologel Diabetic Foot Ulcer Study Group. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage 2006 52 : 68 70.
22. Zaulyanov L, Kirsner RS. A review of a bi-layered living cell treatment (Apligraf) in the treatment of venous leg ulcers and diabetic foot ulcers. Clin Interv Aging 2007 2 : 93 8.
23. Brown LG, Nanney BL, Griffen J, Cramer AB, Yancey JM, Curtsinger LJ, Holtzin L, Schultz GS, Jurkiewicz MJ, Lynch JB. Enhancement of wound healing by topical treatment with epidermal growth factor. N Engl J Med 1989 321 : 76 9.
24. Alert J, Rodríguez J, Lombardero J, Pírez R. Acción radioprotectora local del factor de crecimiento epidérmico humano recombinante: reporte preliminar. Interfer Biotecnol 1989 6 : 62 6.
25. Brown GL, Curtsinger L, Jurkiewicz MJ, Nahai F, Schultz G. Stimulation of healing of chronic wounds by epidermal growth factor. Plast Reconstr Surg 1991 88 : 189 194.
26. Falanga V, Eaglstein WH, Bucalo B, Katz MH, Harris B, Carson P. Topical use of human recombinant epidermal growth factor (h-EGF) in venous ulcers. J Dermatol Surg Oncol 1992 18 : 604 606.
27. Borges H, Martínez A, López LD, Ung Lu E, Gonzalez T, Lopez-Saura P. El Factor de Crecimiento Epidérmico humano recombinante acelera la cicatrización de quemaduras en niños. Estudio a doble ciegos. Biotecnol Apl 1994 11 : 205 209.
28. Cohen IK, Crossland MC, Garrett A, Diegelmann RF. Topical application of epidermal growth factor onto partial-thickness wounds in human volunteers does not enhance reepithelialization. Plast Reconstr Surg 1995 96 : 251 254.
29. Gonzalez T, Quiñones M, Labarta V, Fernandez M, Charles-Edouard D y Lopez-Saura P. Aplicación tópica de factor de crecimiento epidérmico humano recombinante en ulceras post-flebíticas Biotecnol Apl 1995 12 : 185 186.
30. Rodríguez J, Fernandez G, Gonzalez T, Castro MD, Hernández F, Díaz A y Lopez-Saura P. Uso del factor de crecimiento epidérmico humano recombinante en el tratamiento del acne Biotecnol Apl 1995 12 : 186 187.
31. Viswanathan V, Pendsey S, Sekar N, Murthy GSR. A phase III study to evaluate the safety and efficacy of recombinant human epidermal growth factor (REGEN-D™ 150) in healing diabetic foot ulcers. Wounds 2006 18 : 186 196.
32. Acosta JB, Savigne W, Valdez C, Franco N, Alba JS, del Rio A, López-Saura P, Guillén G, Lopez E, Herrera L, Férnandez- Montequín J. Epidermal growth factor intralesional infiltrations can prevent amputation in patients with advanced diabetic foot wounds. Int Wound J 2006 3 : 232 239.
33. Fernández-Montequín JI, Infante-Cristiá E, Valenzuela- Silva C, Franco-Pérez N, Savigne-Gutierrez W, Artaza-Sanz H, Morejón-Vega L, González-Benavides C, Eliseo-Musenden O, García-Iglesias E, Berlanga-Acosta J, Silva-Rodríguez R, Betancourt BY, López-Saura PA Cuban Citoprot-P Study Group. Intralesional injections of Citoprot-P (recombinant human epidermal growth factor) in advanced diabetic foot ulcers with risk of amputation. Int Wound J 2007 4 : 333 343.
34. Mohan VK. Recombinant human epidermal growth factor (REGEN-D 150): effect on healing of diabetic foot ulcers. Diabetes Res Clin Pract 2007 78 : 405 411.
35. Tabrizi MN, Chams-Davatchi C, Esmaeeli N, Noormohammadpoor P, Safar F, Etemadzadeh H, Ettehadi HA, Gorouhi F. Accelerating effects of epidermal growth factor on skin lesions of pemphigus vulgaris: a double-blind, randomized, controlled trial. J Eur Acad Dermatol Venereol 2007 21 : 79 84.
36. Fernández-Montequín JI, Betancourt BY, Leyva-Gonzalez G, Mola EL, Galán-Naranjo K, Ramírez-Navas M, Bermúdez-Rojas S, Rosales F, García-Iglesias E, Berlanga-Acosta J, Silva-Rodriguez R, Garcia-Siverio M, Martinez LH. Intralesional administration of epidermal growth factor-based formulation (Heberprot-P) in chronic diabetic foot ulcer: treatment up to complete wound closure. Int Wound J 2009 6 : 67 72.
37. Elder JB, Gillespie IE, Ganguli P, Delamore WI, Gregory H. Effect of urogastrone in the Zollinger-Ellison syndrome. Lancet 1975 306 : 424 425.
38. Koffman GG, Elder JB, Ganguli PC. Effect of urogastrone on gastric secretion and serum gastrin concentrations in patients with duodenal ulcerations. Gut 1982 23 : 951 956.
39. Walker-Smith JA, Phillips AD, Walford N, Gregory H, Fitzgerald JD, Maccullagh K, Wright NA. Intravenous epidermal growth factor/urogastrone increases small intestinal cells proliferation in the congenital microvillous atrophy. Lancet 1985 326 : 1239 1240.
40. Drumm B, Cutz E, Tomkins KB, Cook D, Hamilton R, Sherman P. Urogastrone/epidermal growth factor in treatment of congenital microvillous atrophy. Lancet 1988 331 : 111 112.
41. Sullivan PB, Brueton MJ, Tabara ZB, Goodlad RA, Lee CY, Wright NA. Epidermal growth factor in necrotizing enteritis. Lancet 1991 338 : 53 4.
42. Itoh M, Matsuo Y. Gastric ulcer treatment with intravenous human epidermal growth factor: a double-blind controlled clinical study. J Gastroenterol Hepatol 1994 9 (Suppl 1 S78 S83.
43. Haedo W, Gonzalez T, Mas JA, Franco S, Gra B, Soto G, Alonso A, López-Saura P. Oral human recombinant epidermal growth factor in the treatment of patients with duodenal ulcers. Rev Esp Enferm Apar Dig 1996 88 : 409 413.
44. Palomino A, Hernández-Bernal F, Haedo W, Franco S, Más JA, Fernández JA, Soto G, Alonso A, González T, López-Saura P. A multicenter, randomized, double-blind clinical trial examining the effect of oral human recombinant epidermal growth factor on the healing of duodenal ulcers. Scand J Gastroenterol 2000 35 : 1016 1022.
45. Sinha A, Nightingale J, West KP, Berlanga-Acosta J, Playford RJ. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 2003 349 : 350 357.
46. Sigalet DL, Martin GR, Butzner JD, Buret A, Meddings JB. A pilot study of the use of epidermal growth factor in pediatric short bowel syndrome. J Pediatr Surg 2005 40 : 763 768.
47. Sullivan PB, Lewindon PJ, Cheng C, Lenehan PF, Kuo BS, Haskins JR, Goodlad RA, Wright NA, de la Iglesia FA. Intestinal mucosa remodeling by recombinant human epidermal growth factor (1-48) in neonates with severe necrotizing enterocolitis. J Pediatr Surg 2007 42 : 462 469.
48. Yarden Y. The EGFR family and its ligands in human cancer: signaling mechanisms and therapeutic opportunities. Eur J Cancer 2001 37 (Suppl 4 3 8.
49. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006 7 : 505 516.
50. Canguilhem B, Pradines A, Baudouin C, Boby C, Lajoie-Mazenc I, Charveron M, Favre G. RhoB protects human keratinocytes from UVB-induced apoptosis through epidermal growth factor receptor signaling. J Biol Chem 2005 280 : 43257 43263.
51. Wang X, McCullough KD, Franke TF, Holbrook NJ. Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem 2000 275 : 14624 14631.
52. Barrandon Y, Green H. Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-alpha and epidermal growth factor. Cell 1987 50 : 1131 1137.
53. Wells A. EGF receptor. Int J Biochem Cell Biol 1999 31 : 637 643.
54. Tokumarua S, Higashiyam S, Endo T, Nakagawa T, Yamamori K, Hanakawa Y, Ohmoto H, Yoshino K, Shirakata Y, Matsuzawa Y, Hashimoto K, Taniguchi N. Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing. J Cell Biol 2000 151 : 209 220.
55. Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 1997 137 : 1445 1457.
56. Mainiero F, Pepe A, Yeon M, Ren Y, Giancotti FG. The intracellular functions of α6β4 integrin are regulated by EGF. J Cell Biol 1996 134 : 241 253.
57. Maheshwari G, Wells A, Griffith LG, Lauffenburger DA. Biophysical integration of effects of epidermal growth factor and fibronectin on fibroblast migration. Biophys J 1999 76 : 2817 2823.
58. Wenczack BA, Lynch JB, Nanney LB. Epidermal growth factor receptor distribution in burn wounds. Implications for growth factor-mediated repair. J Clin Invest 1992 90 : 2392 2401.
59. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003 83 : 835 870.
60. Pastore S, Mascia F, Mariani V, Girolomoni G. The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol 2008 128 : 1365 1374.
61. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer 2001 1 : 46 54.
62. Anzano MA, Roberts AB, Smith JM, Sporn MB, De Larco JE. Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type alpha and type beta transforming growth factors. Proc Natl Acad Sci USA 1983 80 : 6264 6268.
63. Berlanga J, Prats P, Remirez D, Gonzalez R, Lopez-Saura P, Aguiar J, Ojeda M, Boyle JJ, Fitzgerald AJ, Playford RJ. Prophylactic use of epidermal growth factor reduces ischemia/reperfusion intestinal damage. Am J Pathology 2002 161 : 373 379.
64. Warner BW, Erwin CR. Critical roles for EGF receptor signaling during resection-induced intestinal adaptation. J Pediatr Gastroenterol Nutr 2006 43 (Suppl 1 S68 S73.
65. Girdler NM. The effect of epidermal growth factor mouthwash on cytotoxic-induced oral ulceration. A phase I clinical trial. Am J Clin Oncol 1995 18 : 403 406.
66. Dorticós E, Pavon V, Jaime JC, Reboredo M, Lopez-Saura P, Berlanga-Acosta J, Hernandez P. Successful application of epidermal growth factor for the treatment of hemorrhagic cystitis after bone marrow transplantation. Bone Marrow Transplant 2003 31 : 615 616.
67. Stoscheck CM, King LE. Role of epidermal growth factor in carcinogenesis. Cancer Res 1986 46 : 1030 1037.
68. Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression Oncologist 2002 7 : 31 9.
69. Nair RR, Warner BB, Warner BW. Role of epidermal growth factor and other growth factors in the prevention of necrotizing enterocolitis. Semin Perinatol 2008 32 : 107 113.
70. Maraschin fnmR, Bussi R, Conz A, Luciana O, Pirovano R, Nyska A. Toxicological evaluation of u-hEGF. Toxicol Pathol 1995 23 (3 356 366.
71. Sonis ST, Costa JN, Evitts SM, Lindquist LE, Nicolson M. Effect of epidermal growth factor on ulcerative mucositis in hamsters that receive cancer chemotherapy. Oral Surg Oral Med Oral Pathol 1992 74 : 749 755.
72. Reeves JR, Richards RC, Cooke T. The effects of intracolonic EGF on mucosal growth and experimental carcinogenesis. Br J Cancer 1991 63 : 223 226.
73. Brzozowski T, Kont PC, Kont SJ, Konturek P. Mucosal irritant, adaptive cytoprotection, and adaptation to topical ammonia in the rat stomach. Scand J Gastroenterol 1996 31 : 837 846.
74. Sasaki M, Fitzgerald AJ, Mandir M, Berlanga-Acosta J, Goodlad RA. Keratinocyte growth factor and epidermal growth factor can reverse the intestinal atrophy associated with elemental diets in mice. Exp Physiol 2003 88 : 261 267.
75. Knowles AF, Salas Prato M, Villela J. Epidermal growth factor inhibits growth while increasing the expression of an ecto-calcium-ATPase of a human hepatoma cell line. Biochem Biophys Res Commun 1985 126 : 8 14.
76. Barnes DW. Epidermal growth factor inhibits growth of A431 human epidermoid carcinoma in serum-free culture. J Cell Biol 1982 93 : 1 4.
77. Xia L, Yuan YZ, Xu ChD, Zhang YP, Qiao MM, Xu JX. Effects of epidermal growth factor on the growth of human gastric cancer cell and the implanted tumor of nude mice. World J Gastroenterol 2002 8 : 455 458.
78. Bashir O, Fitzgerald AJ, Mandir M, Berlanga-Acosta J, Playford RJ, Goodlad RA. Effect of epidermal growth factor administration on intestinal cell proliferation, crypt fission and polyp formation in multiple intestinal neoplasia (Min) mice. Clin Sci 2003 105 : 323 330.
79. Vinter-Jensen L, Juhl CO, Poulsen SS, Djurhuus JC, Dajani EZ, Nexo E. Chronic administration of epidermal growth factor to pigs induce growth especially of the urinary tract with accumulation of epithelial glycoconjugates. Lab Invest 1995 73 : 788 793.
80. Juhl CO, Vinter-Jensen L, Poulsen SS, Orntoft RF, Dajani EZ. Chronic treatment with epidermal growth factor causes esophageal epithelial hyperplasia in pigs and rats. Dig Dis Sci 1995 40 : 2717 2723.
81. Vinter-Jensen L, Smerup M, Kissmeyer-Nielsen P, Poulsen SS. Chronic systemic treatment with epidermal growth factor in the rat increases the mucosal surface of the small intestine. Regul Pept 1995 60 : 117 124.
82. Vinter-Jensen L, Smerup M, Jorgensen PE, Juhl CO, Orntoft T, Poulsen SS, Nexo E. Chronic treatment with epidermal growth factor stimulates growth of the urinary tract in the rat. Urol Res 1996 24 : 1521 1525.
83. Kissmeyer-Nielsen P, Vinter-Jensen L. Time-dependent changes in the luminal surface and mass of the rat colon during prolonged systemic treatment with epidermal growth factor. Scand J Gastroenterol 2000 35 : 300 305.
84. Kissmeyer-Nielsen P, Vinter-Jensen L, Smerup M. Effects of longterm epidermal growth factor treatment on the normal rat colon. Gut 1996 38 : 582 586. (Pubitemid 26111379)
85. Vinter-Jensen L, Jorgensen PE, Poulsen SS, Nexo E. The effects of chronic administration of epidermal growth factor (EGF) to rats on the levels of endogenous EGF in the submandibular glands and kidneys. Regul Pept 1996 67 : 179 185.
86. Vinter-Jensen L, Juhl CO, Dajani EZ, Nielsen K, Djurhuus JC. Chronic systemic treatment with epidermal growth factor induces smooth muscle cell hyperplasia and hypertrophy in the urinary tract of mature Goettingen minipigs. Br J Urol 1997 79 : 532 538.
87. Vinter-Jensen L, Juhl CO, Eika B, Gregersen H, Dajani EZ. Chronic systemic treatment with epidermal growth factor induces hypergastrinaemia in Goettingen minipigs. Scand J Gastroenterol 1995 30 : 422 427.
88. Vinter-Jensen L, Juhl CO, Teglbjaerg PS, Poulsen SS, Dajani EZ, Nexo E. Systemic treatment with epidermal growth factor in pigs induces ductal proliferations in the pancreas. Gastroenterology 1997 113 : 1367 1374.
89. Yasui W, Takekura N, Kameda T, Oda N, Ito M, Ito H, Tahara E. Effect of epidermal growth factor on rat stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine. Acta Pathol Jpn 1990 40 : 165 171.
90. Tsujimoto H, Yura Y, Yoshioka Y, Kusaka J, Yoshida H, Sato M. Effect of epidermal growth factor administration on the development of mouse salivary gland carcinomas. J Oral Pathol Med 1999 28 : 30 6.
91. Harada K, Shiota G, Kawasaki H. Effect of local administration of epidermal growth factor on 9,10-dimethyl-1,2-benzanthracene-induced tumour formation in hamster cheek pouch. Eur J Cancer B Oral Oncol 1995 31 : 27 31.
92. Malt RA, Chester JF, Gaissert HA, Ross JS. Augmentation of chemically induced pancreatic and bronchial cancers by epidermal growth factor. Gut 1987 28 : Suppl): 249 251.
93. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990 61 : 203 212.
94. Kuo BS, Kusmik W, Pole J, Elsea S, Chang J, Hwang KK. Pharmacokinetic evaluation of two human epidermal growth factors (hEGF51 and hEGF53) in rats. Drug Metab Dispos 1992 20 : 23 30.
95. Coowanitwong I, Keay SK, Natarajan K, Garimella TS, Mason CW, Grkovic D, Bauer KS. Toxicokinetic study of recombinant human heparin-binding epidermal growth factor-like growth factor (rhHB-EGF) in female Sprague Dawley rats. Pharm Res 2008 25 : 542 550.
96. Stern DF, Hare DL, Cecchini MA, Weinberg RA. Construction of a novel oncogene based on synthetic sequences encoding epidermal growth factor. Science 1987 235 : 321 325.
97. Sporn MB, Roberts AB. Autocrine growth factors and cancer. Nature 1985 313 : 745 747.
98. Tönjes RR, Löhler J, O'Sullivan JF, Kay GF, Schmidt GH, Dalemans W, Pavirani A, Paul D. Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice. Oncogene 1995 10 : 765 768.
99. Erwin CR, Helmrath MA, Shin CE, Falcone RA Jr., Stern LE, Warner BW. Intestinal overexpression of EGF in transgenic mice enhances adaptation after small bowel resection Am J Physiol 1999 277 (3 pt 1 G533 40.
100. Chan SY, Wing-Chuen RW. Expression of epidermal growth factor in transgenic mice causes growth retardation. J Biol Chem 2000 275 : 38693 38698.
101. Borlak J, Meier T, Halter R, Spanel R, Spanel-Borowski K. Epidermal growth factor-induced hepatocellular carcinomas: gene expression profiles in precursor lesions, early stage and solitary tumors. Oncogene 2005 24 : 1809 1819.
102. Giraud AS. Lessons from genetically engineered animal models X. Trefoil peptide and EGF receptor/ligand transgenic mice. Am J Physiol Gastrointest Liver Physiol 2000 278 : G501 6.
103. Loeb LA. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 1991 51 : 3075 3079.
104. Owens DM, Caroline Wei SJ, Smart RC. Carcinogenesis: A multihit, multistage model of chemical carcinogenesis. Carcinogenesis 1999 9 : 1837 1844.
105. Chan KS, Carbajal S, Kiguchi K, Clifford J, Sano S, DiGiovanni J. epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis. Cancer Res 2004 64 : 2382 2389.
106. Wang XJ, Liefer KM, Greenhalgh DA, Roop DR. 12-O-tetradecanoylphorbol-13- acetate promotion of transgenic mouse epidermis coexpressing transforming growth factor-alpha and v-fos: acceleration of autonomous papilloma formation and malignant conversion via c-Ha-ras activation. Mol Carcinog 1999 26 : 305 311.
107. Greenhalgh DA, Wang XJ, Roop DR. Multistage epidermal carcinogenesis in transgenic mice: cooperativity and paradox. J Investig Dermatol Symp Proc 1996 1 : 162 176.
108. Kuwai T, Nakamura T, Sasaki T, Kitadai Y, Kim JS, Langley RR, Fan D, Wang X, Do KA, Kim SJ, Fidler IJ. Targeting the EGFR, VEGFR, and PDGFR on colon cancer cells and stromal cells is required for therapy. Clin Exp Metastasis 2008 25 : 477 489.
109. Egger B, Carey HV, Procaccino F, Chai NN, Sandgren EP, Lakshmanan J, Buslon VS, French SW, Buchler MW, Eysselein VE. Reduced susceptibility of mice overexpressing transforming growth factor to dextran sodium sulfate induced colitis. Gut 1998 43 : 64 70.
110. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986 315 : 1650 1659.
111. Kowal-Vern A and Criswell BK. Burn scar neoplasms: A literature review and statistical analysis. Burns 2005 31 : 403 413.
112. Sabin SR, Goldstein G, Rosenthal HG, Haynes KK. Aggressive squamous cell carcinoma originating as a Marjolin's ulcer. Dermatol Surg 2004 30 (2 Pt 1 229 230.
113. Martins-Green M, Boudreau N, Bissell MJ. Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res 1994 54 : 4334 4341.
114. Bartle EJ, Sun JH, Wang XW, Schneider BK. Cancers arising from burn scars. A literature review and report of twenty-one cases. J Burn Care Rehabil 1990 11 : 46 9.