The Effect of Recombinant Human Epidermal Growth Factor on Cisplatin and Radiotherapy Induced Oral Mucositis in Mice

마우스에서 Cisplatin과 방사선조사로 유발된 구내염에 대한 재조합 표피성장인자의 효과

  • Na, Jae-Boem (Departments of Diagnostic Radiology, Gyeongsang National University School of Medicine) ;
  • Kim, Hye-Jung (Departments of Pharmacology, Gyeongsang National University School of Medicine) ;
  • Chai, Gyu-Young (Departments of Radiation Oncology, Gyeongsang National University School of Medicine) ;
  • Lee, Sang-Wook (Department of Radiation Oncology, University of Ulsan College of Medicine) ;
  • Lee, Kang-Kyoo ( Department of Radiation Oncology, Wonkwang University College of Medicine) ;
  • Chang, Ki-Churl (Departments of Pharmacology, Gyeongsang National University School of Medicine) ;
  • Choi, Byung-Ock (Department of Radiation Oncology, The Catholic University of Korea College of Medicine) ;
  • Jang, Hong-Seok (Department of Radiation Oncology, The Catholic University of Korea College of Medicine) ;
  • Jeong, Bea-Keon (Departments of Radiation Oncology, Gyeongsang National University School of Medicine) ;
  • Kang, Ki-Mun (Departments of Radiation Oncology, Gyeongsang National University School of Medicine)
  • 나재범 (경상대학교 의학전문대학원 영상의학교실) ;
  • 김혜정 (경상대학교 의학전문대학원 약리학교실) ;
  • 채규영 (경상대학교 의학전문대학원 방사선종양학교실, 경상대학교 건강과학연구원) ;
  • 이상욱 (울산대학교 의과대학 방사선종양학교실) ;
  • 이강규 (원광대학교 의과대학 방사선종양학교실) ;
  • 장기철 (경상대학교 의학전문대학원 약리학교실) ;
  • 최병옥 (가톨릭대학교 의과대학 방사선종양학교실) ;
  • 장홍석 (가톨릭대학교 의과대학 방사선종양학교실) ;
  • 정배권 (경상대학교 의학전문대학원 방사선종양학교실, 경상대학교 건강과학연구원) ;
  • 강기문 (경상대학교 의학전문대학원 방사선종양학교실, 경상대학교 건강과학연구원)
  • Published : 2007.12.30

Abstract

Purpose: To study the effect of recombinant human epidermal growth factor (rhEGF) on oral mucositis induced by cisplatin and radiotherapy in a mouse model. Materials and Methods: Twenty-four ICR mice were divided into three groups-the normal control group, the no rhEGF group (treatment with cisplatin and radiation) and the rhEGF group (treatment with cisplatin, radiation and rhEGF). A model of mucositis induced by cisplatin and radiotherapy was established by injecting mice with cisplatin (10 mg/kg) on day 1 and with radiation exposure (5 Gy/day) to the head and neck on days $1{\sim}5$. rhEGF was administered subcutaneously on days -1 to 0 (1 mg/kg/day) and on days 3 to 5 (1 mg/kg/day). Evaluation included body weight, oral intake, and histology. Results: For the comparison of the change of body weight between the rhEGF group and the no rhEGF group, a statistically significant difference was observed in the rhEGF group for the 5 days after day 3 of. the experiment. The rhEGF group and no rhEGF group had reduced food intake until day 5 of the experiment, and then the mice demonstrated increased food intake after day 13 of the of experiment. When the histological examination was conducted on day 7 after treatment with cisplatin and radiation, the rhEGF group showed a focal cellular reaction in the epidermal layer of the mucosa, while the no rhEGF group did not show inflammation of the oral mucosa. Conclusion: These findings suggest that rhEGF has a potential to reduce the oral mucositis burden in mice after treatment with cisplatin and radiation. The optimal dose, number and timing of the administration of rhEGF require further investigation.

목적: 마우스 모델에서 cisplatin과 방사선조사로 구내염을 유발시킨 후 재조합 표피성장인자 (recombinant human epidermal growth factor, rhEGF)을 처치하여 그 효과를 알아보고자 하였다. 대상 및 방법: 마우스 24마리를 대상으로 정상대조군 8마리와 실험군은 각각 rhEGF 처치군과 미처치군으로 8마리씩 분류하였으며 실험군은 10 mg/kg의 cisplatin을 방사선조사 첫날 동시에 1회 복강 내 투여하였고, 방사선조사는 5일간 1회 5 Gy씩, 5일간 25 Gy를 조사하였다. RhEGF 처치군은 방사선조사 2일 전부터 2일간 1 mg/kg의 rhEGF를 피하주사하였으며 방사선조사3일째부터 3일간 1 mg/kg를 피하주사하여 총 5 mg/kg의 rhEGF를 투여하였다. 마우스의 체중변화, 먹이섭취 및 조직학적 변화를 평가하였다. 결 과: 마우스 체중변화는 rhEG F처치군이 실험 3일째부터 5일간 rhEGF 미처치군과 비교하여 통계적으로 유의한 체중의 차이를 관찰할 수 있었다. 먹이섭취는 실험군(rhEGF 처치군과 미처치군)에서 실험 5일째까지 감소하였다가 13일째부터 먹이섭취의 증가를 보여주었다. Cisplatin과 방사선조사 후 7일째의 조직학적 검사에서는 rhEGF 처치군에서 마우스의 점막 표피층의 변성이 관찰되었으나 rhEGF 미처치군에서는 점막층의 염증 반응이 관찰되었다. 결 론: Cisplatin과 방사선 조사로 마우스에서 발생한 구내염에서 rhEGF를 투여한 경우 체중 변화와 먹이섭취의 유의한 개선을 관찰하였으며 조직학적 검사에서 점막 손상의 회복을 확인하였다. 향후 임상적으로 rhEGF가 항암화학요법과 방사선치료로 인한 구내염을 줄일 수 있는 가능성을 확인하였다.값은 11개월이었고 2년, 3년 생존율은 31.5%, 15.8%였다. 결 론: 2기 췌장암 환자들은 국소 재발 및 원격 전이의 가능성이 높은 고위험군으로 국소 제어율 및 전체 생존율의 향상을 위해서 수술 후 효과적인 방사선치료의 적극적인 시행 및 이후의 보조적인 전신 항암화학요법을 권고하여 시행하는 것이 바람직하다. 평가 검사는 모두 제조사의 시험지침서에 부합하였다. 결론적으로, 이는 본 GE $Advance^{TM}$ PET 시스템이 임상에의 적용에 적합함을 보여주었다.mens사의 상용 분석 프로그램에는 해당 기능이 없어 계산값의 비교를 통한 검증은 수행하지 못하였고, 수화(hydration)와 탈수(dehydration) 각각의 조건에 따른 신장기능 분석에 적용하였을 때, 판별 기준이 되는 유의미한 값을 산출하여 타당성 검증을 대신하였다. 결론: 이 연구에서 개발한 핵의학 영상의 정량적 분석을 통한 신장기능 분석 프로그램을 사용하여 신장 기능을 분석한 결과, 타당성 있는 결과를 도출하여 그 유용성을 입증하였다. 이 개발 프로그램은 좀 더 다양한 임상응용 목적의 분석기능을 사용자가 직접 개발, 추가하기가 용이하여 기존 상용 프로그램보다 연구적 활용범위가 크다고 사료된다.2.2{\pm}0.4\;(1.6{\sim}3.2){\mu}g/ml$와 $1.4{\pm}0.2\;(0.8{\sim}1.6){\mu}g/ml$로서(p=0.16), 표준균주 3종 모두에서 Infecton의 MBC 또한 ciprofloxacin에 비해 $2{\sim}4$배가 높았다. 결론: Tc-99m Infecton은 ciprofloxacin 보다는 약하였지만 표준균주에 대해 생체외 항균력을 보였다.를

Keywords

References

  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. Cohen S, Carpenter G. Human epidermal growth factor: isolation and chemical and biological properties. Proc Natl Acad Sci USA 1975;72:1317-1321 https://doi.org/10.1073/pnas.72.4.1317
  3. Steidler NE, Reade PC. Histomorphological effects of epidermal growth factor on skin and oral mucosa in neonatal mice. Arch Oral Biol 1980;25:37-43 https://doi.org/10.1016/0003-9969(80)90153-3
  4. Cohen S. The epidermal growth factor (EGF). Cancer 1983; 51:1787-1791 https://doi.org/10.1002/1097-0142(19830515)51:10<1787::AID-CNCR2820511004>3.0.CO;2-A
  5. Waterfield MD. Epidermal growth factor and related molecules. Lancet 1989;1:1243-1246
  6. Weaver LT, Gonnella PA, Israel EJ, Walker WA. Uptake and transport of epidermal growth factor by the small intestinal epithelium of the fetal rat. Gastroenterology 1990;98: 828-837 https://doi.org/10.1016/0016-5085(90)90004-K
  7. Carpenter G. Epidermal growth factor is a major growthpromoting agent in human milk. Science 1980;210:198-199 https://doi.org/10.1126/science.6968093
  8. Jung KI, Kim SH, Moon SY, et al. Effects of recombinant epidermal growth factor on experimental radiation-induced oral mucositis in rats. J Korean Soc Ther Radiol Oncol 2006;24: 67-76
  9. Bensadoun RJ, Magne N, Marcy PY, Demard F. Chemotherapy- and radiotherapy-induced mucositis in head and neck cancer patients: new trends in pathophysiology, prevention and treatment. Eur Arch Otorhinolaryngol 2001;258:481- 487 https://doi.org/10.1007/s004050100368
  10. Rose-Ped AM, Bellm LA, Epstein JB, et al. Complications of radiation therapy for head and neck cancers. The patient's perspective. Cancer Nurs 2002;25:461-467 https://doi.org/10.1097/00002820-200212000-00010
  11. Ruescher TJ, Sodeifi A, Scrivani SJ, et al. The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Cancer 1998;82:2275-2281 https://doi.org/10.1002/(SICI)1097-0142(19980601)82:11<2275::AID-CNCR25>3.0.CO;2-Q
  12. Rapoport AP, Miller Watelet LF, Linder T, et al. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants. J Clin Oncol 1999;17:2446-2453 https://doi.org/10.1200/JCO.1999.17.8.2446
  13. Armstrong TS. Stomatitis in the bone marrow transplant patient. An overview and proposed oral care protocol. Cancer Nurs 1994;17:403-410
  14. Plevova P. Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: a review. Oral Oncol 1999;35:453-470 https://doi.org/10.1016/S1368-8375(99)00033-0
  15. Worthington HV, Clarkson JE. Prevention of oral mucositis and oral candidiasis for patients with cancer treated with chemotherapy: cochrane systematic review. J Dent Educ 2002; 66:903-911
  16. Antonadou D, Pepelassi M, Synodinou M, Puglisi M, Throuvalas N. Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;52: 739-747 https://doi.org/10.1016/S0360-3016(01)02683-9
  17. Castagna L, Benhamou E, Pedraza E, et al. Prevention of mucositis in bone marrow transplantation: a double blind randomised controlled trial of sucralfate. Ann Oncol 2001;12: 953-955 https://doi.org/10.1023/A:1011119721267
  18. Anderson PM, Schroeder G, Skubitz KM. Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 1998;83:1433-14 https://doi.org/10.1002/(SICI)1097-0142(19981001)83:7<1433::AID-CNCR22>3.0.CO;2-4
  19. Dazzi C, Cariello A, Giovanis P, et al. Prophylaxis with GM-CSF mouthwashes does not reduce frequency and duration of severe oral mucositis in patients with solid tumors undergoing high-dose chemotherapy with autologous peripheral blood stem cell transplantation rescue: a double blind, randomized, placebo-controlled study. Ann Oncol 2003;14: 559-563 https://doi.org/10.1093/annonc/mdg177
  20. Guo H, Seixas-Silva JA Jr, Epperly MW, et al. Prevention of radiation-induced oral cavity mucositis by plasmid/ liposome delivery of the human manganese superoxide dismutase (SOD2) transgene. Radiat Res 2003;159:361-370 https://doi.org/10.1667/0033-7587(2003)159[0361:PORIOC]2.0.CO;2
  21. Borges L, Rex KL, Chen JN, et al. A protective role for keratinocyte growth factor in a murine model of chemotherapy and radiotherapy-induced mucositis. Int J Radiat Oncol Biol Phys. 2006;66:254-262 https://doi.org/10.1016/j.ijrobp.2006.05.025
  22. Saadeh CE. Chemotherapy- and radiotherapy-induced oral mucositis: review of preventive strategies and treatment. Pharmacotherapy 2005;25:540-554 https://doi.org/10.1592/phco.25.4.540.61035
  23. Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004;100:2026-2046 https://doi.org/10.1002/cncr.20163
  24. Nanney LB, Magid M, Stoscheck CM, King LE Jr. Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages. J Invest Dermatol 1984;83:385-393 https://doi.org/10.1111/1523-1747.ep12264708
  25. Brown GL, Curtsinger L 3rd, Brightwell JR, et al. Enhancement of epidermal regeneration by biosynthetic epidermal growth factor. J Exp Med 1986;163:1319-1324 https://doi.org/10.1084/jem.163.5.1319
  26. Brown GL, Nanney LB, Griffen J, et al. Enhancement of wound healing by topical treatment with epidermal growth factor. N Engl J Med 1989;321:76-79 https://doi.org/10.1056/NEJM198907133210203
  27. 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 https://doi.org/10.1097/00006534-199108000-00001
  28. Chao JC, Liu KY, Chen SH, Fang CL, Tsao CW. Effect of oral epidermal growth factor on mucosal healing in rats with duodenal ulcer. World J Gastroenterol 2003;9:2261-2265 https://doi.org/10.3748/wjg.v9.i10.2261
  29. Saibishkumar EP, Patel FD, Ghoshal S, et al. Results of salvage radiotherapy after inadequate surgery in invasive cervical carcinoma patients: a retrospective analysis. Int J Radiat Oncol Biol Phys 2005;63:828-833 https://doi.org/10.1016/j.ijrobp.2005.04.002
  30. LoRusso P, Pazdur R, Redman BG, Kinzie J, Vaitkevicius V. Low-dose continuous infusion 5-fluorouracil and cisplatin: phase II evaluation in advanced colorectal carcinoma. Am J Clin Oncol 1989;12:486-490 https://doi.org/10.1097/00000421-198912000-00005
  31. Lee SW, Jung KI, Kim YW, et al. Effect of epidermal growth factor against radiotherapy-induced oral mucositis in rats. Int J Radiat Oncol Biol Phys 2007;67:1172-1178 https://doi.org/10.1016/j.ijrobp.2006.10.038