D-甲硫胺酸改善順鉑誘導大鼠心臟毒性以及厭食之探討

Improvement of Cisplatin-induced Cardiotoxicity and Anorexia by D-methionine in Rats

黃冠婷

D型甲硫胺酸 ； 順鉑 ； 厭食 ； 心臟毒性 ； D- methionine ； cisplatin ； anorexia ； cardiotoxicity

中山醫學大學營養學系碩士班學位論文

2017年

碩士

歐珠琴

繁體中文

順鉑 (Cisplatin) 是一種含鉑且常見的化學治療藥物，由於cisplatin會產生嚴重的副作用，如：耳毒性、腎毒性、神經毒性、心臟毒性、厭食/惡病質及腸胃道毒性等。D型甲硫胺酸 (D-methionine) 是L型甲硫胺酸的右旋異構物，目前已知藉由其抗氧化特性，降低cisplatin所引起的耳毒性與腎毒性，然而，D-methionine對於cisplatin引起的厭食與心臟毒性是否具有保護作用，尚未被探討，本實驗藉由大鼠模式探討D-methionine是否可改善cispaltin所誘導的厭食與心臟毒性。我們將Wistar品系雄性大鼠隨機分成四組，每組5-8隻，其中，控制組 (Control) 與順鉑組 (Cisplatin) 在實驗的前3天至第18天，管餵一般飲用水，且分別在實驗的第1、8、15天進行腹腔注射0.9%NaCl與cisplatin，劑量皆為5 mg/kg；順鉑合併D型甲硫胺酸組 (Cisplatin+D-methionine) 與D型甲硫胺酸組 (D-methionine) 分別在注射第一劑cisplatin與0.9%NaCl的前三天，開始灌食D-methionine 300 mg/kg直到實驗的第18天，並分別在實驗的第1、8、15天進行腹腔注射cisplatin與0.9%NaCl，劑量皆為5 mg/kg，最後在實驗的第19天進行犧牲。我們檢測與食慾調節相關的因子 (例如:飢餓素、瘦體素、色胺酸羥化酶1、5-HT3 receptor、5-HT2C receptor、NPY、AgRP、POMC、CART) ，藉由生理紀錄器測量心跳、收縮壓、舒張壓、平均動脈壓、心電圖，以及心臟毒性指標 (CK-MB、LDH) 與發炎反應 (IL-6、IL-1β、TNF-α) 、氧化壓力 (MDA、GSH、GPx、SOD) ，作為心臟毒性指標檢測。研究結果顯示，在厭食方面，D-methionine可以顯著改善cisplatin誘導的體重與攝食量降低，減少胃內容物殘留量並增加胃排空，透過降低腸道中色胺酸羥化酶1 (TPH1) 的活性、5- HT3 receptor的陽性反應以及降低下視丘中5-HT2C receptor基因表現等改善胃腸功能失調進而減緩厭食的發生；此外，D-methionine透過增加血清中瘦體素的含量，而促進下視丘中POMC與CART的基因表現，與降低NPY與AgRP的基因表現，以維持能量的平衡狀態。在心臟毒性方面，D-methionine可以輕微改善心臟功能異常，包括心跳、收縮壓、舒張壓以及平均動脈壓，但是無法改善cisplatin所引起的心臟毒性 (LDH與CK-MB) 與發炎反應 (IL-6、IL-1β、TNF-α) ；我們也發現cisplatin並不會造成心律不整、胸主動脈受損、心臟組織損傷以及氧化壓力。 因此，口服D-methionine具有改善cisplatin所引起厭食的潛力，但無法減緩心臟毒性。

Cisplatin, a platinum-containing compound is one of the most common chemotherapeutic drugs and leads to many serious side effects, such as ototoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, anorexia/cachexia and gastrointestinal toxicity. D-methionine, a dextral isomer of L-methionine is a sulfur-containing antioxidant. Owing to its antioxidant properties, D-methionine may attenuate ototoxicity and nephrotoxicity caused by cisplatin. However, effects of D-methionine on cisplatin-induced anorexia and cardiotoxicity have not been explored yet. In this study, we investigated whether D-methionine could attenuate cisplatin-induced anorexia and cardiotoxicity in rat model. Male Wistar rats were randomly divided into four groups of which from five to eight rats each. The control group and cisplatin group were administrated water from three days before to the 18th day of the experiment and injected with 0.9% NaCl and cisplatin (5 mg/kg) via intraperitoneal (i.p.) on the 1st, 8th and 15th day of the experiment respectively. Cisplatin plus D-methionine group and D-methionine alone group were pre-administrated daily with D-methionine (300 mg/kg) 3 day before cisplatin and 0.9% NaCl treatment until the study is completed. Also cisplatin and 0.9% NaCl were i.p. injected on the 1st, 8th and 15th day of the experiment, respectively. All animals were sacrificed on day 19 of the experiment. We detected the appetite regulated factors such as ghrelin, leptin, tryptophan hydroxylase 1, 5-HT3 receptor, 5-HT2C receptor, NPY, AgRP, POMC, CART, and used physiological recording machine to determine heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure and electrocardiogram. The cardiotoxicity marker (CK-MB, LDH) ,inflammatory response (IL-6, IL-1β, TNF-α) and oxidative stress (MDA, GSH, GPx, SOD) were measured and deemed as cardiotoxicity index. As for anorexia, the results showed that D-methionine can significantly improve cisplatin-induced weight loss and food intake, decrease gastric contents, enhance gastric emptying in the stomach tissue. D-methionine could reduce the activity of tryptophan hydroxylase 1 (TPH1), increase the positive response of 5-HT3 receptor in the intestine and decrease gene expression of 5-HT2C receptor in the hypothalamus in cisplatin-treated rats. In addition, to maintain energy balance in cisplatin-treated rats, D-methionine increased plasma levels of leptin in serum, which lead to enhance the gene expression of POMC, CART and decrease the gene expression of NPY and AgRP. By the results of cisplatin-induced cardiotoxicity, we found D-methionine can slightly improve the abnormal status of heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure, while it cannot ameliorate LDH and CK-MB activity and inflammatory response (IL-6 , IL-1β, TNF-α) after cisplatin injection. Besides, cisplatin did not cause arrhythmia, thoracic aorta damage, cardiac tissue damage and oxidative stress. These results indicate that oral D-methionine may have potential for improving cisplatin-induced anorexia but can not ameliorate cisplatin induced cardiotoxicity.

1. Abdellatief SA, Galal AA, Farouk SM, Abdel-Daim MM (2017) Ameliorative effect of parsley oil on cisplatin-induced hepato-cardiotoxicity: A biochemical, histopathological, and immunohistochemical study. Biomed Pharmacother 86: 482-491
   連結：
2. Abe M, Hirashima Y, Kasamatsu Y, Kado N, Komeda S, Kuji S, Tanaka A, Takahashi N, Takekuma M, Hihara H, Ichikawa Y, Itonaga Y, Hirakawa T, Nasu K, Miyagi K, Murakami J, Ito K (2016) Efficacy and safety of olanzapine combined with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy in gynecological cancer: KCOG-G1301 phase II trial. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 24: 675-682
   連結：
3. Adali F, Gonul Y, Kocak A, Yuksel Y, Ozkececi G, Ozdemir C, Tunay K, Bozkurt MF, Sen OG (2016) Effects of thymoquinone against cisplatin-induced cardiac injury in rats. Acta Cir Bras 31: 271-7
   連結：
4. Adam CL, Archer ZA, Findlay PA, Thomas L, Marie M (2002) Hypothalamic gene expression in sheep for cocaine- and amphetamine-regulated transcript, pro-opiomelanocortin, neuropeptide Y, agouti-related peptide and leptin receptor and responses to negative energy balance. Neuroendocrinology 75: 250-6
   連結：
5. Al-Majed AA, Sayed-Ahmed MM, Al-Yahya AA, Aleisa AM, Al-Rejaie SS, Al-Shabanah OA (2006) Propionyl-L-carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitine-depleted rat model. Pharmacol Res 53: 278-86
   連結：
6. Alhadeff AL, Holland RA, Zheng H, Rinaman L, Grill HJ, De Jonghe BC (2017) Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss. J Neurosci 37: 362-370
   連結：
7. Andrews PL, Davis CJ, Bingham S, Davidson HI, Hawthorn J, Maskell L (1990) The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J Physiol Pharmacol 68: 325-45
   連結：
8. Aponte Y, Atasoy D, Sternson SM (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 14: 351-5
   連結：
9. Argiles JM, Busquets S, Stemmler B, Lopez-Soriano FJ (2014) Cancer cachexia: understanding the molecular basis. Nature reviews Cancer 14: 754-62
   連結：
10. Atasoy D, Betley JN, Su HH, Sternson SM (2012) Deconstruction of a neural circuit for hunger. Nature 488: 172-7
    連結：
11. Baraban SC (1998) Neuropeptide Y and limbic seizures. Rev Neurosci 9: 117-28
    連結：
12. Barabas K, Milner R, Lurie D, Adin C (2008) Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol 6: 1-18
    連結：
13. Becouarn Y, Agostini C, Trufflandier N, Boulanger V (2001) Oxaliplatin: available data in non-colorectal gastrointestinal malignancies. Crit Rev Oncol Hematol 40: 265-72
    連結：
14. Benevenga NJ (1974) Toxicities of methionine and other amino acids. J Agric Food Chem 22: 2-9
    連結：
15. Blom HJ, Boers GH, van den Elzen JP, Gahl WA, Tangerman A (1989) Transamination of methionine in humans. Clin Sci (Lond) 76: 43-9
    連結：
16. Bovelli D, Plataniotis G, Roila F, Group EGW (2010) Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol 21 Suppl 5: v277-82
    連結：
17. Burstow M, Kelly T, Panchani S, Khan IM, Meek D, Memon B, Memon MA (2009) Outcome of palliative esophageal stenting for malignant dysphagia: a retrospective analysis. Dis Esophagus 22: 519-25
    連結：
18. Cabezos PA, Vera G, Martin-Fontelles MI, Fernandez-Pujol R, Abalo R (2010) Cisplatin-induced gastrointestinal dysmotility is aggravated after chronic administration in the rat. Comparison with pica. Neurogastroenterol Motil 22: 797-805, e224-5
    連結：
19. Campbell KC, Martin SM, Meech RP, Hargrove TL, Verhulst SJ, Fox DJ (2016) D-methionine (D-met) significantly reduces kanamycin-induced ototoxicity in pigmented guinea pigs. Int J Audiol 55: 273-8
    連結：
20. Campbell KC, Meech RP, Klemens JJ, Gerberi MT, Dyrstad SS, Larsen DL, Mitchell DL, El-Azizi M, Verhulst SJ, Hughes LF (2007) Prevention of noise- and drug-induced hearing loss with D-methionine. Hear Res 226: 92-103
    連結：
21. Campbell KC, Rybak LP, Meech RP, Hughes L (1996) D-methionine provides excellent protection from cisplatin ototoxicity in the rat. Hear Res 102: 90-8
    連結：
22. Cavalcante JC, Candido PL, Sita LV, do Nascimento ES, Jr., Cavalcante Jde S, de Oliveira Costa MS, Bittencourt JC, Elias CF (2011) Comparative distribution of cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus of the capuchin monkey (Cebus apella) and the common marmoset (Callithrix jacchus). Brain Res 1425: 47-61
    連結：
23. Chen Y, Brott D, Luo W, Gangl E, Kamendi H, Barthlow H, Lengel D, Fikes J, Kinter L, Valentin JP, Bialecki R (2013) Assessment of cisplatin-induced kidney injury using an integrated rodent platform. Toxicol Appl Pharmacol 268: 352-61
    連結：
24. Chowdhury S, Sinha K, Banerjee S, Sil PC (2016) Taurine protects cisplatin induced cardiotoxicity by modulating inflammatory and endoplasmic reticulum stress responses. Biofactors 42: 647-664
    連結：
25. Chronwall BM (1985) Anatomy and physiology of the neuroendocrine arcuate nucleus. Peptides 6 Suppl 2: 1-11
    連結：
26. Cloven NG, Re A, McHale MT, Burger RA, DiSaia PJ, Rose GS, Campbell KC, Fan H (2000) Evaluation of D-methionine as a cytoprotectant in cisplatin treatment of an animal model for ovarian cancer. Anticancer Res 20: 4205-9
    連結：
27. Cote F, Thevenot E, Fligny C, Fromes Y, Darmon M, Ripoche MA, Bayard E, Hanoun N, Saurini F, Lechat P, Dandolo L, Hamon M, Mallet J, Vodjdani G (2003) Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci U S A 100: 13525-30
    連結：
28. Cubeddu LX, Hoffmann IS (1993) Participation of serotonin on early and delayed emesis induced by initial and subsequent cycles of cisplatinum-based chemotherapy: effects of antiemetics. J Clin Pharmacol 33: 691-7
    連結：
29. Dash PK, Hergenroeder GW, Jeter CB, Choi HA, Kobori N, Moore AN (2016) Traumatic Brain Injury Alters Methionine Metabolism: Implications for Pathophysiology. Front Syst Neurosci 10: 36
    連結：
30. Davis MP, Dreicer R, Walsh D, Lagman R, LeGrand SB (2004) Appetite and cancer-associated anorexia: a review. J Clin Oncol 22: 1510-7
    連結：
31. Decatris MP, Sundar S, O'Byrne KJ (2004) Platinum-based chemotherapy in metastatic breast cancer: current status. Cancer Treat Rev 30: 53-81
    連結：
32. Demkow U, Stelmaszczyk-Emmel A (2013) Cardiotoxicity of cisplatin-based chemotherapy in advanced non-small cell lung cancer patients. Respir Physiol Neurobiol 187: 64-7
    連結：
33. Di Francesco AM, Ruggiero A, Riccardi R (2002) Cellular and molecular aspects of drugs of the future: oxaliplatin. Cell Mol Life Sci 59: 1914-27
    連結：
34. Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M (2008) Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. Am J Clin Pathol 130: 688-95
    連結：
35. Dugbartey GJ, Peppone LJ, de Graaf IA (2016) An integrative view of cisplatin-induced renal and cardiac toxicities: Molecular mechanisms, current treatment challenges and potential protective measures. Toxicology 371: 58-66
    連結：
36. Ekborn A, Laurell G, Johnstrom P, Wallin I, Eksborg S, Ehrsson H (2002) D-Methionine and cisplatin ototoxicity in the guinea pig: D-methionine influences cisplatin pharmacokinetics. Hear Res 165: 53-61
    連結：
37. El-Awady el SE, Moustafa YM, Abo-Elmatty DM, Radwan A (2011) Cisplatin-induced cardiotoxicity: Mechanisms and cardioprotective strategies. European journal of pharmacology 650: 335-41
    連結：
38. El-Sawalhi MM, Ahmed LA (2014) Exploring the protective role of apocynin, a specific NADPH oxidase inhibitor, in cisplatin-induced cardiotoxicity in rats. Chem Biol Interact 207: 58-66
    連結：
39. Engineer DR, Garcia JM (2012) Leptin in anorexia and cachexia syndrome. Int J Pept 2012: 287457
    連結：
40. Ezeoke CC, Morley JE (2015) Pathophysiology of anorexia in the cancer cachexia syndrome. J Cachexia Sarcopenia Muscle 6: 287-302
    連結：
41. Finkelstein JD, Martin JJ, Harris BJ (1988) Methionine metabolism in mammals. The methionine-sparing effect of cystine. J Biol Chem 263: 11750-4
    連結：
42. Flier JS, Maratos-Flier E (1998) Obesity and the hypothalamus: novel peptides for new pathways. Cell 92: 437-40
    連結：
43. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395: 763-70
    連結：
44. Fujitsuka N, Asakawa A, Uezono Y, Minami K, Yamaguchi T, Niijima A, Yada T, Maejima Y, Sedbazar U, Sakai T, Hattori T, Kase Y, Inui A (2011) Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival. Transl Psychiatry 1: e23
    連結：
45. Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G, Harel-Bellan A, Castedo M, Kroemer G (2014) Systems biology of cisplatin resistance: past, present and future. Cell Death Dis 5: e1257
    連結：
46. Garcia JM, Garcia-Touza M, Hijazi RA, Taffet G, Epner D, Mann D, Smith RG, Cunningham GR, Marcelli M (2005) Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia. J Clin Endocrinol Metab 90: 2920-6
    連結：
47. Garlick PJ (2006) Toxicity of methionine in humans. J Nutr 136: 1722S-1725S
    連結：
48. Geng ZH, Huang L, Song MB, Song YM (2015) Protective effect of a polysaccharide from Salvia miltiorrhiza on isoproterenol (ISO)-induced myocardial injury in rats. Carbohydr Polym 132: 638-42
    連結：
49. Gershon MD (1999) Review article: roles played by 5-hydroxytryptamine in the physiology of the bowel. Alimentary pharmacology & therapeutics 13 Suppl 2: 15-30
    連結：
50. Gloire G, Legrand-Poels S, Piette J (2006) NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72: 1493-505
    連結：
51. Herman EH, Zhang J, Rifai N, Lipshultz SE, Hasinoff BB, Chadwick DP, Knapton A, Chai J, Ferrans VJ (2001) The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity. Cancer Chemother Pharmacol 48: 297-304
    連結：
52. Hesketh PJ, Van Belle S, Aapro M, Tattersall FD, Naylor RJ, Hargreaves R, Carides AD, Evans JK, Horgan KJ (2003) Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 39: 1074-80
    連結：
53. Hirose A, Sato E, Fujii H, Sun B, Nishioka H, Aruoma OI (2007) The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice. Toxicol Appl Pharmacol 222: 152-8
    連結：
54. Hiura Y, Takiguchi S, Yamamoto K, Kurokawa Y, Yamasaki M, Nakajima K, Miyata H, Fujiwara Y, Mori M, Doki Y (2012) Fall in plasma ghrelin concentrations after cisplatin-based chemotherapy in esophageal cancer patients. Int J Clin Oncol 17: 316-23
    連結：
55. Hubert GW, Kuhar MJ (2008) Cocaine administration increases the fraction of CART cells in the rat nucleus accumbens that co-immunostain for c-Fos. Neuropeptides 42: 339-43
    連結：
56. Hussein A, Ahmed AA, Shouman SA, Sharawy S (2012) Ameliorating effect of DL-alpha-lipoic acid against cisplatin-induced nephrotoxicity and cardiotoxicity in experimental animals. Drug Discov Ther 6: 147-56
    連結：
57. Ince S, Arslan Acaroz D, Neuwirth O, Demirel HH, Denk B, Kucukkurt I, Turkmen R (2014) Protective effect of polydatin, a natural precursor of resveratrol, against cisplatin-induced toxicity in rats. Food Chem Toxicol 72: 147-53
    連結：
58. Inui A (1999b) Feeding and body-weight regulation by hypothalamic neuropeptides--mediation of the actions of leptin. Trends Neurosci 22: 62-7
    連結：
59. Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M (2004) Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J 18: 439-56
    連結：
60. Jensen BV, Skovsgaard T, Nielsen SL (2002) Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol 13: 699-709
    連結：
61. Jones MM, Basinger MA, Holscher MA (1992) Control of the nephrotoxicity of cisplatin by clinically used sulfur-containing compounds. Fundam Appl Toxicol 18: 181-8
    連結：
62. Ju C, Hamaue N, Machida T, Liu Y, Iizuka K, Wang Y, Minami M, Hirafuji M (2008) Anti-inflammatory drugs ameliorate opposite enzymatic changes in ileal 5-hydroxytryptamine metabolism in the delayed phase after cisplatin administration to rats. European journal of pharmacology 589: 281-7
    連結：
63. Junior AD, Mota LG, Nunan EA, Wainstein AJ, Wainstein AP, Leal AS, Cardoso VN, De Oliveira MC (2007) Tissue distribution evaluation of stealth pH-sensitive liposomal cisplatin versus free cisplatin in Ehrlich tumor-bearing mice. Life Sci 80: 659-64
    連結：
64. Kharbanda KK (2013) Methionine metabolic pathway in alcoholic liver injury. Curr Opin Clin Nutr Metab Care 16: 89-95
    連結：
65. Kharbanda KK, Rogers DD, 2nd, Mailliard ME, Siford GL, Barak AJ, Beckenhauer HC, Sorrell MF, Tuma DJ (2005) Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: protection by betaine. Biochem Pharmacol 70: 1883-90
    連結：
66. Kilpatrick GJ, Bunce KT, Tyers MB (1990) 5-HT3 receptors. Med Res Rev 10: 441-75
    連結：
67. Kim DY, Camilleri M (2000) Serotonin: a mediator of the brain-gut connection. The American journal of gastroenterology 95: 2698-709
    連結：
68. Koh E, Nakamura T, Takahashi H (2004) Troponin-T and brain natriuretic peptide as predictors for adriamycin-induced cardiomyopathy in rats. Circ J 68: 163-7
    連結：
69. Koladiya RU, Jaggi AS, Singh N, Sharma BK (2008) Ameliorative role of Atorvastatin and Pitavastatin in L-Methionine induced vascular dementia in rats. BMC Pharmacol 8: 14
    連結：
70. Lau J, Herzog H (2014) CART in the regulation of appetite and energy homeostasis. Front Neurosci 8: 313
    連結：
71. Li Z, Mulholland M, Zhang W (2016) Ghrelin O-acyltransferase (GOAT) and energy metabolism. Sci China Life Sci 59: 281-91
    連結：
72. Liao Y, Lu X, Lu C, Li G, Jin Y, Tang H (2008) Selection of agents for prevention of cisplatin-induced hepatotoxicity. Pharmacol Res 57: 125-31
    連結：
73. Lin S, Boey D, Couzens M, Lee N, Sainsbury A, Herzog H (2005) Compensatory changes in [125I]-PYY binding in Y receptor knockout mice suggest the potential existence of further Y receptor(s). Neuropeptides 39: 21-8
    連結：
74. Lin S, Boey D, Herzog H (2004) NPY and Y receptors: lessons from transgenic and knockout models. Neuropeptides 38: 189-200
    連結：
75. Liu YL, Malik NM, Sanger GJ, Andrews PL (2006) Ghrelin alleviates cancer chemotherapy-associated dyspepsia in rodents. Cancer Chemother Pharmacol 58: 326-33
    連結：
76. Lo WC, Chang CM, Liao LJ, Wang CT, Young YH, Chang YL, Cheng PW (2015) Assessment of D-methionine protecting cisplatin-induced otolith toxicity by vestibular-evoked myogenic potential tests, ATPase activities and oxidative state in guinea pigs. Neurotoxicol Teratol 51: 12-20
    連結：
77. Loh K, Herzog H, Shi YC (2015) Regulation of energy homeostasis by the NPY system. Trends Endocrinol Metab 26: 125-35
    連結：
78. Lokich J, Anderson N (1998) Carboplatin versus cisplatin in solid tumors: an analysis of the literature. Ann Oncol 9: 13-21
    連結：
79. Lou XY, Cheng JL, Zhang B (2015) Therapeutic effect and mechanism of breviscapine on cisplatin-induced nephrotoxicity in mice. Asian Pac J Trop Med 8: 873-7
    連結：
80. Ma H, Jones KR, Guo R, Xu P, Shen Y, Ren J (2010) Cisplatin compromises myocardial contractile function and mitochondrial ultrastructure: role of endoplasmic reticulum stress. Clin Exp Pharmacol Physiol 37: 460-5
    連結：
81. Maimaitiyiming H, Li Y, Cui W, Tong X, Norman H, Qi X, Wang S (2013) Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function. Am J Physiol Renal Physiol 305: F881-90
    連結：
82. Malik NM, Moore GB, Kaur R, Liu YL, Wood SL, Morrow RW, Sanger GJ, Andrews PL (2008) Adaptive upregulation of gastric and hypothalamic ghrelin receptors and increased plasma ghrelin in a model of cancer chemotherapy-induced dyspepsia. Regul Pept 148: 33-8
    連結：
83. Malik NM, Moore GB, Smith G, Liu YL, Sanger GJ, Andrews PL (2006) Behavioural and hypothalamic molecular effects of the anti-cancer agent cisplatin in the rat: A model of chemotherapy-related malaise? Pharmacology, biochemistry, and behavior 83: 9-20
    連結：
84. Mantovani G, Maccio A, Massa E, Madeddu C (2001) Managing cancer-related anorexia/cachexia. Drugs 61: 499-514
    連結：
85. Marks DL, Ling N, Cone RD (2001) Role of the central melanocortin system in cachexia. Cancer Res 61: 1432-8
    連結：
86. Mihalache L, Gherasim A, Nita O, Ungureanu MC, Padureanu SS, Gavril RS, Arhire LI (2016) Effects of ghrelin in energy balance and body weight homeostasis. Hormones (Athens) 15: 186-96
    連結：
87. Morley JE, Thomas DR, Wilson MM (2006) Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 83: 735-43
    連結：
88. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW (2006) Central nervous system control of food intake and body weight. Nature 443: 289-95
    連結：
89. Morton GJ, Schwartz MW (2001) The NPY/AgRP neuron and energy homeostasis. Int J Obes Relat Metab Disord 25 Suppl 5: S56-62
    連結：
90. Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7: 27-31
    連結：
91. Naziroglu M, Karaoglu A, Aksoy AO (2004) Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats. Toxicology 195: 221-30
    連結：
92. Nelson K, Walsh D, Sheehan F (2002) Cancer and chemotherapy-related upper gastrointestinal symptoms: the role of abnormal gastric motor function and its evaluation in cancer patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 10: 455-61
    連結：
93. Nicolini A, Ferrari P, Masoni MC, Fini M, Pagani S, Giampietro O, Carpi A (2013) Malnutrition, anorexia and cachexia in cancer patients: A mini-review on pathogenesis and treatment. Biomed Pharmacother 67: 807-17
    連結：
94. Noori S, Mahboob T (2010) Antioxidant effect of carnosine pretreatment on cisplatin-induced renal oxidative stress in rats. Indian J Clin Biochem 25: 86-91
    連結：
95. O'Gorman P, McMillan DC, McArdle CS (1998) Impact of weight loss, appetite, and the inflammatory response on quality of life in gastrointestinal cancer patients. Nutr Cancer 32: 76-80
    連結：
96. Ohno T, Kato S, Wakatsuki M, Noda SE, Murakami C, Nakamura M, Tsujii H (2006) Incidence and temporal pattern of anorexia, diarrhea, weight loss, and leukopenia in patients with cervical cancer treated with concurrent radiation therapy and weekly cisplatin: comparison with radiation therapy alone. Gynecol Oncol 103: 94-9
    連結：
97. Pai VB, Nahata MC (2000) Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 22: 263-302
    連結：
98. Pandir D, Kara O, Kara M (2014) Protective effect of bilberry (Vaccinium myrtillus L.) on cisplatin induced ovarian damage in rat. Cytotechnology 66: 677-85
    連結：
99. Park HK, Ahima RS (2015) Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism: clinical and experimental 64: 24-34
    連結：
100. .
101. Campbell KC, Meech RP, Rybak LP, Hughes LF (2003) The effect of D-methionine on cochlear oxidative state with and without cisplatin administration: mechanisms of otoprotection. J Am Acad Audiol 14: 144-56
102. Demkow U, Biatas-Chromiec B, Stelmaszczyk-Emmel A, Radzikowska E, Wiatr E, Radwan-Rohrenschef P, Szturmowicz M (2011) The Cardiac Markers and Oxidative Stress Parameters in Advanced Non-Small Cell Lung Cancer Patients Receiving Cisplatin-Based Chemotherapy. EJIFCC 22: 6-15
103. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH, Douglass HO, Jr., Engstrom PF, Ezdinli EZ, Horton J, Johnson GJ, Moertel CG, Oken MM, Perlia C, Rosenbaum C, Silverstein MN, Skeel RT, Sponzo RW, Tormey DC (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med 69: 491-7
104. Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, Marks D, Mitch WE, Muscaritoli M, Najand A, Ponikowski P, Rossi Fanelli F, Schambelan M, Schols A, Schuster M, Thomas D et al. (2008) Cachexia: a new definition. Clin Nutr 27: 793-9
105. Gandara DR, Perez EA, Phillips WA, Lawrence HJ, DeGregorio M (1989) Evaluation of cisplatin dose intensity: current status and future prospects. Anticancer Res 9: 1121-8
106. Gershon MD, Wade PR, Kirchgessner AL, Tamir H (1990) 5-HT receptor subtypes outside the central nervous system. Roles in the physiology of the gut. Neuropsychopharmacology 3: 385-95
107. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN, Holstege H, Lee CE, Cone RD, Elmquist JK (2002) Activation of central melanocortin pathways by fenfluramine. Science 297: 609-11
108. Inui A (1999a) Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res 59: 4493-501
109. Jones MM, Basinger MA, Holscher MA (1991) Thioether suppression of cisplatin nephrotoxicity in the rat. Anticancer Res 11: 449-53
110. Kaji H, Niioka T, Kojima Y, Yoshida Y, Kawakami Y (1987) Urinary 3-methylthiopropionate excretion and the effect of D- or L-methionine ingestion studied in healthy subjects. Res Commun Chem Pathol Pharmacol 56: 101-9
111. Liu Y, Hamaue N, Endo T, Hirafuji M, Minami M (2003) 5-hydroxytryptamine (5-HT) concentrations in the hippocampus, the hypothalamus and the medulla oblongata related to cisplatin-induced pica of rats. Research communications in molecular pathology and pharmacology 113-114: 97-113
112. Nelson KA, Walsh TD, Sheehan FG, O'Donovan PB, Falk GW (1993) Assessment of upper gastrointestinal motility in the cancer-associated dyspepsia syndrome. J Palliat Care 9: 27-31