达卡巴嗪

达卡巴嗪
临床资料
读音	/dəˈkɑːrbəˌziːn/
商品名（英语：Drug nomenclature）	DTIC-Dome等
其他名称	DTIC
AHFS/Drugs.com	Monograph
MedlinePlus	a682750
给药途径	静脉注射
ATC码	L01AX04 (WHO) ;
法律规范状态
法律规范	美：处方药（℞-only）; 处方药（℞-only）;
药物动力学数据
生物利用度	100%
药物代谢	在体内会被迅速分解和转化为多种不同的代谢物
生物半衰期	5小时
排泄途径	肾脏 (40%维持原达卡巴仁形式)
识别信息
	IUPAC命名法 5-(3,3-Dimethyl-1-triazenyl)imidazole-4-carboxamide; ;
CAS号	4342-03-4
PubChem CID	2942;
DrugBank	DB00851 ;
ChemSpider	10481959 ;
UNII	7GR28W0FJI;
KEGG	D00288 ; C06936;
ChEBI	CHEBI:4305 ;
ChEMBL	ChEMBL476 ;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID0020369 ;
ECHA InfoCard	100.022.179
化学信息
化学式	C6H10N6O
摩尔质量	182.19 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	SMILES CN(C)N=Nc1[nH]cnc1C(N)=O;
	InChI InChI=1S/C6H10N6O/c1-12(2)11-10-6-4(5(7)13)8-3-9-6/h3H,1-2H3,(H2,7,13)(H,8,9)/b11-10+ ; Key:FDKXTQMXEQVLRF-ZHACJKMWSA-N ;

达卡巴仁（英语：Dacarbazine），也称为咪唑甲酰胺（英语：imidazole carboxamide），以DTIC-Dome品牌等于市面销售，是一种用于治疗黑色素瘤和霍奇金淋巴瘤的化学疗法药物。^[2]于治疗霍奇金淋巴瘤时，通常会与长春碱、博莱霉素和阿霉素一起使用（称为ABVD化疗方案（英语：ABVD））。^[2]透过静脉注射给药。^[2]

使用后常见的副作用有食欲不振、呕吐、白血球减少和血小板低下（英语：thrombocytopenia）。^[2]严重的副作用有肝脏问题和过敏反应。^[2]目前尚不清楚个体于怀孕期间使用对胎儿是否安全。^[2]达卡巴仁属于烷化剂和嘌呤类似物家族药物。^[2]

此药品于1975年在美国被批准用于医疗用途。^[2]也被列入世界卫生组织基本药物标准清单。^[3]

医疗用途

截至2006年中期，达卡巴仁通常用作治疗转移性黑色素瘤的单一药物，^[4]^[5]并作为治疗霍奇金淋巴瘤的ABVD化疗方案（英语：ABVD）（包含阿霉素/博莱霉素/长春碱/达卡巴仁）其中之一成分，^[6]以及治疗肉瘤的MAID方案（包含美司钠/阿霉素/异环磷酰胺/达卡巴仁）。^[7]^[8]在德国针对治疗儿童霍奇金淋巴瘤的试验中，达卡巴仁被证明与丙卡巴仁（另一种具有相似化学性质的药物^[9]）有相似的疗效，但可降低来自丙卡巴仁的毒性作用，因此在治疗儿童II & III型T细胞淋巴瘤时，先行采OEPA方案（包含长春新碱/依托泊苷/泼尼松/阿霉素），之后再采COPDAC方案（包含环磷酰胺/长春新碱/泼尼松/达卡巴仁）以取代先前的COPP方案（包含环磷酰胺/长春新碱/泼尼松/丙卡巴仁）。^[10]

于2022年发表的研究报告也表示以达卡巴仁取代丙卡巴仁可显著降低罹患霍奇金淋巴瘤成人患者治疗后造血干细胞和祖细胞的突变负担，且临床疗效似乎没明显下降。^[11]

副作用

达卡巴仁与许多化学治疗药物一样，可能有许多严重的副作用，因为它会同时干扰正常细胞生长以及癌细胞生长。最严重的副作用是治疗期间怀孕或生育的小孩可能出现先天性障碍、个体本身不孕症（可能为永久性）或是免疫抑制（抵抗感染或疾病的能力降低）。^[12]达卡巴仁被认为具有高度恶心和呕吐作用（英语：Chemotherapy-induced nausea and vomiting）（CINV），^[13]大多数患者会预先服用地塞米松和止吐剂（如5-HT3拮抗剂（英语：5-HT3 antagonist），例如昂丹司琼）和/或NK1受体拮抗剂（英语：NK1 receptor antagonist）（例如阿瑞吡坦（英语：aprepitant））。其他显著的副作用有头痛、疲劳和偶尔的腹泻。

瑞典国家健康福利委员会（英语：National Board of Health and Welfare (Sweden)）已于药物标签上发布黑框警告，并建议有肝脏问题的个体避免使用达卡巴仁。^[14]

作用机转

达卡巴仁被肝脏微粒体酶活化为一甲基三氮唑咪唑甲酰胺 (monomethyl triazeno imidazole carboxamide，MTIC)，这是一种烷基化化合物。^[15]会引起DNA 甲基化、修饰和交联，而抑制DNA、RNA和蛋白质的合成。^[16]

合成

将亚硝酸添加到5-氨基咪唑-4-甲酰胺核糖核苷酸（英语：5-aminoimidazol-4-carboxamide）中，生成5-重氮咪唑-4-甲酰胺（5-diazoimidazol-4-carboxamide），再与二甲胺反应生成达卡巴仁。^[17]

历史

达卡巴仁首次于1959年由阿拉巴马州南方研究所（英语：Southern Research）（非营利组织）合成。^[18]研究经费由美国联邦提供协助。此药品于1975年5月获得美国食品药物管理局（FDA）批准作医疗用途，商品名为DTIC-Dome。最初由拜耳公司销售。

社会与文化

赫士睿（Hospira，后被辉瑞并入）、梯瓦药业、费森尤斯药业（Fresenius Kabi）、Hikma Pharmaceuticals药业、Bedford Pharma药业均有提供达卡巴仁的通用名药物。^[19]

参见

^ Elks J, Ganellin CR (编). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 1990: 344–. ISBN 978-1-4757-2087-7. doi:10.1007/978-1-4757-2085-3.
^ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 ^2.6 ^2.7 Dacarbazine. The American Society of Health-System Pharmacists. [2016-12-08]. （原始内容存档于2017-09-11）.
^ World Health Organization. The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. hdl:10665/371090 . WHO/MHP/HPS/EML/2023.02.
^ Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. Journal of Experimental & Clinical Cancer Research. March 2000, 19 (1): 21–34. PMID 10840932.
^ Bhatia S, Tykodi SS, Thompson JA. Treatment of metastatic melanoma: an overview. Oncology. May 2009, 23 (6): 488–496. PMC 2737459 . PMID 19544689.
^ Rueda Domínguez A, Márquez A, Gumá J, Llanos M, Herrero J, de Las Nieves MA, Miramón J, Alba E. Treatment of stage I and II Hodgkin's lymphoma with ABVD chemotherapy: results after 7 years of a prospective study. Annals of Oncology. December 2004, 15 (12): 1798–1804. PMID 15550585. doi:10.1093/annonc/mdh465 .
^ Elias A, Ryan L, Aisner J, Antman KH. Mesna, doxorubicin, ifosfamide, dacarbazine (MAID) regimen for adults with advanced sarcoma. Seminars in Oncology. April 1990, 17 (2 Suppl 4): 41–49. PMID 2110385.
^ Pearl ML, Inagami M, McCauley DL, Valea FA, Chalas E, Fischer M. Mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy for gynecological sarcomas. International Journal of Gynecological Cancer. 2001, 12 (6): 745–748. PMID 12445253. S2CID 25246937. doi:10.1046/j.1525-1438.2002.01139.x.
^ Jelić S, Babovic N, Kovcin V, Milicevic N, Milanovic N, Popov I, Radosavljevic D. Comparison of the efficacy of two different dosage dacarbazine-based regimens and two regimens without dacarbazine in metastatic melanoma: a single-centre randomized four-arm study. Melanoma Research. February 2002, 12 (1): 91–98. PMID 11828263. S2CID 32031568. doi:10.1097/00008390-200202000-00013.
^ Mauz-Körholz C, Hasenclever D, Dörffel W, Ruschke K, Pelz T, Voigt A, Stiefel M, Winkler M, Vilser C, Dieckmann K, Karlén J, Bergsträsser E, Fosså A, Mann G, Hummel M, Klapper W, Stein H, Vordermark D, Kluge R, Körholz D. Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study. Journal of Clinical Oncology. August 2010, 28 (23): 3680–3686. PMID 20625128. doi:10.1200/jco.2009.26.9381 .
^ Blood（2022）: 1761–1764 https://www.researchgate.net/publication/365818412_Replacing_Procarbazine_with_Dacarbazine_in_Escalated_Beacopp_Dramatically_Reduces_the_Post_Treatment_Haematopoietic_Stem_and_Progenitor_Cell_Mutational_Burden_in_Hodgkin_Lymphoma_Patients_with_No_Appa. [2024-02-11]. 缺少或|title=为空 (帮助)
^ Dacarbazine Injection. IndiaMart. [2024-2-11]. （原始内容存档于2024-02-28）.
^ Aoki S, Iihara H, Nishigaki M, Imanishi Y, Yamauchi K, Ishihara M, Kitaichi K, Itoh Y. Difference in the emetic control among highly emetogenic chemotherapy regimens: Implementation for appropriate use of aprepitant. Molecular and Clinical Oncology. January 2013, 1 (1): 41–46. PMC 3956247 . PMID 24649120. doi:10.3892/mco.2012.15.
^ Alla aktuella ändringar för Dacarbazine medac Pulver till infusionsvätska, lösning 500 mg, Medac. FASS.se. [2011-08-19]. （原始内容存档于2011-10-01）.
^ Kewitz S, Stiefel M, Kramm CM, Staege MS. Impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression on dacarbazine resistance of Hodgkin's lymphoma cells. Leukemia Research. January 2014, 38 (1): 138–143. PMID 24284332. doi:10.1016/j.leukres.2013.11.001.
^ Dacarbazine. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. PMID 31644220.
^ Vardanyan RS, Hruby VJ. 30 - Antineoplastics. Synthesis of Essential Drugs. 2006: 389–418. ISBN 9780444521668. doi:10.1016/B978-044452166-8/50030-3.
^ Marchesi F, Turrizani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L. Triazene compounds: Mechanism of action and related DNA repair systems. Pharmacological Research. October 2007, 56 (4): 275–287. PMID 17897837. doi:10.1016/j.phrs.2007.08.003.
^ Dacarbazine. DRUGBANK oNLINE. [2024-02-11]. （原始内容存档于2023-12-02）.

[1] Elks J, Ganellin CR (编). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 1990: 344–. ISBN 978-1-4757-2087-7. doi:10.1007/978-1-4757-2085-3.

[AHFS2016-2] 2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 ^2.6 ^2.7 Dacarbazine. The American Society of Health-System Pharmacists. [2016-12-08]. （原始内容存档于2017-09-11）.

[WHO23rd-3] World Health Organization. The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. hdl:10665/371090 . WHO/MHP/HPS/EML/2023.02.

[4] Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. Journal of Experimental & Clinical Cancer Research. March 2000, 19 (1): 21–34. PMID 10840932.

[5] Bhatia S, Tykodi SS, Thompson JA. Treatment of metastatic melanoma: an overview. Oncology. May 2009, 23 (6): 488–496. PMC 2737459 . PMID 19544689.

[6] Rueda Domínguez A, Márquez A, Gumá J, Llanos M, Herrero J, de Las Nieves MA, Miramón J, Alba E. Treatment of stage I and II Hodgkin's lymphoma with ABVD chemotherapy: results after 7 years of a prospective study. Annals of Oncology. December 2004, 15 (12): 1798–1804. PMID 15550585. doi:10.1093/annonc/mdh465 .

[7] Elias A, Ryan L, Aisner J, Antman KH. Mesna, doxorubicin, ifosfamide, dacarbazine (MAID) regimen for adults with advanced sarcoma. Seminars in Oncology. April 1990, 17 (2 Suppl 4): 41–49. PMID 2110385.

[8] Pearl ML, Inagami M, McCauley DL, Valea FA, Chalas E, Fischer M. Mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy for gynecological sarcomas. International Journal of Gynecological Cancer. 2001, 12 (6): 745–748. PMID 12445253. S2CID 25246937. doi:10.1046/j.1525-1438.2002.01139.x.

[9] Jelić S, Babovic N, Kovcin V, Milicevic N, Milanovic N, Popov I, Radosavljevic D. Comparison of the efficacy of two different dosage dacarbazine-based regimens and two regimens without dacarbazine in metastatic melanoma: a single-centre randomized four-arm study. Melanoma Research. February 2002, 12 (1): 91–98. PMID 11828263. S2CID 32031568. doi:10.1097/00008390-200202000-00013.

[10] Mauz-Körholz C, Hasenclever D, Dörffel W, Ruschke K, Pelz T, Voigt A, Stiefel M, Winkler M, Vilser C, Dieckmann K, Karlén J, Bergsträsser E, Fosså A, Mann G, Hummel M, Klapper W, Stein H, Vordermark D, Kluge R, Körholz D. Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study. Journal of Clinical Oncology. August 2010, 28 (23): 3680–3686. PMID 20625128. doi:10.1200/jco.2009.26.9381 .

[11] Blood（2022）: 1761–1764 https://www.researchgate.net/publication/365818412_Replacing_Procarbazine_with_Dacarbazine_in_Escalated_Beacopp_Dramatically_Reduces_the_Post_Treatment_Haematopoietic_Stem_and_Progenitor_Cell_Mutational_Burden_in_Hodgkin_Lymphoma_Patients_with_No_Appa. [2024-02-11]. 缺少或|title=为空 (帮助)

[12] Dacarbazine Injection. IndiaMart. [2024-2-11]. （原始内容存档于2024-02-28）.

[13] Aoki S, Iihara H, Nishigaki M, Imanishi Y, Yamauchi K, Ishihara M, Kitaichi K, Itoh Y. Difference in the emetic control among highly emetogenic chemotherapy regimens: Implementation for appropriate use of aprepitant. Molecular and Clinical Oncology. January 2013, 1 (1): 41–46. PMC 3956247 . PMID 24649120. doi:10.3892/mco.2012.15.

[14] Alla aktuella ändringar för Dacarbazine medac Pulver till infusionsvätska, lösning 500 mg, Medac. FASS.se. [2011-08-19]. （原始内容存档于2011-10-01）.

[15] Kewitz S, Stiefel M, Kramm CM, Staege MS. Impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression on dacarbazine resistance of Hodgkin's lymphoma cells. Leukemia Research. January 2014, 38 (1): 138–143. PMID 24284332. doi:10.1016/j.leukres.2013.11.001.

[16] Dacarbazine. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. PMID 31644220.

[17] Vardanyan RS, Hruby VJ. 30 - Antineoplastics. Synthesis of Essential Drugs. 2006: 389–418. ISBN 9780444521668. doi:10.1016/B978-044452166-8/50030-3.

[18] Marchesi F, Turrizani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L. Triazene compounds: Mechanism of action and related DNA repair systems. Pharmacological Research. October 2007, 56 (4): 275–287. PMID 17897837. doi:10.1016/j.phrs.2007.08.003.

[19] Dacarbazine. DRUGBANK oNLINE. [2024-02-11]. （原始内容存档于2023-12-02）.

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