Öz
Vesikan ajanlar, özellikle sülfür mustard (SM) ve nitrojen mustard (NM) analogları, yıkıcı kimyasal toksisite ile onkolojide terapötik potansiyel arasında çarpıcı bir ikilik sergiler. SM’in sitotoksik yüzü, bifonksiyonel alkilleme, glutatyon/ATP tükenmesi ve PARP hiperaktivasyonu yoluyla hızlı hücresel hasara yol açar. Bu süreç onkozis/nekroz, akut deri vezikülasyonu, göz hasarı ve solunum yolu yaralanmaları ile kendini gösterir. On yıllar içinde, genotoksik yüz, kalıcı DNA zincirler arası çapraz bağlar, oksidatif stres, kronik inflamasyon ve alan kanserleşmesi yoluyla ortaya çıkarak akciğer ve deri skuamöz hücreli kanser riskini artırır. Özellikle İran-Irak Savaşı gaz mağdurlarına yapılan epidemiyolojik çalışmalar bu uzun vadeli kanser risklerini doğrulamıştır. Mekanistik araştırmalar, reaktif oksijen türleri aracılı mutagenez, kök hücre nişi bozulması ve klonal çoğalmanın vesikan kaynaklı karsinogenezde merkezi rol oynadığını göstermektedir. Çelişkili olarak, aynı alkilleyici mekanizmalar NM’ların terapötik gelişimini tetiklemiş, modern kemoterapinin temelini oluşturmuş ve ikincil malignite ile biyogüvenlik kaygılarını ortaya koymuştur. Gelecek araştırmalar erken teşhis biyobelirteçleri, PARP ve reseptör etkileşimli protein kinaz 1inhibitörleri ile akut toksisitenin azaltılması ve antitümör etkinliği korurken genomik hasarı minimize eden ileri taşıyıcı sistemler üzerine odaklanmalıdır. Vesikan ajanların tarihi, toksik bir kimyasalın mekanizmalarının anlaşılmasıyla tedavi aracına dönüştürülebileceğini ve kanser tedavisinin evrimini nasıl yönlendirebileceğini göstermektedir. Bu derleme, PubMed indeksli ‘vezikan ajanlar’, ‘sülfür mustard’, ‘nitrojen mustard’, ‘kemoterapi’ ve ‘karsinogenez’ gibi anahtar kelimelerin taranarak İngilizce ve Türkçe literatürün incelenmesiyle derlenmiştir.
Anahtar Kelimeler: Vesikan ajanlar, sülfür mustard, nitrojen mustard, kemoterapi, karsinogenez, alkilleyici ajan, kimyasal savaş
Kaynakça
Fitzgerald GJ. Chemical warfare and medical response during World War I. Am J Public Health. 2008;98:611-625. Erratum in: Am J Public Health. 2008;98:1158.
Szinicz L. History of chemical and biological warfare agents. Toxicology. 2005;214:167-81.
Balali-Mood M, Hefazi M. The pharmacology, toxicology, and medical treatment of sulphur mustard poisoning. Fundam Clin Pharmacol. 2005;19:297-315.
Jan Y, Heck D, Laskin D, Laskin J. DNA damage signaling in the cellular responses to mustard vesicants. Toxicology letters. 2020.
Kehe K, Balszuweit F, Steinritz D, Thiermann H. Molecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering. Toxicology. 2009;263:12-9.
Ghanei M, Harandi AA. Long term consequences from exposure to sulfur mustard: a review. Inhal Toxicol. 2007;19:451-6.
Khateri S, Ghanei M, Keshavarz S, Soroush M, Haines D. Incidence of lung, eye, and skin lesions as late complications in 34,000 Iranians with wartime exposure to mustard agent. J Occup Environ Med. 2003;45:1136-43.
Laskin JD, Black AT, Jan YH, et al. Oxidants and antioxidants in sulfur mustard-induced injury. Ann N Y Acad Sci. 2010;1203:92-100.
Sezigen S, Eyison RK, Ortatatli M, Kilic E, Kenar L. Myelosuppression and acute hematological complications of sulfur mustard exposure in victims of chemical terrorism. Toxicol Lett. 2020;318:92-8.
Balali-Mood M, Hefazi M. Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol. 2006;99:273-82.
Xiaoji Z, Xiao M, Rui X, et al. Mechanism underlying acute lung injury due to sulfur mustard exposure in rats. Toxicol Ind Health. 2016;32:1345-57.
Beigi Harchegani A, Khor A, Tahmasbpour E, Ghatrehsamani M, Bakhtiari Kaboutaraki H, Shahriary A. Role of oxidative stress and antioxidant therapy in acute and chronic phases of sulfur mustard injuries: a review. Cutan Ocul Toxicol. 2019;38:9-17.
Panahi Y, Roshandel D, Sadoughi MM, Ghanei M, Sahebkar A. Sulfur Mustard-Induced Ocular Injuries: Update on Mechanisms and Management. Curr Pharm Des. 2017;23:1589-97.
Munro NB, Talmage SS, Griffin GD, et al. The sources, fate, and toxicity of chemical warfare agent degradation products. Environ Health Perspect. 1999;107:933-74.
Noort D, Benschop HP, Black RM. Biomonitoring of exposure to chemical warfare agents: a review. Toxicol Appl Pharmacol. 2002;184:116-26.
Ludlum DB, Austin-Ritchie P, Hagopian M, Niu TQ, Yu D. Detection of sulfur mustard-induced DNA modifications. Chem Biol Interact. 1994;91:39-49.
Jost P, Svobodova H, Stetina R. Induction and repair of DNA cross-links induced by sulfur mustard in the A-549 cell line followed by a comet assay. Chem Biol Interact. 2015;237:31-37.
Deans AJ, West SC. DNA interstrand crosslink repair and cancer. Nat Rev Cancer. 2011;11:467-80.
Smith WJ, Dunn MA. Medical defense against blistering chemical warfare agents. Arch Dermatol. 1991;127:1207-13.
Layali I, Shahriary A, Rahmani Talatappe N, Tahmasbpour E, Rostami H, Beigi Harchegani A. Sulfur mustard triggers oxidative stress through glutathione depletion and altered expression of glutathione-related enzymes in human airways. Immunopharmacol Immunotoxicol. 2018;40:290-296.
Ramos E, Gil-Martín E, De Los Ríos C, et al. Melatonin as modulator for sulfur and nitrogen mustard-induced inflammation, oxidative stress and DNA damage: molecular therapeutics. Antioxidants (Basel). 2023;12:397.
Mol MA, van de Ruit AM, Kluivers AW. NAD+ levels and glucose uptake of cultured human epidermal cells exposed to sulfur mustard. Toxicol Appl Pharmacol. 1989;98:159-65.
Gould NS, White CW, Day BJ. A role for mitochondrial oxidative stress in sulfur mustard analog 2-chloroethyl ethyl sulfide-induced lung cell injury and antioxidant protection. J Pharmacol Exp Ther. 2009;328:732-9.
Rosenthal DS, Simbulan-Rosenthal CM, Iyer S, Spoonde A, Smith W, Ray R, Smulson ME. Sulfur mustard induces markers of terminal differentiation and apoptosis in keratinocytes via a Ca2+-calmodulin and caspase-dependent pathway. J Invest Dermatol. 1998;111:64-71.
Ghabili K, Agutter PS, Ghanei M, Ansarin K, Panahi Y, Shoja MM. Sulfur mustard toxicity: history, chemistry, pharmacokinetics, and pharmacodynamics. Crit Rev Toxicol. 2011;41:384-403.
Zhang B, Zhang Y. Necroptosis in sulfur mustard-induced toxicity. J Appl Toxicol. 2021;41(1):33–41.
Chappell G, Pogribny IP, Guyton KZ, Rusyn I. Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: a systematic literature review. Mutat Res Rev Mutat Res. 2016;768:27-45.
Zubel T, Hochgesand S, John H, et al. A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure. Arch Toxicol. 2019;93:61-79.
Panahi Y, Fattahi A, Zarei F. Ghasemzadeh N. Next-generation sequencing approaches for the study of genome and epigenome toxicity induced by sulfur mustard. Arch Toxicol 2018;92:3443-3457.
Yu W, Tu Y, Long Z, et al. Reactive oxygen species bridge the gap between chronic inflammation and tumor development. Oxid Med Cell Longev. 2022;2022:2606928.
Zafarghandi MR, Soroush MR, Mahmoodi M, Naieni KH, Ardalan A, Dolatyari A, Falahati F, Mirmohammadkhani M, Mousavi B, Ghanei M. Incidence of cancer in Iranian sulfur mustard exposed veterans: a long-term follow-up cohort study. Cancer Causes Control. 2013;24:99-105.
Hosseini-khalili A, Haines DD, Modirian E, Soroush M, Khateri S, et al. Mustard gas exposure and carcinogenesis of lung. Mutat Res. 2009;678:1-6.
Owens M, Thyagarajan A, Travers JB, Sahu RP. Mechanistic insights and pharmacological approaches for nitrogen and sulfur mustards and their implications as therapeutic agents. J Appl Toxicol. 2025;45:1417-1425.
Gilman A. The initial clinical trial of nitrogen mustard. Am J Surg. 1963;105:574-8.
Chabner BA, Roberts TG Jr. Timeline: chemotherapy and the war on cancer. Nat Rev Cancer. 2005;5:65-72.
Pedersen-Bjergaard J, Andersen MK, Christiansen DH. Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation. Blood. 2000;95:3273-9.
