Antineoplastic Drugs as a Potential Risk Factor in Occupational Settings: Mechanisms of Action at the Cell Level, Genotoxic Effects, and Their Detection Using Different Biomarkers

U članku je prikazana osnovna podjela antineoplastičnih lijekova prema mehanizmima djelovanja na razini stanice. Objašnjeni su mehanizmi genotoksičnosti najvažnijih vrsta lijekova koji se primjenjuju u okviru uobičajenih protokola za liječenje zloćudnih novotvorina. Navedena je važeća klasifi kacija antineoplastika prema kancerogenom potencijalu, podaci o mutagenom potencijalu te je prikazana njihova podjela u skladu s anatomsko-terapijsko-kemijskim sustavom klasifi kacije. Sustavno su prikazani najvažniji rezultati svjetskih i hrvatskih istraživanja na populacijama radnika izloženih antineoplasticima, provedenih u razdoblju 1980.-2009. s pomoću četiri najčešće primjenjivane metode: analize izmjena sestrinskih kromatida, analize kromosomskih aberacija, mikronukleus-testa i komet-testa. Objašnjena su osnovna načela navedenih metoda te raspravljene njihove prednosti i nedostaci. Biološki pokazatelji daju važne podatke o individualnoj osjetljivosti profesionalno izloženih ispitanika koji mogu poslužiti unaprjeđenju postojećih uvjeta rada i upravljanju rizicima pri izloženosti genotoksičnim agensima. Na osnovi prednosti i nedostataka citogenetičkih metoda zaključeno je da je mikronukleus-test, koji podjednako uspješno dokazuje klastogene i aneugene učinke, jedna od najboljih metoda dostupnih za otkrivanje štetnih djelovanja antineoplastičnih lijekova koji su u aktivnoj primjeni.This article brings an overview of the mechanisms of action of antineoplastic drugs used in the clinical setting. It also describes the genotoxic potentials of the most important classes of antineoplastic drugs involved in standard chemotherapy protocols. Classifi cation of antineoplastic drugs according to the IARC monographs on the evaluation of carcinogenic risks to humans is accompanied by data on their mutagenicity and the most recent updates in the Anatomical Therapeutic Chemical (ATC) Classifi cation System. We report the main fi ndings of biomonitoring studies that were conducted in exposed healthcare workers all over the world between 1980 and 2009 using four biomarkers: sister chromatid exchanges, chromosome aberrations, micronuclei. and the comet assay. The methods are briefl y explained and their advantages and disadvantages discussed. Biomarkers provide important information on individual genome sensitivity, which eventually might help to improve current working practices and to manage the risks related with exposure to genotoxic agents. Taking into consideration all known advantages and drawbacks of the existing cytogenetic methods, the micronucleus assay, which is able to detect both clastogenic and aneugenic action, is the most suitable biomarker for assessing harmful effects of antineoplastic drugs currently used in health care

Carcinogenicity of Biopharmaceuticals

This book provides an overview of the nonclinical testing strategies that are used to asses and de-risk the genotoxicity and carcinogenicity properties of human pharmaceuticals. It includes a review of relevant ICH guidelines, numerous case studies where follow-up studies were conducted to further investigate positive findings, and practical considerations for the use of alternative and emerging tests

Megacólon tóxico fatal por cytomegalovirus em paciente com retocolite ulcerativa idiopática: relato de caso e revisão de literatura Fatal toxic megacolon due to cytomegalovirosis in a patient with ulcerative colitis: case report and review

Racional - O megacólon tóxico é complicação grave e pouco freqüente na retocolite ulcerativa idiopática. Ocorre, geralmente, em pacientes cuja doença ativa é resistente ao tratamento clínico e, em algumas situações, o fator desencadeante é desconhecido. A infecção pelo cytomelogalovirus em seres humanos em geral é evento subclínico; entretanto, em pacientes imunocomprometidos a primoinfecção ou mesmo a reativação de infecção latente pode ter amplas repercussões clínicas, uma das quais o desencadeamento de megacólon tóxico. Objetivo - Descrever um caso de megacólon tóxico fatal por cytomegalovirose em paciente com retocolite ulcerativa idiopática. Paciente - Masculino, 38 anos, com clínica de diarréia e perda ponderal cuja investigação mostrou tratar-se de retocolite ulcerativa idiopática e para a qual foi instituída terapêutica imunossupressora vigorosa. Resultados - Evoluiu com quadro clínico de megacólon tóxico, sendo submetido a colectomia total. Complicações clínicas culminaram no óbito pós-operatório e o estudo anatomopatológico do cólon revelou doença ativa, associada a ulcerações confluentes na base das quais foram observadas células com alterações características da cytomegalovirose. Conclusão - A cytomegalovirose deve ser considerada como um dos agentes causadores de megacólon tóxico em retocolite ulcerativa.<br>Background - The toxic megacolon is a rare and severe complication of ulcerative colitis. In general it complicates patients with active colitis that are resistant to clinical treatment and, in some cases, the developing factor is unknown. Cytomegalovirus infection in humans in general is a subclinical condition. However, in patients with immunodeficiency the primary infection or the reactivation of latent infection could have enormous clinical effects. One of these effects is the toxic megacolon. Aim - To report a case of fatal toxic megacólon due to cytomegalovirosis in a patient with ulcerative colitis. Patient - A male patient, 38 years old, with complaints of diarrhea and weight loss. The diagnosis of ulcerative colitis was made and a vigorous immunossupressive therapy was performed. Results - Due to the evolution to a toxic megacolon the patient was submitted to colectomy. In the post-operatory period there were severe clinical complications and the patient died. The pathological study of the colon revealed active ulcerative colitis, associated with confluent ulcerations and numerous cells with cytomegalic nuclear inclusions. Conclusion - The cytomegalovirosis must be considered as one of the causal agent of toxic megacolon in ulcerative colitis