[医药卫生]药物的致癌性.ppt

The concept of a “complete” vs. an “incomplete” carcinogen When one foreign chemical is suffient to cause cancer, either as a direct or indirect carcinogen, it is said to be complete When it requires a tumor promoter to cause cancer, it is an incomplete carcinogen Promotors are compounds that induce cells, like the mutated cancer initiator cell, to grow and divide, making more Fifteen example key events representing diverse carcinogenic modes of action DNA reactivity (covalent binding) Gene mutation Chromosomal breakage Aneuploidy Enzyme-mediated effects on DNA damage or repair Epigenetic effects Cell signaling: nuclear receptor-mediated Cell signaling: other than nuclear receptor-mediated Immune response modulation Inflammation Cytotoxicity and compensatory cell proliferation Mitogenicity Chronic metabolic or physiologic overload Nutrient deficiency related Interference with intercellular communication ICH Guideline S1B on Testing for Carcinogenicity of Pharmaceuticals choosing one 2-year rodent carcinogenicity study (rat) plus one other study that supplements the 2-year study and providing additional information that is not readily available from the 2-year study: either (1) a short- or medium-term in vivo rodent test system or (2) a 2-year carcinogenicity study in a second rodent species (mouse). the short- or medium-term models was intended to focus on the use of in vivo models providing insight into carcinogenic endpoints such as initiation–promotion rodent models and models of carcinogenesis using transgenic or neonatal rodents 药物致癌性评价方法 Stipulated Rationale for Choosing a Short- or Medium-Term Test System as Supplement to One 2- Year Bioassay ? The mechanism of carcinogenesis in the model should most likely be relevant to humans, and therefore the use of the model should be applicable to human risk assessment. ? The use of the model should supplement the 2-year carcinogenicity study and it should provide additional information that is not readily avai