Carcinogenicity study of the drugs

A problem about possibility of conducting clinical trials of pharmacological agents (PA) from the point of view of its carcinogenic safety may be solved based on short screening tests (SSTs) but not after receiving results of 2-3-year experiments on tumor induction in animals, which may be surplus in case of insufficient effectiveness of PA in clinical practice.

In case of negative results in SSTs an additional assessment on carcinogenicity for mammals by the traditional method is needed for medicines having structural similarity with known carcinogens or when getting of uncertain or inconsistent results. New fixed combinations of pharmacological agents which are planned for wide clinical use and having structural similarity of any component of a combination with known carcinogens, mutagens or their metabolites should also be tested in mammals.

Carcinogenicity: general provisions of study

SSTs for revealing potential carcinogenicity are based on the contemporary data about mechanisms of chemical carcinogenesis. The full scope of the concept “carcinogenic compounds” includes all substances which are able to increase in a population the number of tumors in different locations compared to the appropriate control. It includes not only full carcinogens which are capable to induce tumors without additional influences, but also the inducing agents, promoters and co-carcinogens.

Nowadays the process of chemical carcinogenesis is conventionally divided into two stages: initiation and promotion. On the first stage there are persistent changes in genetic apparatus of a cell; on the second –conditions for preferred proliferation of transformed cells are made mainly due to epigenetic effects.

On initiation stage the most essential event is DNA damage by highly reactive metabolites of carcinogens, which results in appearance of point mutations, transposition of blocks of genes and etc. It is supposed that in those cases when these events are related with sites of proto-oncogenes, the last ones may be activated and initiate malignant transformation of a cell. The same result may be in case of inactivation of suppressor genes (anti-oncogenes). The high degree of causal relationship between mutagenesis and carcinogenesis and also high coincidence rate of carcinogenic and mutagenic properties among different chemical compounds led to the creation of numerous tests in which the ability to cause DNA damage, gene and chromosomal mutations serves as an index of expected blastomogenic activity.

Promoters at biologically active concentrations do not damage DNA but cause pleiotropic action on cells by changing in particular the structure and function of cell membranes and breaking permeability of intercellular contacts. Accordingly, there are SSTs intended to reveal these features.

One of the integral indices of carcinogenic activity of an agent may be its ability to make cells malignant in a culture, which is used in some SSTs.

Assessment of cancerogenic properties of medicines is performed according to the Manual for conducting preclinical studies of drugs. Under the editorship of Mironov A.N., Bunatyan N.D. et al., M., publishing house “Grif and K”, 2012; ICH – Guidance for Industry S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals.

DNA-comet assay. SYBR Green I dye. DNA in cells after processing by 8 mM etilmetansulfonate

DNA-comet assay. SYBR Green I dye. DNA in cells after processing by 8 mM etilmetansulfonate

451 Carcinogenicity Studies
453 Combined Chronic Toxicity/Carcinogenicity Studies
478 Genetic Toxicology: Rodent Dominant Lethal Test
482 Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells in vitro
487  In Vitro Mammalian Cell Micronucleus Test