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.
|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|
- Kryshen K.L., Muzhikyan A.A., Gaidai D.S., Zaikin K.O., Katelnikova A.E., Samsonov M.Y., Mukhametshina E.I., Konopleva G.E., Shipaeva E.V., Dmitrieva A.A., Shagiakhmetov F.S., Popova A.O., Makarova M.N., Makarov V.G. A two-year study of cancerogenic potential of the new opioid receptor antagonist ondelopran in rats // Research’n Practical Medicine Journal. – 2019. – 6(2). – Р. 58-68. ABSTRACT. Opioid receptor antagonists are widely used for the treatment of alcohol dependence. Currently, original drug Odelepran (INN: ondelopran) with a unique binding profile to all three types of human opioid receptors (μ, κ, δ) is being developed by R-Pharm. Aim of the study. To investigate a cancerogenic potential of the new opioid receptor antagonist ondelopran in a twoyear study in rats. Materials and methods. The study cancerogenic potencial was performed in male and female Wistar rats at the age of 8–10 weeks at the start of experiment. All animals were allocated to 8 groups. Each group consisted of 50 animals of each sex. Test item (ondelopran film-coated tablets, 125 mg), was administered to the animals intragastrically as a tablets suspension in 1% starch solution daily, 5 days a week for 24 months in two doses: 10 mg/kg (equivalent therapeutic dose for humans) and 100 mg/kg. Animals of control groups were administered with placebo and vehicle (1% starch solution). Clinical observation and examination of animals were conducted weekly to detect any signs of intoxication; dynamics of the body weight and registration of animal deaths were also assessed. To assess the rate of the pathological changes, the macro- and microscopic examination of inner organs and neoplasms was conducted. Results. During the study the mortality rates did not differ between the groups. Clinical signs and symptoms of intoxication upon administration of the tested item and placebo were not observed. Neoplasms were found in the organs of all groups of animals. More than 30 variants of neoplasms were identified upon pathomorphological examination. The identified tumors are typical for rats and considered as spontaneous age-related pathology. There was no statistically significant differences between groups in the total incidence of tumors. Conclusion. To conclude the above said, the test item of the ondelopran film-coated tablets, 125 mg have no carcinogenic properties [Full text is available in Russian] https://doi.org/10.17709/2409-2231-2019-6-2-6
- Kryshen K.L., Gaidai D.S., Katelnikova A.E., Muzhikyan A.A., Mukhametshina E.I., Samsonov M.Y., Konopleva G.E., Shipaeva E.V., Dmitrieva A.A., Shagiakhmetov F.S., Popova A.O, Makarova M.N., Makarov V.G. A two-year carcinogenicity study of the new opioid receptor antagonist ondelopran in rats // Toxicology letters. – 2019. – Vol. 314S1 – S305-306. A two-year carcinogenicity study of the new opioid receptor antagonist ondelopran in rats