Genotoxicity Study

• Genotoxicity tests include in vitro and in vivo tests used to detect the mutagenic potential of test substances that directly or indirectly induce genetic damage through different mechanisms. These tests can detect DNA damage and its fixation. The fixation of DNA damage in the form of genetic mutations, extensive chromosomal damage, or recombination is generally considered to underlie heritable effects and is an important factor in the multistage development of malignant tumors. Changes in the number of chromosomes are also associated with tumorigenesis and may indicate the possibility of non-diploid reproductive cells.
  Compounds that are positive in genotoxicity tests are considered to be potential human carcinogens and/or mutagens. Results of genotoxicity test may play an important role in the interpretation of carcinogenicity test results. Therefore, in the process of drug development, the purpose of genotoxicity test is to predict whether the test substance is mutagenic through a series of tests, and play an important role in reducing the risks for clinical trial subjects and the population who will use the drug after marketing authorization.

Service items:

• According to the endpoint of the genotoxicity test, the studies can be divided into three major categories： gene mutation, chromosomal aberration, and DNA damage; according to the test system, they can be divided into in vitro studies and in vivo studies. No single study can detect all mutagenic mechanisms related to tumorigenesis. Therefore, a combination of studies is usually used to comprehensively assess the mutagenic risk of the test substance.
  According to the endpoint of the genotoxicity test, the studies can be divided into three major categories： gene mutation, chromosomal aberration, and DNA damage; according to the test system, they can be divided into in vitro studies and in vivo studies. No single study can detect all mutagenic mechanisms related to tumorigenesis. Therefore, a combination of studies is usually used to comprehensively assess the mutagenic risk of the test substance.
  Option one:        (1) A bacterial reverse mutation test(2) An in vitro cytogenetic test to detect chromosomal damage (in vitro metaphase chromosome aberration test or in vitro micronucleus test), or an in vitro mouse lymphoma cell Tk gene mutation test; (3) An in vivo genotoxicity test, usually a rodent hematopoietic cell chromosome damage test, used to detect micronucleus or metaphase cell chromosome aberrations.
• Option two:         (1) A bacterial reverse mutation test(2) In vivo genotoxicity tests using two different tissues, usually a rodent hematopoietic cell micronucleus test and a second in vivo test. In vivo studies could be conducted with single-dose or repeated-dose study designs.

  If the test result is negative, the test substance does not possess mutagenic potential . Test substances with positive results from the standard battery of tests may require further studies depending on their therapeutic use.

Main research contents:

• Ames and Mini-Ames tests: bacteria are used as test system to observe the mutation of genes. Compared with the Ames test, Mini-Ames reduces the amount of culture medium and test substance used in each dish at the same concentration of the test substance, and is often used for screening candidate compounds.
  Chromosomal aberration test: Typically conducted using Chinese hamster lung fibroblast (CHL) cells as test cells. The test cells are exposed to the test substance under in vitro culture conditions, and then the structural and quantitative changes in the chromosomes are evaluated under microscopic observation through staining of cell chromosomes.
  Micronucleus test: It is a commonly genetic toxicity test and used to evaluate the degree of genetic damage of test substances to biological cells. This test mainly determines whether a substance is genetically toxic by observing the formation of micronuclei in the cell nucleus.

Test cycle:

• Test Name	Test Cycle
  Bacterial reverse mutation test data delivery	Experimental results will be obtained one week after adding the sample
  Turnaround time of bacterial reverse mutation test	About two months to finalize the report
  Chromosome aberration experimental data delivery	About one month to get the experimental results
  Turnaround time of chromosomal aberration study	About two months at the earliest for the final report
  Micronucleus experimental data delivery	Experimental results will be available in about one month
  Turnaround time of micronucleus study	About two months at the earliest for the final report

Service advantages:

• Medicilon possesses a state-of-the-art platform, AAALAC-certified laboratories and experienced scientists to ensure that drug efficacy and safety assessments are conducted in the most professional manner while complying with global regulatory standards. From preclinical research to IND filing, Medicilon provides flexible service options to help customers achieve their development goals effectively. With a dedicated team of experts in drug safety evaluation and practical experience, we ensure high-quality data and rapid turnaround times, supporting various drug safety assessments. Our toxicology studies can be conducted according to non-GLP or GLP standards. The R&D platform was rated as Shanghai R&D Public Service Platform. As of December 15^th, 2023, Medicilon has completed 24 complete IND projects (including APIs, preparations, PD, PK, and safety evaluation).

Experimental instruments:

• Instruments for Ames test:Vertical laminar flow cleaning workbench, biological safety cabinet, oven, mold incubator, automatic culture medium preparer, refrigerator, Freezer, ultra-low temperature refrigerator, autoclave, pure water meter, balance, pipette, microplate reader, gas bath constant temperature oscillator, vortex mixer, dispensing pump, mini desktop vacuum pump
  Instruments for chromosome test:Centrifuge, electric thermostatic water bath, refrigerator, freezer, ultra-low temperature refrigerator, autoclave, pure water meter, water-jacketed carbon dioxide incubator, automatic cell counter, inverted microscope, pipette, microscope, vertical laminar flow cleaning workbench
  Instruments for micronucleus test: microscope

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