Drugs are one of the most important treatment methods for diseases, especially for early prevention and control of conditions, and have an irreplaceable role. However, some drugs may be carcinogenic while having the pharmacological effects of preventing and treating diseases, so conducting carcinogenicity tests before drug marketing is also an essential part of drug development.
According to the latest global cancer burden data released by the World Health Organization’s International Agency for Research on Cancer (IARC), China is the world’s number one country regarding new cancer cases and deaths, making it a true “cancer power.” Cancer, the number one killer of human health today, is a disease that people are familiar with but avoid. With the rapid increase in cancer incidence, more and more people are suffering from “cancer panic,” many unscrupulous businessmen take advantage of this psychology to exaggerate or conceal the carcinogenicity of certain items for profit.
In medical science, cancer refers to malignant tumors originating from epithelial tissues, so “cancer” generally refers to all malignant tumors. Cancer has biological characteristics such as abnormal cell differentiation and proliferation, uncontrolled growth, infiltration, metastasis, etc. Its occurrence is a multifactorial and multi-step complex process divided into three processes: carcinogenesis, cancer promotion, and evolution.
However, the etiology of cancer is not yet fully understood, and the factors related to it are mainly exogenous (lifestyle habits, environmental pollution, occupational, natural and biological factors, chronic irritation and trauma, medical factors) and endogenous (genetic factors, immune factors, endocrine factors). In the list of carcinogens issued by the World Health Organization, the more representative ones, such as tobacco, alcohol, aflatoxin, salted fish, Helicobacter pylori (infection), aristolochic acid, betel nut, etc., are classified as a class of carcinogens.
Also, some drugs may be carcinogenic while having the pharmacological effect of preventing and treating diseases. Drug-induced carcinogenesis can be divided into two major categories: general drug-induced carcinogenesis and anticancer drug-induced carcinogenesis.
General drug carcinogenesis
When some drugs are used for a long time and in large doses, they may entirely suppress the body’s humoral and cellular immune functions. When cellular immunity is stopped, the body cannot remove the newly mutated cancer cells in time, leading to cancer. According to clinical pharmacological studies, dozens of drugs have been classified as possible cancer-causing drugs:
- Chloramphenicol (including chloramphenicol tablets, injections, and eye drops, which can cause leukemia)
- Phenobarbital (can cause brain tumors and liver cancer)
- Azathioprine (can cause lymphoma)
- Amphetamines (can cause lymphoma)
- Progesterone (can cause cervical and ovarian cancer)
- Amphiregulin (can cause breast cancer)
- Iron dextran (can cause soft tissue sarcoma at the injection site)
- Phenytoin sodium (can cause lymphoma)
- Protaxon (can cause leukemia)
- Coal tar ointment (can cause skin cancer)
- Antamine (can cause malignant tumors of the gastrointestinal and respiratory tracts)
Anticancer drugs cause cancer
The reason is that anticancer drugs fundamentally interfere with cell metabolism, inhibit cell proliferation, lead to cell mutation, cause chromosomal aberration and cell metamorphosis, and induce cancer; moreover, anticancer drugs can inhibit humoral and cellular immunity, and cause immune guardianship disorder, leading to new tumors. For example:
- Tamoxifen (triamcinolone): the drug of choice for the treatment of breast cancer in women, which can cause endometrial cancer and stomach cancer;
- Cyclophosphamide (CTX), nitrogen mustard: can cause bladder cancer and lymphosarcoma, and can cause malformations in pregnant women
- Methotrexate (MTX): a folic acid-based antineoplastic drug commonly used in China to treat psoriasis, can cause kidney cancer, nasopharyngeal carcinoma, and cervical cell carcinoma
- Setipate, 6-mercaptopurine (6-MP), and Marilan, etc.: can cause skin cancer and leukemia, etc.
- Leucovorin: can induce bronchial and vulvar cancers
- Azathioprine: can cause lymphoma and cervical cancer
Therefore, carcinogenicity testing of drugs is also an essential part of drug development. Carcinogenicity testing aims to identify the potential tumorigenicity in animals and thus evaluate the associated risk to humans. Carcinogenicity testing is necessary when:
- There is Evidence of the potential carcinogenicity of such drugs to humans
- Their conformational relationships suggest a risk of carcinogenicity
- Evidence of precancerous lesions in repeated dosing toxicity tests
- Prolonged retention of the prodrug or its metabolites in the tissues resulting in local tissue reactions or other pathophysiological changes
Need for additional testing:
The relevance of the results of animal carcinogenicity tests to human safety evaluations is often a source of controversy. Further studies may be needed to explore the mode of action and thus determine whether there is a potential for carcinogenic effects in humans. Studies of the mechanism of action are valuable in evaluating the relevance of tumor appearance in animals to human safety.
Drug carcinogenicity testing must be performed after certain critical study information is available, including the results of genotoxicity studies, drug administration populations, clinical dosing regimens, animal and human pharmacokinetics (selectivity, dose-response relationships), and results of repeated administration toxicity tests. Suppose repeated administration toxicity tests in any species of animals (including non-rodents) may indicate that the subject is immunosuppressive, hormonally active, or otherwise considered harmful to humans. In that case, this information should be deemed in the experiments’ design to evaluate potential carcinogenicity further. The selection of a specific carcinogenicity test method should be problem-specific. Due to the complexity of the carcinogenic process, only some test methods can predict the potential carcinogenicity of all drugs in use.
The current carcinogenicity tests are mainly long-term and additional in vivo carcinogenicity tests. These are complemented by other in vivo carcinogenicity tests performed in rodents in the short or medium term or a second long-term carcinogenicity test to provide additional information not readily available from long-term carcinogenicity tests.
Many studies have shown that the diversity of test procedures can elicit rodent carcinogenic responses. Still, some are considered irrelevant or of minimal relevance to human risk assessment. Thus, conducting one long-term carcinogenicity test (rather than two) may make resources available for other methods to reveal potential carcinogenicity relevant to humans. The scientific evaluation and judgment of all the data from a long-term carcinogenicity trial and other appropriate trial studies, a method known as the “weight of evidence approach,” can improve the accuracy of determining the carcinogenicity of a test substance in humans.
The standard animal carcinogenicity test is a lifetime test using two sexes and two animals, 50 animals per dose group. Usually, rats and mice are used, more than three dose groups, and details of the required histopathological examination. Positive Evidence of chemical carcinogenicity should include the following:
- The number of tumors in each organ and site
- The induction of rare tumors
- The latency period for the appearance of tumors
- The increase in the total number of tumors seen
The traditional method of selecting high doses in chemical carcinogenicity tests uses the maximum tolerated dose (MTD) as a criterion, generally derived from 3-month toxicity test data. These indicators should be considered in dose selection for drug carcinogenesis trials: pharmacokinetic indicators, absorption saturation, pharmacodynamic indicators, maximum feasible dose, dose limits, etc.
Medicilon has a quality management system of drug safety evaluation based on AAALAC Accreditation and domestic and international GLP standards， is available for system evaluation services covering multiple toxicity endpoints, and features globally recognized pathology research results to support our safety evaluation.
Medicilon’s preclinical research department, which can conduct carcinogenicity testing, has a GLP laboratory, experienced toxicologists, pathologists, and clinical testing technical teams to provide professional safety evaluation solutions, test data, and reports to fully support our clients’ preclinical IND to NDA studies worldwide. Currently, we can conduct conventional long-term rodent carcinogenicity tests and have extensive experience in working short-term or mid-term rodent in vivo test systems (e.g., Tg.rasH2 mouse model), and can provide scientific, rational, and practical test combinations based on the characteristics of the subjects.
