Evaluation of Cell Proliferation in Rat Mammary Glands Is Not Predictive of the Carcinogenic Potential of Insulin In Vivo
| Autor: | Anne-Marie Mølck, Ingrid Sjögren, Jette Nowak, Vivi F. H. Jensen, Inger Thorup, Peter R. Brinck |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Carcinogenesis medicine.medical_treatment Mammary gland Toxicology Rats Sprague-Dawley Random Allocation 03 medical and health sciences 0302 clinical medicine Insulin Detemir Predictive Value of Tests In vivo Internal medicine medicine Animals Hypoglycemic Agents Carcinogen Cell Proliferation 030304 developmental biology Insulin detemir Estrous cycle 0303 health sciences biology business.industry Cell growth Insulin Rats Proliferating cell nuclear antigen Insulin Long-Acting Endocrinology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Female business Biomarkers medicine.drug |
| Zdroj: | International Journal of Toxicology. 39:560-576 |
| ISSN: | 1092-874X 1091-5818 |
| Popis: | For nonclinical safety-assessment of insulin analogues in vivo, mitogenic effects are compared to that of human insulin. Besides histopathologic evaluation, this usually includes assessment of cell proliferation (CP) in mammary glands. Insulin analogue X10 is recommended as positive control, due to its known carcinogenic effect in rat mammary glands. Here, we discuss the mitogenic effect of insulin in vivo and use of X10 as positive control. We present results from 4 nonclinical rat studies evaluating effects of repeated dosing with insulin detemir (≤26 weeks) or degludec (52 weeks) in mammary glands. Studies included human insulin-dosed groups as comparators, CP, and histopathologic evaluation. One study included an X10-dosed group (26 weeks), another ≤3 weeks of dosing with X10 or human insulin evaluating effects of these comparators. Neither human insulin, insulin detemir, degludec, nor X10 induced mammary tumors or increased CP in the studies. The CP marker proliferating cell nuclear antigen varied within/between studies and was not correlated with the remaining markers or CP fluctuations during estrous cycle, whereas the other CP markers, Ki-67 and 5-bromo-2′-deoxyuridine (BrdU), correlated with estrous cycle changes and each other. In conclusion, we propose that the mitogenic effect of insulin in rat mammary glands is weak in vivo. Cell proliferation evaluation in nonclinical safety assessment studies is not predictive of the carcinogenic potential of insulin, thus, the value of including this end point is debatable. Moreover, X10 is not recommended as positive control, due to lack of proliferative effects. Typical CP markers vary greatly in quality, BrdU seemingly most reliable. |
| Databáze: | OpenAIRE |
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