Abstract
For mutagenicity testing, primary lymphocytes or mammalian cell lines are employed. However, the true target for carcinogenic action of mutagenic chemicals may be stem cells. Since hematopoietic cancers induced by chemical agents originate at the hematopoietic stem cell (HSC) stage and since one of the side effects of chemotherapeutic cancer treatment is the induction of secondary tumors, often leukemias, HSC may be a suitable cell system. We compared the sensitivity of HSC with the genotoxicity testing cell line TK6 for chromosomal mutations. HSC were less sensitive than TK6 cells for the genotoxic effects of the model genotoxins and chemotherapeutic agents doxorubicin, vinblastine, methyl methanesulfonate (MMS) and equally sensitive for mitomycin C (MMC). However, loss of viability after mitomycin C treatment was higher in HSC than in TK6 cells. Among the factors that may influence sensitivity for genomic damage, the generation or response to reactive oxygen species (ROS) and the effectiveness of DNA damage response can be discussed. Here we show that HSC can be used in a standard micronucleus test protocol for chromosomal mutations and that their sensitivity was not higher than that of a classical testing cell line.
Highlights
For mutagenicity testing, primary lymphocytes or mammalian cell lines are employed
hematopoietic stem cell (HSC) have been used as toxicological test system[15], but here we demonstrate the utility of a standard testing micronucleus protocol with chemotherapeutic agents in HSC
The question of the feasibility of the micronucleus test is important with regard to the relevance of mutagenicity testing in hematopoietic cells
Summary
Primary lymphocytes or mammalian cell lines are employed. the true target for carcinogenic action of mutagenic chemicals may be stem cells. Concerning DNA damage, it is thought that stem cells have very rigid controls and that unrepaired lesions will likely lead to cell death, in order to protect the organism and to keep the stem cell pool genetically intact[3,4] Because it is highly relevant whether the tested substance is able to induce mutations in stem cells, the question arises whether lymphocytes and cell lines are a suitable surrogate system for stem cells in genotoxicity testing. One of the side effects of chemotherapeutic cancer treatment is the induction of secondary tumors[7,8], about 5% of which are leukemias and lymphomas[8] For both aspects, i.e. testing of substances for admission, and assessment of the mutagenicity of chemotherapeutic agents, HSC may be a suitable cell system. Doxorubicin is a mutagenic intercalating and radical-generating anthracycline, the alkaloid vinblastine is a spindle poison and aneugenic agent, MMS is an alkylating agent which is often used as positive control in mutation assays, and the cytotoxic antibiotic MMC is an effective DNA-crosslinker
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