The incidence of positive results in the mouse lymphoma TK assay (MLA) in pharmaceutical screening and their prediction by MultiCase MC4PC

• Published in: Mutagenesis Vol. 26; no. 4; pp. 529 - 532
• Main Authors: Fellows, Michael D., Boyer, Scott, O'Donovan, Michael R.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2011
• Subjects: Animals; Biological and medical sciences; Carcinogenicity Tests - methods; Cell Line, Tumor; Drug Evaluation, Preclinical; Fundamental and applied biological sciences. Psychology; Lymphoma - pathology; Mice; Molecular and cellular biology; Molecular genetics; Mutagenesis. Repair; Software; Structure-Activity Relationship; Thymidine Kinase - genetics; Screening; Thymidine kinase; Vertebrata; Mammalia; Mutagenesis; Mouse; Enzyme; Transferases; Rodentia; Prediction; Lymphoma; Incidence
• ISSN: 0267-8357; 1464-3804
• DOI: 10.1093/mutage/ger012

There are published data indicating that the mouse lymphoma TK assay (MLA) has an unacceptably high incidence of positive results, hence it was decided to review the MLA data generated in this laboratory for potential drug candidates. Of the 355 compounds tested, only 52 (15%) gave positive results so, even if it is assumed that all of these are non-carcinogens, the incidence of 'false positive' predictions of carcinogenicity is much lower than the 61% apparent from analysis of the literature. Furthermore, only 19 compounds (5%) were positive by a mechanism that could not be associated with the compounds primary pharmacological activity or positive responses in other genotoxicity assays. It should be noted that the majority of these compounds were not bacterial mutagens so, in most cases, the positive results were an additional indicator of genotoxicity. However, data are not available to assess any risk they might present. At least for pharmaceuticals, it appears that the MLA does not generate as many positive results as is commonly believed, and it is against this incidence that the performance of other in vitro genotoxicity tests should be compared. The predictive accuracy of the program MultiCase MC4PC was also examined using these results. The sensitivity and specificity were found to be 62 and 38%, respectively; in fact, 62% of all compounds were predicted to be positive irrespective of whether they were actually positive or negative. It was concluded that, in its current state of development, M4PC cannot be considered sufficiently accurate to be used to predict the activity of pharmaceuticals in the MLA.