Investigations into the induction of aneuploidy and polyploidy in mammalian cells by the anti-tussive agent noscapine hydrochloride.
Noscapine, a non-narcotic, centrally-acting anti-tussive drug induces polyploidy in Chinese hamster CHL cells; further studies were carried out to investigate whether similar effects could be induced in other rodent cells (Chinese hamster V79) and in human lymphocytes. In both cases, large increases in the frequency of polyploid cells were induced at test concentrations ranging from 15 to 120 micrograms/ml after 24 and 48 h continuous treatment in the absence of S9 mix. In addition, spindle damage was observed in V79 cells and human skin fibroblasts after 24 h treatment with test concentrations of 30 and 60 micrograms/ml. Furthermore, after treatment of human skin fibroblasts there was a marked increase in the proportion of cells containing chromosomes which had become dislocated from the spindle. Treatment of the mouse/human hybrid cell line R3-5 induced a significant increase in the number of 6-thioguanine resistant colonies and it was confirmed cytogenetically that these colonies had arisen due to loss of human chromosome 2. From these experiments it can be concluded that noscapine induces polyploidy in both rodent and human somatic cells, and that this could arise through a direct effect upon spindle structure and/or function. The aneugenic properties of noscapine are less certain and further work is required in this area. Exposure to the drug through its therapeutic use (15mg up to four times daily) could exceed, at least locally within the gastrointestinal (GI) tract, the concentration range shown to be active in these in vitro studies. An immediate topical hazard might exist within the buccal cavity and GI tract, but further confirmation of these in vitro results are required using suitable in vivo systems before definite conclusions can be made regarding any potential hazard associated with the administration of this drug.
Gatehouse
D G
DG
Genetic and Reproductive Toxicology Department, Glaxo Group Research, Ware, Hertfordshire, UK.
Stemp
G
G
Pascoe
S
S
Wilcox
P
P
Hawker
J
J
Tweats
D J
DJ
D000782:Aneuploidy; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts; D006801:Humans; D006822:Hybrid Cells; D008214:Lymphocytes / Q000187:drug effects; D016296:Mutagenesis; D009665:Noscapine / Q000633:toxicity*; D011123:Polyploidy; D008941:Spindle Apparatus / Q000187:drug effects*; D013866:Thioguanine / Q000494:pharmacology
D009665:Noscapine; D013866:Thioguanine