Clastogenic effects of two tyrosine kinase inhibitors, tyrphostin 23 and tyrphostin 46, on a transformed (CHO-K1) and on a primary embryonic chinese hamster cell line (CHE).
Protein tyrosine kinases (PTKs) play fundamental roles in signal transduction pathways. Many proliferative diseases are characterized by deregulation of PTK activity, therefore PTKs appear as promising targets in the design of anticancer drugs. Tyrphostins are a family of synthetic compounds which efficiently target specific PTKs without competing for ATP and thus are much less cytotoxic with respect to conventional therapeutic agents. We tested two tyrphostin derivatives, Tyrphostin 23 and Tyrphostin 46, on a transformed (CHO-K1) and on a primary embryonic Chinese hamster cell line (CHE) to determine whether these compounds had a genotoxic effect. We found that the tyrphostins increased sister chromatid exchange frequency in both cell lines, but induced chromosomal aberrations only in the transformed CHO-K1 cell line when treatment was in the S phase of the cell cycle, and not in primary CHE cells. Such a result could have important therapeutic implications: it could mean that deregulation of signal transduction pathways in cells which already have a deficit in cell cycle control could cause chromosomal aberrations.
Bassi
L
L
Department of Agrobiology and Agrochemistry, University of Tuscia, Via S. Camillo de Lellis, I-01100 Viterbo, Italy.
Buzzi
R
R
Fiore
M
M
Palitti
F
F
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002461:Cell Line, Transformed; D002869:Chromosome Aberrations; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects; D004791:Enzyme Inhibitors; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D008957:Models, Genetic; D009153:Mutagens; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013997:Time Factors; D020032:Tyrphostins
D004791:Enzyme Inhibitors; D009153:Mutagens; D020032:Tyrphostins; C086599:tyrphostin A46; D011505:Protein-Tyrosine Kinases; C060641:tyrphostin A23