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 transducti on pathways. Many proliferative diseases are characterized by deregulation of PTK activity, therefore PTKs appear as promising targets in the design o f anticancer drugs. Tyrphostins are a family of synthetic compounds which e fficiently 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 transform ed (CHO-K1) and on a primary embryonic Chinese hamster cell line (CHE) to d etermine whether these compounds had a genotoxic effect. We found that the tyrphostins increased sister chromatid exchange frequency in both cell line s, 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 primar y CHE cells. Such a result could have important therapeutic implications: i t could mean that deregulation of signal transduction pathways in cells whi ch already have a deficit in cell cycle control could cause chromosomal abe rrations.