Received for publication June 1, 2004.
Revised August 23, 2004.
Accepted for publication August 24, 2004.

THE COMBI-TARGETING CONCEPT: DISSECTION OF THE BINARY MECHANISM OF ACTION OF THE COMBI-TRIAZENE SMA41 IN VITRO AND ANTITUMOR ACTIVITY IN VIVO

Abstract

We have previously reported the synthesis of SMA41, a unimolecular combination of an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor of the quinazoline class and a DNA-damaging monomethyltriazene termed "combi-molecule." Hydrolysis of SMA41 gives rise to an intact TK inhibitor (SMA52) capable of inhibiting EGF-induced EGFR autophosphorylation and a DNA-targeting methyldiazonium species. Herein we showed that SMA41 blocked EGF-induced EGFR autophosphorylation by an irreversible mechanism, suggesting that it may covalently damage the receptor in these cells. More importantly, this was associated with significant inhibition of MAP kinase activation in A431 cells. On the other hand, in cells treated with ¹⁴C-SMA41, radio-HPLC detection of both N7- and O6-methylguanine revealed an almost complete repair of the O6-methylguanine lesions and a greater tolerance of the N7-methylguanine adducts 24 h post-treatment. In contrast to temozolomide (a cyclic triazene used in the clinic) and the reversible inhibitor SMA52, SMA41 induced significant cell cycle arrest in S, G2 and M phases after a 2 h drug exposure. Furthermore, in vivo studies demonstrated that SMA41 was well-tolerated and at 200 mg/kg, it showed approximately 2-fold greater antiproliferative activity than SMA52 in A431 cells implanted in immunocompromised SCID mice. These results suggest that the binary targeting properties of SMA41 are associated with a binary cascade of events in the cells that appear to culminate into significant growth inhibition in vitro and in vivo.

Key words: AGT, DNA damage, EGFR, MGMT, temozolomide, triazene

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