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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

The Combi-Targeting Concept: Dissection of the Binary Mechanism of Action of the Combi-Triazene SMA41 in Vitro and Antitumor Activity in Vivo

Cancer Drug Research Laboratory, Department of Medicine, McGill University Health Center/Royal Victoria Hospital, Montreal, Quebec, Canada

We have previously reported the synthesis of SMA41, a unimolecular combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of the quinazoline class and a DNA-damaging monomethyltriazene termed "combimolecule". Hydrolysis of 1-[4-(m-tolylamino)-6-quinazolinyl]-3-methyltriazene (SMA41) gives rise to an intact TKI [6-amino-4-(3-methylanilino)quinazoline; SMA52] capable of inhibiting epidermal growth factor (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 mitogen-activated protein kinase activation in A431 cells. In cells treated with [¹⁴C]SMA41, radio-high-performance liquid chromatography 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 24 h after a 2-h drug exposure. Furthermore, in vivo studies demonstrated that SMA41 was well tolerated. 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 seem to culminate into significant growth inhibition in vitro and in vivo.

This article has been cited by other articles:

				Q. Qiu, J. Domarkas, R. Banerjee, N. Merayo, F. Brahimi, J. P. McNamee, B. F. Gibbs, and B. J. Jean-Claude The Combi-Targeting Concept: In vitro and In vivo Fragmentation of a Stable Combi-Nitrosourea Engineered to Interact with the Epidermal Growth Factor Receptor while Remaining DNA Reactive Clin. Cancer Res., January 1, 2007; 13(1): 331 - 340. [Abstract] [Full Text] [PDF]