The combi-targeting concept: dissection of the binary mechanism of action of the combi-triazene SMA41 in vitro and antitumor activity in vivo.
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.
Matheson
Stephanie L
SL
Cancer Drug Research Laboratory, Department of Medicine, McGill University Health Center/Royal Victoria Hospital, 687 Pine Ave. West, M7.19, Montreal, QC H3A 1A1, Canada.
McNamee
James P
JP
Wang
Taiqui
T
Alaoui-Jamali
Moulay A
MA
Tari
Ana M
AM
Jean-Claude
Bertrand J
BJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001835:Body Weight; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004815:Epidermal Growth Factor / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011799:Quinazolines; C421705:SMA-41; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases