Mechanism of action of a novel "combi-triazene" engineered to possess a polar functional group on the alkylating moiety: evidence for enhancement of potency.
Previous studies showed that SMA41, a 3-methyltriazene termed "combi-molecules" possessing a dual epidermal growth factor receptor (EGFR)/DNA targeting properties induced potent antiproliferative activity against alkylating-agent-resistant cells expressing EGFR in vitro. However, despite its marked potency, its antitumour activity in vivo was significantly hampered by its poor hydrosolubility and the moderate reactivity of its alkylating moiety. To circumvent this problem, we designed the quinazolinotriazene ZRBA1 to contain a N,N-dimethylaminoethyl group grafted to the 3-position of the triazene chain where it could serve both as a water soluble and a more potent alkylating moiety. ZRBA1 exhibited five-fold stronger EGFR tyrosine kinase (TK) inhibitory activity (IC(50)=37nM) than SMA41, decomposed into a 6-amino-quinazoline FD105 (IC(50)=200nM) and preferentially blocked EGF- over platelet-derived growth factor (PDGF)-or serum-induced cell growth. ZRBA1 induced DNA damage, concomitantly blocked EGF-stimulated EGFR phosphorylation by a partially irreversible mechanism in MDA-MB-468 breast cancer cells, and induced partially irreversible antiproliferative activity. It also prevented EGFR-mediated MAP kinase activation and, in contrast to FD105 and SMA41, induced high levels of apoptosis. Furthermore, ZRBA1 showed significantly greater antitumor activity (p<0.05) than SMA41 in the human MDA-MB-468 breast cancer xenograft model. The results in toto indicate that the appendage of N,N-dimethylaminoethyl to combi-triazenes may be an alternative to the reduced hydrosolubility and also to the lack of potency of monofunctional combi-triazenes against resistant tumours.
Cancer Drug Research Laboratory, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West Rm M-719, Montreal, Quebec, Canada H3A 1A1.
Fouad
F
Brahimi
Zakaria
Z
Rachid
James P
JP
McNamee
Moulay A
MA
Alaoui-Jamali
Ana M
AM
Tari
Bertrand J
BJ
Jean-Claude
D017209:Apoptosis; D045744:Cell Line, Tumor; D020552:Comet Assay; D004249:DNA Damage; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D006868:Hydrolysis; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D014226:Triazenes / Q000737:chemistry / Q000494:pharmacology*
D010982:Platelet-Derived Growth Factor; D011799:Quinazolines; D014226:Triazenes; C503825:ZRBA1 compound; D066246:ErbB Receptors