Molecular analysis of the in vivo metabolism and biodistribution of metabolically and non-metabolically activated combi-molecules of the triazene class.
Combi-molecules are novel agents designed to be hydrolyzed into two bioactive species: an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor + a DNA alkylating agent. With the purpose of enhancing the tumour concentration of the bioactive species, we synthesized and compared the activities of RB107, a quinazolinotriazene designed to generate the bioactive BJ2000 upon hydrolysis, ZRDM and RB107ZR that require metabolic activation to generate BJ2000. The results showed that RB107 released the highest level of BJ2000 and its degradation product FD105 in vivo and high levels of the DNA alkylating methyl diazonium ion in the brain, kidney, liver and the DU145 tumours as confirmed by (14)C-labeling. The results in toto suggest that RB107 was stable enough to deliver the bioactive species to the tumour site and for optimal tumour distribution of the bioactive species, combi-molecules of the triazene class must be designed to be primarily degraded by hydrolytic cleavage and not by metabolic activation.
Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University/Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada.
Qiyu
Q
Qiu
Anne-Laure
AL
Larroque
Bernard
B
Gibbs
Youqiang
Y
Fang
Younes
Y
Lakhrissi
Jean-Paul
JP
Soucy
Shadreck
S
Mzengeza
Zakaria
Z
Rachid
Bertrand J
BJ
Jean-Claude
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution; D014226:Triazenes / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D011355:Prodrugs; D014226:Triazenes; D066246:ErbB Receptors