Formation of active products of benzaldehyde dimethane sulfonate (NSC 281612, DMS612) in human blood and plasma and their activity against renal cell carcinoma lines.
Benzaldehyde dimethane sulfonate (BEN, DMS612, NSC281612) is an alkylating agent with activity against renal cell carcinoma and is being evaluated clinically. To support clinical trials, we developed an LC-MS/MS assay to detect and quantitate BEN and its metabolites/decomposition products. We tested the stability and products of BEN and benzoic acid dimethane sulfonate (BA) in plasma, blood and five renal carcinoma cell lines in vitro. Further, we determined the IC(50) of BEN, BA and four of their products in these cell lines. Low temperature and pH stabilized the analytes, and utilizing this resulted in an accurate, precise and reproducible assay. The half-lives of BEN and BA added to plasma in vitro were 220 and 5 min, while the half-life of BEN in whole blood was 18 min. The generation and degradation of up to 12 analytes were monitored, and structures confirmed with available authentic standards. The IC(50) for BEN was 5- to 500-fold lower than that of any of its products, while the cellular metabolic activity toward BEN correlated with ALDH activity and IC(50) values. We detected six of the in vitro products and their respective glucuronides in murine plasma after dosing BEN. The information gained from these experiments will be instrumental in the evaluation of the pharmacology of BEN in ongoing human trials.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Robert A
RA
Parise
Bean N
BN
Anyang
Julie L
JL
Eiseman
Merrill J
MJ
Egorin
Joseph M
JM
Covey
Jan H
JH
Beumer
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001547:Benzaldehydes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid / Q000379:methods; D005260:Female; D020719:Glucuronides / Q000097:blood; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008698:Mesylates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods; D013696:Temperature; D013997:Time Factors; D062366:para-Aminobenzoates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
C578465:4-(bis(2-((methylsulfonyl)oxy)ethyl)amino)-2-methylbenzoic acid; D018906:Antineoplastic Agents, Alkylating; D001547:Benzaldehydes; D020719:Glucuronides; D008698:Mesylates; C492379:NSC281612; D062366:para-Aminobenzoates; D000444:Aldehyde Dehydrogenase