Abstract
BackgroundThe initial pharmacokinetic study of a new anticancer agent (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum (IV) (LA-12) was complemented by proteomic screening of rat plasma. The objective of the study was to identify new LA-12 target proteins that serve as markers of LA-12 treatment, response and therapy monitoring.MethodsProteomic profiles were measured by surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS) in 72 samples of rat plasma randomized according to LA-12 dose and time from administration. Correlation of 92 peak clusters with platinum concentration was evaluated using Spearman correlation analysis.ResultsWe identified Retinol-binding protein 4 (RBP4) whose level correlated with LA-12 level in treated rats. Similar results were observed in randomly selected patients involved in Phase I clinical trials.ConclusionsRBP4 induction is in agreement with known RBP4 regulation by amantadine and cisplatin. Since retinol metabolism is disrupted in many cancers and inversely associates with malignancy, these data identify a potential novel mechanism for the action of LA-12 and other similar anti-cancer drugs.
Highlights
The initial pharmacokinetic study of a new anticancer agent (OC-6-43)-bis(acetato)(1-adamantylamine) amminedichloroplatinum (IV) (LA-12) was complemented by proteomic screening of rat plasma
We studied the biological properties of an alternative platinum(IV) complex called LA-12, (OC-6-43)-bis(acetato) (1-adamantylamine)amminedichloroplatinum(IV), containing 1-adamantylamine instead of cyclohexylamine non-leaving ligand [6] which provides different chemical and biological properties and which has entered into clinical evaluation
To independently verify that the identified peak in the rat experimental system is Retinol-binding protein 4 (RBP4) and to investigate RBP4 induction by LA-12 in humans, we analyzed plasma samples using western blotting with an RBP4 specific antibody. This antibody to human RBP4 was not effective in rat samples, we demonstrated that circulating RBP4 levels correlated well with platinum levels in human plasma of 12 randomly selected patients involved in Phase I clinical trials of LA-12
Summary
The initial pharmacokinetic study of a new anticancer agent (OC-6-43)-bis(acetato)(1-adamantylamine) amminedichloroplatinum (IV) (LA-12) was complemented by proteomic screening of rat plasma. Carboplatin (cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II)) and oxaliplatin (trans-[R, R-cyclohexane-1,2-diammine]oxalatoplatinum(II)), have been approved by the Food and Drug Administration for clinical use [2,3]. The requirement for their intravenous administration, in addition to substantial side effects, led to the development of a new generation of platinum-based drugs such as satraplatin ((OC-6-43)-bis (acetato)amminedichloro(cyclohexylamine)platinum(IV)), known as JM216, the first orally administered platinum compound evaluated in clinical trials [2,4,5]. LA-12 has shown higher anti-tumor activity in comparison with cisplatin and satraplatin, favorable pharmacokinetics and relatively low acute toxicity in a panel of pre-clinical in vivo studies [9,10,11]. LA-12 has been shown to have a greater inhibitory effect than cisplatin on heat shock protein 90 function [16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
