Safe decontamination of cytostatics from the nitrogen mustards family. Part one: cyclophosphamide and ifosfamide

Abstract

IntroductionMacrocrystalline oxides of alkaline earth metals (Mg and Ca) or light metals (Al and Ti) can respond to standard warfare agents such as sulfur mustard, soman, or agent VX. In this paper, we compared the decontamination ability of sodium hydroxide (NaOH) and sodium hypochlorite (NaClO) for nitrogen mustards (cyclophosphamide [CP] and ifosfamide [IFOS]) with a new procedure using a destructive sorbent based on nanocrystalline and nanodispersive titanium dioxide (TiO2) as a new efficient and cheap material for complete decontamination of surfaces.MethodsTitanium (IV) dioxide nanoparticles were prepared by the homogeneous hydrolysis of titanium(IV) oxysulfate (TiOSO4) with urea. The as-prepared TiO2 nanoparticles were used for the fast and safe decontamination of cytostatics from the nitrogen mustard family (CP and IFOS) in water. The adsorption–degradation process of cytostatics in the presence of TiO2 was compared with decontamination agents (0.01 M solution of sodium hydroxide and 5% solution of sodium hypochlorite). The mechanism of the decontamination process and the degradation efficiency were determined by high-performance liquid chromatography with mass spectrometry.ResultsIt was demonstrated that a 0.01 M solution of sodium hydroxide (NaOH) decomposes CP to 3-((amino(bis(2-chloroethyl)amino)phosphoryl)oxy)propanoic acid and sodium hypochlorite formed two reaction products, namely, IFOS and 4-hydroxy-cyclophosphamide. IFOS is cytotoxic, and 4-hydroxy-cyclophosphamide is a known metabolite of CP after its partial metabolism by CYP/CYP450. IFOS degrades in the pres¬ence of NaOH to toxic IFOS mustard. Titanium(IV) dioxide nanoparticles adsorbed on its surface CP after 5 minutes and on IFOS after 10 minutes. The adsorption–degradation process of CP in water and in the presence of TiO2 led to 4-hydroxy-cyclophosphamide and IFOS, respectively, which decayed to oxidation product 4-hydroxy-ifosfamide.ConclusionNanodispersive TiO2 is an effective degradation agent for decontamination of surfaces from cytostatics in medical facilities.

Historical Perspective and Current Trends in Anticancer Drug Development

“…Recognition followed that less toxic analogs might show potential in the field of cancer therapy, which led to the synthesis of nitrogen derivatives of mustard gas. Currently, several structural analogs of mustard gas are used in oncological therapy, including cyclophosphamide, chlorambucil, ifosfamide, and melphalan [24,25] (Figure 2).…”

“…Recognition followed that less toxic analogs might show potential in the field of cancer therapy, which led to the synthesis of nitrogen derivatives of mustard gas. Currently, several structural analogs of mustard gas are used in oncological therapy, including cyclophosphamide, chlorambucil, ifosfamide, and melphalan [24,25] (Figure 2). Active metabolites of these compounds attach an alkyl group to DNA guanine, resulting in the formation of irreversible intra-and interchain DNA cross-links, which inhibit DNA replication and eventually lead to apoptosis (Figure 3) [26][27][28][29].…”

Suvremena sredstva za dekontaminaciju bojnih otrova

“…Utvrdili su da je pomoću getita dopiranog cirkonijem moguće postići gotovo potpunu razgradnju somana i VX-a u vremenu od približno 30 min. 3,28,37,41 Zahtjev za razvojem poboljšanih materijala sposobnih za brzu adsorpciju i dekontaminaciju kemijskih ratnih agensa u sobnim uvjetima usmjerio je istraživanja prema novoj generaciji sorbensa i katalitički aktivnih materijala, koji uključuju metalne okside, polioksometalate i metal-organske mreže.…”

Removal of anthracycline cytostatics from aquatic environment: Comparison of nanocrystalline titanium dioxide and decontamination agents

“…Recently, we have dealt with a detailed study of the degradation of cytostatics pertaining to the class of anthracycline derivatives (doxorubicin and epirubicin) [23], anthraquinone derivates (mitoxantrone) [24] and nitrogen mustards family (cyclophosphamide and ifosfamide) [25] in decontamination agents (NaOH, NaClO) and on the surface of nanostructured adsorbents (TiO 2 , MnO 2 ).…”