Disease relevance of C07645

• These NMR studies utilized a human histiocytic lymphoma cell line (U937), embedded in agarose gel threads, and perfused with medium containing synthetically derived metabolites (4-hydroxycyclophosphamide, aldophosphamide, and phosphoramide mustard) [1].
• 31P NMR and cell perfusion techniques were used to investigate the conversion of the individual enantiomers of aldophosphamide (AP) to carboxyphosphamide (CBP) as catalyzed by aldehyde dehydrogenase in human erythroleukemia K562 cells [2].

High impact information on C07645

• Certain mouse and human hematopoietic progenitor cells also contain an aldehyde dehydrogenase that catalyzes the detoxification of aldophosphamide, but the specific identity of this enzyme remains to be established [3].
• Thus, competition between N-isopropyl-p-formylbenzamide and aldophosphamide for the catalytic site on the enzyme should strongly favor the former, and the rate at which aldophosphamide is detoxified should be markedly retarded [3].
• The prototypic drug compound 2-hexenopyranoside of aldophosphamide was prepared, which releases aldophosphamide by acid-catalyzed hydrolysis [4].
• Acetaldophosphamide (A-ALD), a novel in vitro active and stable derivative of aldophosphamide, kills human bone marrow-derived granulocyte-macrophage colony-forming cells (GM-CFC) independent of the cell cycle [5].
• However, the aldophosphamide intermediate inactivated by human class 1 ALDH (hALDH-1) has not proven to be a good substrate for the purified hALDH-3 [6].

Biological context of C07645

• Cyclophosphamide and 4-Hydroxycyclophosphamide/aldophosphamide kinetics in patients receiving high-dose cyclophosphamide chemotherapy [7].
• Class 1 aldehyde dehydrogenases (ALDH-1) function as drug resistance gene products by catalyzing the irreversible conversion of aldophosphamide, an active metabolite of cyclophosphamide, to an inert compound [8].
• Succinic semialdehyde dehydrogenase-catalyzed biotransformation of aldophosphamide may also be of some in vivo importance [9].
• These findings suggest that the acquired resistance against 4HC is a consequence of transcriptional activation of two genes, i.e., one encoding the G6PD, a major enzyme regenerating anti-alkylating GSH, and the other encoding ALDH1, which has a high activity for oxidation of aldophosphamide derived from 4HC [10].
• Cell death resulting from 4-HO-CP/AP perfusions was mimicked by perfusion with acrolein or an acrolein producing but non-alkylating, dechloro-CP analog [11].

Anatomical context of C07645

• 1 microM, estimated aggregate erythrocyte ALDH-1-catalyzed aldophosphamide oxidation, viz [12].
• 2. The cell membrane was permeable to 4-hydroxycyclophosphamide and aldophosphamide and less permeable to phosphoramide mustard [13].

Associations of C07645 with other chemical compounds

• Direct oxidation of the CPA metabolic intermediate aldophosphamide (ALDO) is catalyzed efficiently in vitro by the class 1 ALDH isozyme, but the involvement of the class 3 isozyme in OAP resistance is problematic since in vitro studies do not show efficient oxidation of ALDO [14].
• The reaction kinetics of cis-2b, -2c, and -2d are qualitatively similar to those of 2a in that they undergo ring opening to the respective aldophosphamide intermediates 3, which can reclose to the cis- or trans-4-hydroxy isomers or undergo base-catalyzed beta-elimination to generate the corresponding phosphoramide mustard products 4 [15].
• Tumors resistant to chemotherapeutic oxazaphosphorines such as cyclophosphamide often overexpress aldehyde dehydrogenase (ALDH), some isozymes of which catalyze the oxidization of aldophosphamide, an intermediate of cyclophosphamide activation, with formation of inert carboxyphosphamide [16].
• Catalysis of aldophosphamide and acetaldehyde or benzaldehyde oxidation was apparently by the same isozyme(s) in the soluble fraction [17].
• The Km values for aldose reductase- and aldehyde reductase-catalyzed reduction of aldophosphamide to alcophosphamide were 0.15 and 1.6 mM, respectively [18].

Gene context of C07645

• The two polymorphic forms of hALDH3 had identical kinetics with either benzaldehyde or aldophosphamide as substrate [16].
• Three, namely ALDH-1, ALDH-2 and succinic semialdehyde dehydrogenase, catalyzed the oxidation of aldophosphamide; Km values were 52, 1193, and 560 microM, respectively [9].
• Aldose reductase and aldehyde reductase accounted for 94 and 6%, respectively, of total placental pyridine nucleotide-dependent enzyme-catalyzed aldophosphamide (160 microM) reduction [18].

Analytical, diagnostic and therapeutic context of C07645

• Serum cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide concentrations were assayed on the first cycle of the treatment by reversed-phase high-pressure liquid chromatography with ultraviolet detection [19].

References