Cyclophosphamide (CP) is metabolized to the reactive intermediates, phosphoramide mustard (PAM) and acrolein (AC), which have generally different molecular binding targets. Sodium 2-mercaptoethanesulfonic acid (MESNA) has been used clinically to alleviate hemorrhagic cystitis caused by CP chemotherapy, has exhibited anticarcinogenic effects in rats exposed to CP during a long-term bioassay, and...

The DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) has been shown to protect cells from the toxic and mutagenic effect of alkylating agents by removing lesions from the O6 position of guanine. O6-Benzylguanine (BG) is a potent inactivator of AGT, resulting in an increase in the sensitivity of cells to the toxic effects of chemotherapeutic alkylating agents. Chinese hamster ovary ...

Nitroheterocyclic prodrugs have been used to treat trypanosomal diseases for more than 40 years. Recently, the key step involved in the activation of these compounds has been elucidated and shown to be catalyzed by a type I nitroreductase (NTR). This class of enzyme is normally associated with bacteria and is absent from most eukaryotes, with trypanosomes being a major exception. Here we exploi...

In this study, the synthesis and spectroscopic characterization of new phosphoramides based on 3-amino-5-methylisoxazole with the formula R2P(O)[NH-C4H4NO], R = C6H5O (1), C6H5 (2), RP(O)[NH-C4H4NO]2, R = C6H5O (3), CH3-C6H4O (4), C6H5NH (5), (C6H5)ClP(O)[NH-C4H4NO] (6) and two lanthanide complexes [Ln(2)2(NO3)3(EtOH)]·EtOH, Ln(III) = Ce (7) and Eu (8), have been reported. The structural study ...

Lipopolysaccharides (LPSs) and lipooligosaccharides (LOSs) are major components of the cell surface of Gram-negative bacteria with diverse roles in bacterial pathogenesis of animals and plants that include elicitation of host defenses. Little is known about the mechanisms of perception of these molecules by plants and about the associated signal transduction pathways that trigger plant immunity...

Human class 1 aldehyde dehydrogenase (hALDH-1) can oxidize aldophosphamide, a key aldehyde intermediate in the activation pathway of cyclophosphamide and other oxazaphosphorine (OAP) anti-cancer alkylating agents. Overexpression of class 1 ALDH (ALDH-1) has been observed in cells selected for survival in the presence of OAPs. We used transfection to induce de novo expression of human ALDH-1 in ...

Previous investigations with a spectrum of tu mors demonstrated that nitrogen mustards (17) and triethylene melamine (19) had a definite in hibitory or destructive action on certain types of tumors. In view of the fact that the biological ac tivity of these compounds is believed to be due to the formation of ethylenimmonium ions in the case of the former (7) and the presence of ethylenimine gro...

Cyclophosphamide is used to treat a wide range of human malignancies. However, it is also a known carcinogen associated with induction of therapy-related leukemia and bladder cancer. The DNA repair protein, O-alkylguanine-DNA alkyltransferase (AGT), protects cells from the toxic and mutagenic effects of O-alkylating agents. We report here the contribution of AGT in protecting against the toxic ...

O-Benzylguanine (BG) inactivates O-alkylguanineDNA alkyltransferase (AGT), resulting in an increase in the sensitivity of cells to the toxic effects of Oalkylating agents. BG significantly enhances the cytotoxicity and decreases the mutagenicity of nitrogen mustards [i.e., phosphoramide mustard (PM), melphalan, and chlorambucil], a group of alkylating agents not known to produce O-adducts in DN...