The interest in octamethylpyrophosphoramide (schradan) as a systemic insecticide (l-3) and in the treatment of myasthenia gravis (4) emphasizes the need for a better understanding of its mode of toxic action. Exposure of mammals to schradan leads to death, with the typical symptoms of acetylcholine poisoning after a definite lag period (5, 6). Yet schradan is only about one-millionth as effecti...

The anti-neoplastic prodrug, cyclophosphamide, requires biotransformation to phosphoramide mustard (PM), which partitions to volatile chloroethylaziridine (CEZ). PM and CEZ are ovotoxicants, however their ovarian biotransformation remains ill-defined. This study investigated PM and CEZ metabolism mechanisms through the utilization of cultured postnatal day 4 (PND4) Fisher 344 (F344) rat ovaries...

BACKGROUND The diaphragm is resistant to competitive neuromuscular blocking agents. Because of the competitive mechanism of action of tubocurarine, the rate of hydrolysis of acetylcholine at the neuromuscular junction may modulate its neuromuscular blocking effect. The authors compared the neuromuscular blocking effect of tubocurarine on isolated diaphragm and extensor digitorum longus (EDL) mu...

Cyclophosphamide (CP) is an alkylating agent and its tumor cell-killing activity is mainly due to its DNA alkylation. Phosphoramide mustard and acrolein are the two active metabolites of CP. CP metabolites can react with carboxyl (-C[O]OH), mercapto (-SH), amino (-NH2), phosphate (-PO3H2) and hydroxyl (-OH) groups, and can form cross-links with DNA and proteins (Todorova et al., 2009). The prec...

It has been known for over a decade that the alkylating agent Cyclophosphamide (CY) has a differential effect on the immune system, exerting greater toxicity against B than T lymphocytes CY selectively depletes the B-cell rich peripheral splenic pulp and exerts a greater inhibition of stimulation of B-cells by pokeweed mitogen than T cells by phytohaemagglutinin (PHA; Stockman et al., 1973). Th...

Gene directed-enzyme prodrug therapy (GDEPT) is an approach for sensitization of tumor cells to an enzymatically activated, otherwise nontoxic, prodrug. Cytochrome P450 2B1 (CYP2B1) metabolizes the prodrugs cyclophosphamide (CPA) and ifosfamide (IFA) to produce the cytotoxic substances phosphoramide mustard and isophosphoramide mustard as well as the byproduct acrolein. We have constructed a re...