Phosphoramide Drugs In Ww1
It is somewhat ironic to discover that the pharmacophore of phosphoramide drugs currently used as antitumor agents was originally utilized for the purpose of chemical warfare, most prominently so in World War I. Sulfur mustard, the precursor to phosphoramide drugs, was employed to great effect as a wounding agent in the characteristic trench warfare of WWI; Being a dense gas, sulfur mustard settled in trenches and created persistent environmental hazards for troops. Exposure to sulfur mustard, while usually non-fatal, induced symptoms of blistering, respiratory illness, inflammation of the eyes, vomiting, and internal bleeding, consequently incapacitating exposed soldiers for weeks at a time.
In contrast with its terrifying application toward
human conflict, one of the first experimental therapeutic implementations of mustard occurred in 1942 with the administration of nitrogen mustard to a cancer patient known as JD, for whom radiotherapy and surgery had failed. Doctors Gilman and Goodman at the Yale School of Medicine persuaded JD to undergo nitrogen mustard chemotherapy, and the resulting successes of this treatment arguably contributed much impetus towards the development and study of nitrogen mustard and derivatives as potential and actual anticancer agents in use today. In fact, Gilman is an author of a 1946 publication in the journal Science detailing both the cytotoxic effects (“...resembles in many ways that of x-rays.”) and the mechanism of action (“...intramolecular cyclization...to form a cyclic onium cation with liberation of Cl-.”) of sulfur and nitrogen mustards. It may be of interest to note that the initial development of nitrogen mustards as therapeutics occurred before the structure of DNA was solved, and although the reactivity of the cyclic onium cation was accepted as the mechanism of drug action, it was not fully understood at the time the reason for therapeutic effect when applied against certain tumors. The damaging effects of mustards on rapidly multiplying cells known from its historical use as a warfare agent in addition to subsequent experimentation both in vitro and in vivo upon animals contributed to a hypothesis of mustard nucleotoxicity, the verification of which occurring much later. At the time of publication approximately 150 patients had received nitrogen mustard treatment, with varying but sufficient success to warrant further development.
In contrast with its terrifying application toward
human conflict, one of the first experimental therapeutic implementations of mustard occurred in 1942 with the administration of nitrogen mustard to a cancer patient known as JD, for whom radiotherapy and surgery had failed. Doctors Gilman and Goodman at the Yale School of Medicine persuaded JD to undergo nitrogen mustard chemotherapy, and the resulting successes of this treatment arguably contributed much impetus towards the development and study of nitrogen mustard and derivatives as potential and actual anticancer agents in use today. In fact, Gilman is an author of a 1946 publication in the journal Science detailing both the cytotoxic effects (“...resembles in many ways that of x-rays.”) and the mechanism of action (“...intramolecular cyclization...to form a cyclic onium cation with liberation of Cl-.”) of sulfur and nitrogen mustards. It may be of interest to note that the initial development of nitrogen mustards as therapeutics occurred before the structure of DNA was solved, and although the reactivity of the cyclic onium cation was accepted as the mechanism of drug action, it was not fully understood at the time the reason for therapeutic effect when applied against certain tumors. The damaging effects of mustards on rapidly multiplying cells known from its historical use as a warfare agent in addition to subsequent experimentation both in vitro and in vivo upon animals contributed to a hypothesis of mustard nucleotoxicity, the verification of which occurring much later. At the time of publication approximately 150 patients had received nitrogen mustard treatment, with varying but sufficient success to warrant further development.