MUTAGENS OF POTENTIAL SIGNIFICANCE 171 



Motulsky: A few years ago, I became interested in the problem of 

 mutations induced by chemotherapy with alkylating agents in Hodg- 

 kin's disease and related disorders. I wrote to a number of people to 

 get cases of this sort. In most instances, both male and females became 

 sterile after the treatment. 



Goldstein: Apart from their use in the treatment of cancer, alky- 

 lating agents may be used for an entirely different purpose. This, I 

 think, is worth some discussion, because it is a case in which some- 

 thing could easily be done. There is a compound known as phenoxy- 

 benzamine which is a one-armed nitrogen mustard, and which, for 

 reasons that nobody understands, is specifically effective in the body 

 in blocking adrenergic receptors. For the diagnosis of certain types of 

 hypertension, this drug has been used to lower the blood pressure by 

 making the arteriolar receptors unresponsive to circulating sympa- 

 thomimetic compounds. The very long duration of the adrenergic 

 blockade is consistent with an alkylating mechanism. In a compound 

 of this kind, there is a cyclizing to form an immonium ion which is 

 thought to be the active alkylating agent. These active ionic inter- 

 mediates can then be destroyed by hydrolysis in water or in serum, but 

 at rates which vary greatly from compound to compound (53). 



It is not known why this type of alkylating compound has its specific 

 pharmacological effect, but on the basis of its alkylating properties it 

 can be assumed until proved otherwise that such a drug is mutagenic. 

 I think this should raise a serious question about the wisdom of its 

 use especially since other drugs can achieve the same pharmacologic 

 purpose. 



Addendum : There has recently been reported (37) a new class of ganglionic block- 

 ing agents which would presumably be used in the treatment of hypertension. 

 These are modified nitrogen mustards which take advantage of the good oral 

 absorption of uncharged compounds. Once in the blood stream, the cyclic im- 

 monium ion is formed, conferring the positive charge required for effective gan- 

 glionic blockade. These proposed drugs, known as "pronium" compounds, could, I 

 believe, be considered a priori to be mutagenic alkylating agents and hence genetic 

 hazards to man. Since other types of compound are available for reduction of 

 blood pressure, there would seem to be no good reason to risk the therapeutic 

 employment of "pronium" derivatives. 



It was mentioned yesterday that aldehydes have been shown to be 

 mutagenic in a number of organisms, although the mechanism is not 

 clear. They may act through the formation of a complex with peroxides. 

 Certain aldehydes are in use as drugs. 



A straightforward example is methenamine, which is a condensation 

 product of ammonia and formaldehyde. This compound is a urinary 



