468 R. E. HANDSCHUMACHER AND A. D. WELCH 



partial dependence of leukemia cells upon amethopterin. However, in view 

 of the profound effect of amethopterin on the folic acid reductases, the fail- 

 ure of the analog to be reduced by these enzymes, 29 ■ 86 and the remarkable 

 resistance of the agent to metabolic alteration (see below), it appears most 

 unlikely that amethopterin could function in a manner somewhat resem- 

 bling folic acid. 69 ' 77 For these reasons, therefore, the concept of interference 

 by amethopterin with the function of an unknown infectious agent harbored 

 by certain strains of amethopterin-resistant tumor cells, or with some dele- 

 terious host reaction upon such cells, appears worthy of further considera- 

 tion. It must be concluded that the phenomenon of amethopterin-depend- 

 ence has yet to be explained, and that the presumed role of FH 4 in 

 the formation or activity of certain antibodies is deserving of intensive 

 investigation. 



Some aspects of the pharmacology of amethopterin should be mentioned 

 briefly, since recent studies in man, 87 using fluorimetric procedures, indicate 

 that the drug not only is rapidly and completely absorbed from the ali- 

 mentary tract, but also is excreted in the urine without very significant 

 metabolic alteration. However, earlier studies, 88 using a biological assay, 

 indicated partial inactivation of the analog, as have findings with certain 

 microorganisms. 89, 90 In the tissues, amethopterin appears to be distributed 

 largely in the total extracellular water, 87 despite the fact that its toxic effects 

 are exerted primarily on the folic acid reductases of the cytoplasm (at least 

 of liver cells). Since, at body pH levels, the compound is more than 99 % dis- 

 sociated as an acid, it is now predictable 90 ' 91 that only minute amounts of 

 amethopterin should be transported from the blood to the cerebrospinal 

 fluid and the tissues of the brain. 92 Only by intrathecal administration has 

 it been possible to obtain high concentrations of amethopterin in the cere- 

 brospinal fluid. 92 The grave chemotherapeutic importance of this failure 

 of amethopterin to pass from the blood to the cerebral extracellular fluid 

 and thus to reach those neoplastic cells which enter the central nervous 

 system early in various initially amethopterin-sensitive malignant diseases, 

 has been indicated by important recent investigations in patients with acute 

 leukemia 92 or choriocarcinoma. 23, 24 The possibility of altering the structure 



86 S. F. Zakrzewski, Federation Proc. 18, 357 (1959). 



87 M. V. Freeman, J. Pharmacol. Exptl. Therap 122, 154 (1958). 



88 J. H. Burchenal, CJ. B. Waring, R. R. Ellison, and H. C. Reilly, Proc. Soc. Exptl. 

 Biol. Med. 78, 603 (1951). 



89 M. Webb, Biochim. et Biophys. Acta 17, 212 (1955); Biochem. ./. 70, 472 (1958). 



90 B. B. Brodie and C. A. M. Hogben, J. Pharm. and Pharmacol. 9, 345 (1957). 



91 I). P. Rail, J. R. Stabenau, and C. G. Zubrod, J. Pharmacol. Exptl. Therap. 125, 

 185 (1959). 



92 J. W. Whiteside, F. S. Philips, H. W. Dargeon, and J. H. Burchenal, A.M.A.Arch. 

 Internal Med. 101, 279 (1958). 



