THE FOLIC ACID GROUP 597 



9417, which are completely inactivated by methylbis(chloroethyl) amine 

 at four times the LD 50 . 176 



The average survival time of mice with Ak 4 strain of leukemia is 

 prolonged significantly by 2,6-diaminopurine as well as 4-amino-4-des- 

 oxyfolic acid. 177 



Sarcoma 180. 4-Amino-4-desoxyfolic acid at 0.19 to 0.42 mg per kg 

 retards the rate of growth of sarcoma 180 in mice. Inhibitions of tumor 

 growth to the extent of more than 50 per cent and on occasions as high 

 as 94 per cent of the controls are obtained, but the mice lose weight up to 

 20 per cent under these conditions. 178 Pteroyl-a-glutamylglutamic acid 

 administered intraperitoneally or intravenously does not affect growth of 

 the tumor. 176 



4-Amino-4-desoxyfolic acid is fatal to many of the animals under con- 

 ditions giving marked inhibition of tumor growth. 179 



A partial reversal of the inhibition of tumor growth is obtained by 

 administration of folic acid with the 4-amino-4-desoxyfolic acid. Folic 

 acid alone exerts some inhibition of tumor growth when administered at 

 high concentration. 180 



4-Amino-4-desoxy-N 10 -methylfolic acid has a more favorable thera- 

 peutic index than 4-amino-4-desoxyfolic acid. 181 At 1.5 mg per kg per day, 

 the amino methyl analogue shows marked inhibition of growth of sarcoma 

 180, the tumors being only 3-10 per cent of the size of controls after one 

 week, and causes very little loss in weight of the animals, with only 7 per 

 cent fatalities during the injection period. Slightly higher concentrations 

 (2.5 mg per kg per day) of the analogue are lethal to almost half the 

 animals. Male mice appear to tolerate the analogue better than female 

 mice. 181 



4-Amino-4-desoxypteroylaspartic acid also has a more favorable thera- 

 peutic index than 4-amino-4-desoxyfolic acid in inhibition of sarcoma 180 



Bibliography 



1. Wills, L., Brit. Med. J., 1, 1059 (1931). 



2. Wills, L., and Bilimoria, H. S., Indian J. Med. Research, 20, 391 (1932). 



3. Wills, L., and Stewart, A., Brit. J. Exper. Path., 16, 444 (1935). 



4. Day, P. L., Langston, W. C, and Shukers, C. F., /. Nutrition, 9, 637 (1935). 



5. Day, P. L., Langston, W. C, and Darby, W. J., Proc. Soc. Exptl. Biol. Med., 



38, 860 (1938). 



6. Stokstad, E. L. R., and Manning, P. D. V., J. Biol. Chem., 125, 687 (1938). 



7. Hogan, A. G., and Parrott, E. M., /. Biol. Chem., 132, 507 (1940); Proc, 128, 



xlvi (1939). 



8. O'Dell, B. L., and Hogan, A. G., J. Biol. Chem., 149, 323 (1943). 



9. Snell, E. E., and Peterson, W. H., Proc. Am. Soc. Biol. Chem., J. Biol. Chem~ 



Proc, 128, xciv (1939). 



