39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 467 



ence of an amethopterin-sensitive infectious agent was evident. 78 The ex- 

 planation was offered that the infectious agent (presumably lymphocytic 

 choriomeningitis virus) retards the rate of tumor growth, while amethop- 

 terin by inhibiting the effect of the virus on the amethopterin-resistant 

 tumor cells, permits the more rapid proliferation of the neoplastic cells and 

 the earlier death of the mice. It had been shown earlier that a strain of 

 L-1210 lymphoma indeed can carry a filtrable, self-propagating contami- 

 nant (presumably lymphocytic choriomeningitis virus). 79 Treatment with 

 amethopterin (or azaguanine) was found to protect mice from the otherwise 

 fatal effects of infection with the virus of lymphocytic choriomeningitis, 

 even though the infection was not eradicated 80 ; a similar result was obtained 

 in mice given a folic acid-deficient diet. 81 Under either of these conditions 

 the proliferation of the virus was not interfered with, but its damaging 

 effects on susceptible cells were reduced or prevented. 82 Even more remark- 

 able findings have recently been obtained in mice given an amethopterin- 

 resistant line of the tetraploid lymphocytic neoplasm, P-288, intentionally 

 infected with lymphocytic choriomeningitis. 83 Although passage of the in- 

 fected cells through mice which had been immunized against the virus caused 

 the latter to disappear, the administration of amethopterin prevented this 

 disappearance of virus These findings, and others, 84 have suggested that 

 this antimetabolite can interfere markedly with either the formation of or 

 the response to antibodies, or both. A most remarkable example of this type 

 of interference is the finding that a drug-resistant subline of P-288 (free of 

 lymphocytic choriomeningitis) could grow progressively and kill mice of 

 genetically foreign strains (in which mice the neoplastic cells ordinarily will 

 not proliferate continuously), when the animals were treated with ame- 

 thopterin. 83 



Whether a phenomenon of this type contributed to the early observa- 

 tions concerning partial dependence on amethopterin is not known. Cer- 

 tainly, the evidence has not indicated that lymphocytic choriomeningitis or 

 any other demonstrable infectious agent was present in the tumor cells, 

 and manifestations of illness were not seen in the host-animals. 85 Thus, it 

 is not yet possible to offer a biochemical explanation of the phenomenon of 



78 S. R. Humphreys, J. M. Venditti, M. Mantel, and A. Goldin, J. Natl. Cancer Inst., 

 17, 447 (1956). 



79 L. \Y. Law and T. B. Dunn, J. Natl. Cancer Inst. 11, 1037 (1951). 



80 V. H. Haas and S. E. Stewart, Virology 2, 511 (1956). 



81 V. H. Haas, G. M. Briggs, and S. E. Stewart, Science 126, 405 (1957); V. H. Haas, 

 S. E. Stewart, and G. M. Briggs, Virology 3, 15 (1957). 



82 E. M. Lerner, II, and V. H. Haas, Proc. Soc. Exptl. Biol. Med. 98, 395 (1958). 



83 M. Potter and V. H. Haas, J. Natl. Cancer Inst. 22, 801 (1959). 



84 D. E. Uphoff, Proc. Soc. Exptl. Biol. Med. 99, 651 (1958). 

 88 L. \Y. Law, personal communication (1959). 



