Effects of 4,4'-diacetyl-diphenyl-urea-bis(guanylhydrazone) on leukemia L1210.

A new aromatic bisguanylhydrazone derivative, 4,4'-diacetyldiphenyl-urea-bis(guanylhydrazone), markedly prolonged the survival of DBA/2Ha and DBA/2J mice inoculated i.p. or s.c. with leukemia L1210. Drug-induced 50-day cures of leukemic mice occurred with a higher incidence in DBA/2Ha than in DBA/2J mice, and in female than in male mice. The drug was active by parenteral but not by oral route of administration. Single or repeated doses were most effective when given early after tumor inoculation. The effectiveness of 4,4'-diacetyldiphenyl-urea-bis(guanylhydrazone) was reduced when treatment was started 1-2 days prior to the day of death of untreated leukemic mice or when L1210 was inoculated directly into the brain. The selectivity of the antileukemic action of 4,4'-diacetyl-diphenyl-urea-bis (guanylhydrazone) was evidenced by the high therapeutic index of the drug, and by data indicating that the compound acted in conjunction with host defenses directed against the leukemia. By the i.p. route of injection, the potency and the therapeutic index of the new drug were much greater than those of methylglyoxal-bis(guanylhydrazone). No cross-resistance occurred between these 2 compounds, or between 4,4'-diacetyl-diphenylurea-bis(guanylhydrazone) and arabinosyl cytosine. In contrast, the new bisguanylhydrazone was not active against a terephthalanilide-resistant subline of leukemia L1210. Marked synergistic antileukemie effects were observed when 4,4'-diaeetyl-diphenyl-urea-bis(guanylhydrazone) was given in combination with arabinosyl cytosine. Because of the unusual potency of the new agent alone or in combination with arabinosyl cytosine, the elinieai trial of this bisguanylhydrazone has been initiated.