Suppression of murine leukemias by L-asparaginase. Incidence of sensitivity among leukemias of various types: comparative inhibitory activities of guinea pig serum L-asparaginase and Escherichia coli L-asparaginase.

A survey of 109 recently derived leukemias of the mouse revealed that sensitivity to suppression by guinea pig serum is a common property of transplanted leukemias of certain classes. The sensitive leukemias included five that arose spontaneously in mice of strains with a low incidence of leukemia and 21 that were induced by X-radiation. Two GPS-sensitive leukemias were not more sensitive than a GPS-resistant leukemia to a range of standard chemotherapeutic agents. The effectiveness of L-asparaginase EC-2 from Escherichia coli in suppression of the GPS-sensitive leukemia EARAD1 depends upon the conditions of assay. Whereas it is not inhibitory when administered as a single dose at the time of inoculation of the leukemia it is considerably more effective than GPS when used in the treatment of established leukemia. Permanent cures of 7-day generalized transplants of EARAD1 can be effected by the administration of 2000 or more units of EC-2. Immunological factors apparently do not contribute to cure as treated survivors are fully susceptible to rechallenge with minimal numbers of cells from the same leukemia. Reinoculated survivors with progressively growing transplants have been successfully retreated with EC-2. The blood clearance of EC-2 L-asparaginase injected into mice is much more rapid than that of GPS L-asparaginase. After intraperitoneal inoculation of the EC-1 L-asparaginase, which does not have leukemia-inhibitory activity, only very low levels of enzyme activity could be detected in the serum. The effectiveness of EC-2 from E. coli and its availability from a virtually limitless source will make it possible to extend the study of inhibition of leukemias and other tumors by L-asparaginase to species other than small rodents.

Increased synthesis of acid-soluble nuclear material in spleens of tumor-bearing BALB/c mice.

The specific activity (dpm/mg protein) of the acid-soluble nuclear material extracted from spleens or lymph nodes (but not other tissues) of tumor-bearing BALB/c mice was approximately twice that of the corresponding tissues from tumor-free mice of the same age and sex following i.p. injection of L-[U-14C]lysine. Autoradiography of gel electrophoretograms showed the major increases in radioactivity to be in histone H2A and histone H2B. Rabbit anti-mouse lymphocyte serum could prevent the splenic response to tumor only if the serum was given at the time of, or very soon after, the tumor transplant. Immunization with sheep red blood cells or with bovine serum albumin in adjuvant did cause an increase in specific activity of the splenic acid-soluble nuclear material, but there was little difference between samples from normal and tumor-bearing mice when the nuclei were purified before extraction. Use of adjuvant, with or without antigen, prevented the tumor-induced increase in the specific activity of the acid-soluble, histone fraction. Thus, adjuvant-induced suppressor cells were able to interfere with lysine incorporation. It was concluded that the tumor must grow within the host for this manifestation, since mice which were immune to the tumor as a result of vaccination had no increase in lysine incorporation, compared to normal, untreated mice. However, vaccinated mice which did not develop immunity had tumor growth and the associated increased splenic histone synthesis. A regulatory role is suggested for the histones H2A and H2B.