Effect of uracil mustard and several antitumor drugs on the primary antibody response in rats and mice

When 5-bis(2-chloroethyl)aminouracil (Uracil Mustard) was given 1 to 5 hours before antigen (sheep red blood cells) as a single dose of about 0.5 LD50, either orally or intraperitoneally, it did not suppress the antibody synthesis in rats. At oral doses effective for tumor therapy in rats, 0.2 mg per kg daily for 5 days or 1.0 mg per Kg twice weekly for 3 weeks, there was also no indication of suppression of antibody production. The time of administration of Uracil Mustard in relation to the antigen, in order to achieve a depression of antibody synthesis in rats, was 24 and 48 hours after antigen. The depression observed was only at the 4th day and serum titers from the 7th through the 42d day were in the normal range. In contrast, cyclophosphamide, 25 or 50 mg per kg, and 6-mercaptopurine, 80 mg per kg, which are doses with antitumor activity, caused prolonged suppression of antibody production when given 48 hours after antigen. 2-Keto-3-ethoxybutyraldehyde bis(thiosemicarbazone) showed no indication of antibody suppression in the rat at levels of 25, 50, or 100 mg per kg given orally daily for 7 days, beginning 4 days before antigen. Daily oral doses of 25 mg per kg caused regression of established Walker 256 tumors in rats. One intraperitoneal dose of Uracil Mustard at 0.3 LD50 given to BALB mice 1 hour before the injection of human γ-globulin or bovine γ-globulin caused an increase in circulating antibody, as did endotoxin, 5-fluoro-2-deoxyuridine, and cyclophosphamide. Highly toxic doses of Uracil Mustard (40, 60, and 80 µg/mouse) caused depression of antibody synthesis. This was also true of daily doses of 20 μg per mouse. 1-β-D-Arabinofuranosyl-cytosine hydrochloride (Cytarabine hydrochloride) at 0.5 or 1 mg per mouse for 12 daily doses suppressed antibody production. These levels (equivalent to 20–40 mg/kg) are in the dose range used in tumor therapy. One 8 mg per mouse dose of Cytarabine did not suppress antibody formation and in some cases caused enhancement.