Immunosuppression by succinylacetone. II. Prevention of graft-vs-host disease.

Succinylacetone is a seven-carbon organic ketoacid that we have previously shown to inhibit tumor allograft rejection as well as the primary antibody response to sheep erythrocytes in rats. Because it appeared to be such a potent immunosuppressive agent in our initial studies, we evaluated succinylacetone for its ability to block graft-vs-host disease (GVHD) in adult F1 rats injected with parental strain spleen cells. Untreated ACE X Lewis F1 rats given Lewis strain spleen cells died of GVHD, with a mean survival of 24 days.

Augmentation of hematoporphyrin uptake and in vitro-growth inhibition of L1210 leukemia cells by succinylacetone.

Succinylacetone (SA; 4,6-dioxoheptanoic acid), a specific inhibitor of delta-aminolevulinic acid dehydrase (ALAD) (the second enzyme of the heme biosynthetic pathway), was tested for its effect in L1210 cells from inbred DBA/2 mice. ALAD from broken L1210 cells was completely inhibited by 1 microM SA, but in whole cells activity was decreased only 83% after incubation of the cells with 2.5 mM SA for 3 days.

The effects of metalloporphyrins, porphyrins and metals on the activity of delta-aminolevulinic acid synthase in monolayers of chick embryo liver cells.

The effect of various metals, porphyrins and metalloporphyrins on the activity of delta-aminolevulinate synthase (ALAS) was measured in monolayers of chick embryo liver cells in order to determine whether the metal moiety of heme or heme itself is the regulator of ALAS activity. Iron, magnesium, zinc, copper, manganese and nickel did not decrease ALAS activity in non-induced and in cells induced by allyl-isopropylacetamide (AIA). Cobalt decreased both non-induced and induced activity.

Evidence relating the inhibitory effect of cobalt on the activity of delta-aminolevulinate synthase to the intracellular concentration of porphyrins.

This study shows that the inhibition of ALAS activity caused by cobalt is directly correlated with the intracellular porphyrin concentration, thus indicating that cobalt exerts its inhibitory effect on ALAS activity as a result of the formation of cobalt-protoporphyrin.

Growth inhibitory activity of succinylacetone: studies with Walker 256 carcinosarcoma, Novikoff hepatoma and L1210 leukemia.

Succinylacetone (SA, 4,6-dioxoheptanoic acid) inhibits d-aminolevulinic acid dehydrase, the second enzyme of the heme biosynthetic pathway and thereby inhibits heme biosynthesis. In the present study SA is shown to inhibit the growth of the Walker carcinosarcoma (W256) in vitro and in vivo, the Novikoff hepatoma in vivo, and L1210 leukemia in vitro, but only slightly in vivo. Rats can tolerate significantly larger doses of SA for at least twice as long as were administered in the present study without gross evidence of toxicity.