Correlation of ultrastructural and functional damage to mitochondria of ascites L1210 cells treated in vivo with methylglyoxal-bis(guanylhydrazone) or ethidium bromide.

Abstract

Mitochondria of cultured L1210 leukemia cells undergo extensive swelling and structural disruption when exposed to the anticancer agent, methylglyoxal-bis(guanylhydrazone) (MGBG). Similar damage has now been observed in ascites L1210 cells treated in vivo with a single dose (>50 mg/kg) of either MGBG or ethidium bromide (EB). After 24 hr, the mitochondria swell significantly, lose their inner structure, and, in the case of EB treatment, develop numerous electron densities within the matrix. Analysis of the ribonucleotide pools of these cells by high-pressure liquid chromatography reveals that treatment with either MGBG or EB depletes the adenosine triphosphate pools and markedly reduces the overall adenylate energy charge of the cell. Thus, in addition to being structurally damaged, the mitochondria are functionally impaired by both drugs. When MGBG-treated cells are harvested, washed, and placed in untreated mice, all cells recover near to normal ultrastructure after 48 hr, whereas EB-treated cells do not, even after 96 hr. Analysis of the ribonucleotide pools of the MGBG-treated cells indicates that the mitochondira have recovered their functional capabilities as well. The adenylate energy charge for these cells is essentially the same as that for untreated cells. If allowed to remain in the untreated mice, the cells previously treated with MGBG display unaltered leukemogenicity, killing the animals at nearly the same average time as untreated cells. The significance of the contribution of MGBG-induced mitochondrial damage to the antiproliferative action of the drug and its relationship to inhibition of spermidine and spermine biosynthesis by the drug remains to be established.