DEPLETION OF TUMOR GLUTATHIONE INVIVO BY BUTHIONINE SULFOXIMINE - MODULATION BY THE RATE OF CELLULAR PROLIFERATION AND INHIBITION OF CANCERGROWTH

We have investigated in Ehrlich-ascites-tumour-bearing mice the effect of buthionine sulphoximine (BSO), a selective inhibitor of GSH synthe sis, on the rate of GSH depletion of tumour versus normal tissues and its relation to tumour cell proliferation. In normal tissues, GSH and GSSG remain unchanged or close to normal values during tumour growth, even at the last stage of growth when the animal is close to death. Af ter administration of a single dose of BSO (4 mmol/kg), the rates of G SH depletion and recovery in the tumour and in several normal tissues are very different. BSO depletes GSH in cancer cells to a level of 0.3 -0.4 mumol/g. The fall in GSH levels is faster when tumour cells do no t proliferate actively. Four treatments of 4 mmol of BSO/kg at 48 h in tervals induce a significant decrease (about 44%) in tumour growth. Ou r data show that the rate of BSO-induced GSH depletion in cancer cells depends on the stage of tumour growth, and that BSO administration al so inhibits cancer-cell proliferation. A mechanism involving changes i n protein kinase C activity and intracellular pH is proposed to explai n the inhibition of cancer growth elicited by BSO.