HIGH K-M GLUCOSE-PHOSPHORYLATING (GLUCOKINASE) ACTIVITIES IN A RANGE OF TUMOR-CELL LINES AND INHIBITION OF RATES OF TUMOR-GROWTH BY THE SPECIFIC ENZYME-INHIBITOR MANNOHEPTULOSE

Differences in modes of control of glycolysis in tumor cells, compared with normal cells, have suggested that phosphofructokinase may not ca talyse the rate-controlling step. Instead, hexokinase activity may ass ume a more important regulatory role. Hexokinase activities are consis tently lower than those of phosphofructokinase in tumor cells, and the former enzyme may be saturated with its substrate (M. Board et al., B iochem. J. 265: 503-509, 1990). The present work has focused on the gl ucose-phosphorylation step in tumor cell glycolysis. A range of eight human tumor cell-lines, one human tumor tissue, and four rat tumor cel l lines were found to have an additional glucose-phosphorylating activ ity, with properties similar to hepatic glucokinase. Maximal activitie s range from 1.1-20 mmol/min/mg cell protein, and the activity is cons istently absent from any untransformed cell line or tissue tested, exc ept rat liver tissue (18 nmol/ min/mg cell protein). Tumor cell glucok inase activity has been characterized by its high K-m for glucose (8-1 1.8 mM); inhibition by the specific glucokinase inhibitor, mannoheptul ose (I-50, 12.5 nM); and lack of inhibition by 10 mM glucose-6-phospha te. Mannoheptulose also causes inhibition of glucose uptake by tumor c ells (25-75% at 30 mM mannoheptulose) and inhibition of rates of growt h of cultured tumor cell lines (I-50, 21.4 mM). Rates of growth of hum an tumors in experimental animals are dramatically reduced (by 65-79%) by a dose of 1.7 mg/g mannoheptulose daily for 5 days. The potential of the naturally occurring sugar, mannoheptulose (which is purified fr om avocados and is assumed to be of low toxicity), as a cancer treatme nt is discussed.