CYCLOCREATINE (1-CARBOXYMETHYL-2-IMINOIMIDAZOLIDINE) INHIBITS GROWTH OF A BROAD-SPECTRUM OF CANCER-CELLS DERIVED FROM SOLID TUMORS

In an effort to investigate the role of creatine kinase and its substr ates in malignancy we have tested the effect of cyclocreatine [1-carbo xymethyl-2-iminoimidazolidine (CCr)] on the growth of tumor cells in v itro and in vivo. CCr is phosphorylated by creatine kinase to yield a synthetic phosphagen [N-phosphorylcyclocreatine (CCr is similar to P)] with thermodynamic and kinetic properties distinct from those of crea tine phosphate. We show that CCr accumulates as CCr is similar to P in tumor cells expressing a high level of creatine kinase, and that the accumulation of this phosphagen is detrimental to tumor cell growth. T umor cell lines expressing a low level of creatine kinase accumulate m uch less CCr is similar to P, and consequently are growth inhibited on ly at higher concentrations of CCr. When these resistant cells are tra nsfected with a creatine kinase B expression vector, they express crea tine kinase, accumulate CCr is similar to P, and are growth inhibited. In vivo, in nude mouse xenografts, the rate of growth of a high creat ine kinase expressing tumor cell line is inhibited in animals fed 1 % CCr. Our results indicate that CCr inhibits the growth of tumor cells in vitro and in vivo.