Altered methylation complex isozymes as selective targets for cancer chemotherapy

MC2 is a ternary enzyme complex consisting of MAT, methyltransferase and SAHH. Three isozymes of SAHH have been identified from rat and mouse livers based on different kinetic properties. The Km values are 0.35 +/- 0.05 microM, 1.63 +/- 0.38 microM and 0.37 +/- 0.07 mM for SAHH-L, SAHH-I, and SAHH-H respectively. The corresponding low Km isozymes of MAT and SAHH form MCs-L which include RNA MCs, the intermediate Km isozymes form MC-I, and the high Km isozymes form MC-H which is glycine MC. MCs-L are common to all tissues whereas MC-I and MC-H are organ specific enzyme complexes. Low levels of MC-H in the liver of C3H/HeN mouse are correlated with the slow maturation of hepatocytes and the genetic predisposition to develop spontaneous PHC. Rat Novikoff ascites hepatoma and mouse spontaneous PHC have been shown to contain a SAHH isozyme displaying kinetic properties different from the corresponding normal SAHH-L. The abnormal kinetic properties of tumour SAHH are analogous to those of tumour MAT previously shown by the authors to be uniquely associated with malignant tissues. The tumour isozyme, which is named SAHH-LT, has a Km (AR) value of 2.18 +/- 0.22 microM. The altered tumour MC isozymes appear to play an important role in perpetuating malignant growth, because once the tumour growth was inhibited by poly (I) (C), the abnormal kinetic properties were no longer detectable. Thus abnormal tumour MCs may be exploited as selective targets for cancer chemotherapy. Evidence is presented to indicate that antineoplaston is a potent inhibitory effector of tumour rRNA MCs and an effective antitumor agent.