EFFECT OF COMBINATION OF DEOXYPYRIDOXINE WITH KNOWN ANTIPROLIFERATIVEOR IMMUNOSUPPRESSIVE AGENTS ON LYMPHOCYTE SERINE HYDROXYMETHYLTRANSFERASE

Measurements of serine hydroxymethyltransferase (SHMT) in resting lymp hocyte cultures showed that the level of activity of this enzyme is ve ry low. Under the influence of mitogenic stimuli serine hydroxymethylt ransferase activity is induced 5-20-fold. Addition in the cultures of 4-deoxypryidoxine (dB(6)), a potent antagonist of vitamin B-6 coenzyme s, concurrently with the mitogen, inhibits the induction of SHMT. Sepa rate addition in the cultures of four anti-proliferative (AP) and immu nosuppressive (IMS) agents, namely actinomycin, cytarabine, asparagina se and cyclosporine, led to the following observations. (1) The AP and IMS agents produce a decrease in the mitogen-induced activity of SHMT . The higher the concentration of the AP/IMS compound, the greater the decrease of enzymatic activity. (2) When a AP/IMS agent is combined w ith dB(6) its effect on SHMT is considerably greater. (3) Ineffective concentrations of AP/IMS agents become effective when combined with dB (6). (4) The observed changes in SHMT activity are not, as one would e xpect, the same in the case of all four drugs. (5) The combination mak es it possible to use much smaller doses of these agents with much bet ter results, at least as far as the decrease of enzymic activity is co ncerned. This is very promising for clinical use of AP agents in cance r chemotherapy and IMS agents in transplantation especially of the hea rt and lungs, because combining these compounds with dB(6) will make p ossible to use smaller doses over a longer period of time with greater effectiveness. (6) A possible practical application, the development of a simple test for assessing the AP or IMS potency of various compou nds (alone or in combination with dB(6)), has already been proposed.