DIETARY-FOLATE AND FOLYLPOLYGLUTAMATE SYNTHETASE-ACTIVITY IN NORMAL AND NEOPLASTIC MURINE TISSUES AND HUMAN TUMOR XENOGRAFTS

The importance of polyglutamation for the activation of natural folate s and classical antifolates and recent evidence for the role of dietar y folate as a biochemical modulator of antifolate efficacy led us to i nvestigate the influence of changes in dietary folate on folylpolyglut amate synthetase (FPGS) activity. Activities were measured using lomet rexol (6R-5,10-dideazatetrahydrofolic acid) as a substrate for FPGS wi th extracts of murine tissues, murine tumors, and human tumor xenograf ts from mice on standard diet or low folate diet. Tissues and rumors f rom mice on standard diet exhibited a 6-fold range of FPGS activity. K idney had the lowest activity (36 pmol/hr . mg protein), followed by t he human xenograft PANC-1 pancreatic carcinoma (46 pmol/hr . mg protei n), liver (109 pmol/hr . mg protein), murine C3H mammary tumor (112 pm ol/hr . mg protein), and the human xenograft MX-1 mammary carcinoma (2 24 pmol/hr . mg protein). In response to restricted dietary folate, fo ur out of five tissues had significantly increased (25-50%) FPGS activ ity. Only the tumor with highest FPGS activity under standard diet con ditions (MX-1 mammary) did not respond to low folate diet. The results indicate that changes in dietary folate intake can modulate FPGS acti vity significantly in vivo and suggest that the tissue distribution an d toxicities of classical antifolates requiring polyglutamation for ac tivation and cellular retention will be influenced significantly by fo late status of the host. Copyright (C) 1996 Elsevier Science Inc.