Sb. Gates et al., DIETARY-FOLATE AND FOLYLPOLYGLUTAMATE SYNTHETASE-ACTIVITY IN NORMAL AND NEOPLASTIC MURINE TISSUES AND HUMAN TUMOR XENOGRAFTS, Biochemical pharmacology, 52(9), 1996, pp. 1477-1479
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.