PT  - JOURNAL ARTICLE
AU  - Christopher P. Leamon
AU  - Joseph A. Reddy
AU  - Ryan Dorton
AU  - Alicia Bloomfield
AU  - Kristen Emsweller
AU  - Nikki Parker
AU  - Elaine Westrick
TI  - Impact of High and Low Folate Diets on Tissue Folate Receptor Levels and Antitumor Responses Toward Folate-Drug Conjugates
AID  - 10.1124/jpet.108.143206
DP  - 2008 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 918--925
VI  - 327
IP  - 3
4099  - http://jpet.aspetjournals.org/content/327/3/918.short
4100  - http://jpet.aspetjournals.org/content/327/3/918.full
SO  - J Pharmacol Exp Ther2008 Dec 01; 327
AB  - Herein, we present a detailed analysis on the effects of feeding laboratory mice both high and low folic acid (folate)-containing diets as related to associated changes in serum and red blood cell (RBC) folate levels, tissue-derived folate receptor levels, and the ability of folate-drug conjugates to bind and effectuate activity against folate receptor (FR)-positive tumor xenografts. Our data show that serum and RBC folate concentrations sharply drop immediately after mice are switched to low folate diets; however, both parameters reach steady-state, “human-like” levels after 6 weeks. Interestingly, tissue-related folate binding capacities were also lowered during the dietary modulation period, whereas the net uptake of a radiolabeled folate conjugate was simultaneously increased 2.6- and 5-fold in FR-positive kidney and tumor tissue, respectively. Finally, the performances of several clinically and preclinically relevant folate-drug conjugates were evaluated against tumors in mice that were fed high or low folate diets. Except when administered at a dose level 6-fold less than that required to saturate endogenous FRs, no significant loss of antitumor activity was observed. From these findings, we conclude that lowering the dietary intake of folates in mice has little impact on the biological activity of repetitively dosed folate-targeted agents but that low folate diet regimens will reduce serum and RBC folate levels down to levels that more closely approximate the normal human ranges. The American Society for Pharmacology and Experimental Therapeutics