PMID- 11325838
OWN - NLM
STAT- MEDLINE
DCOM- 20010521
LR  - 20151119
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 61
IP  - 9
DP  - 2001 May 1
TI  - Modulation of both endogenous folates and thymidine enhance the therapeutic 
      efficacy of thymidylate synthase inhibitors.
PG  - 3675-81
AB  - Plasma levels of folates and thymidine in mice are about 10-fold higher than in 
      humans and may influence the therapeutic efficacy of thymidylate synthase (TS) 
      inhibitors, such as 5-fluorouracil (5FU) and the antifolates pemetrexed (MTA) and 
      raltitrexed (RTX). Therefore, we tested their therapeutic efficacy in various 
      murine tumor models, grown in mice on a normal and a folate-depleted diet, with 
      high and low thymidine kinase (TK) levels. MTA and RTX were inactive against 
      Colon-26-10 [doubling times gained by treatment; growth delay factor (GDF), 0.5 
      and 0.3, respectively], whereas 5FU was very active (GDF, >10; complete cures). 
      Colon-26-10/F, grown in mice on a folate-depleted diet, was more sensitive to RTX 
      and MTA (GDF, 2.1 and 1.3, respectively) but not to 5FU (GDF, 1.2); however, 
      leucovorin reversed the effect leading to cures. Folate depletion did not reverse 
      resistance of Colon-26A and Colon-26G (low TK) to MTA and RTX, whereas leucovorin 
      only enhanced the 5FU effect in Colon-26A and Colon-26A/F. Folic acid at 15 mg/kg 
      did not improve the therapeutic efficacy of MTA in folate-deficient mice. The 
      folate-depleted diet decreased the reduced folates in Colon-26A/F and 
      Colon-26-G/F tumors less (4-5-fold; P < 0.01) than in Colon-26-10/F tumors 
      (8-fold; P < 0.001). Folate depletion increased TS levels 2-3-fold in all of the 
      models and TK levels 6-fold (P < 0.01) in Colon-26G/F, explaining the lack of 
      activity of MTA and RTX in Colon-26G/F. In contrast, TK-deficient FM3A/TK tumors 
      were much more sensitive to RTX, MTA, and 5FU than parent FM3A tumors, which have 
      comparable TS levels. The rate of thymidine phosphorylysis varied considerably in 
      all of the tumors without a clear relation to antitumor activity. In conclusion, 
      tumor folates may potentiate (5FU) or protect (antifolates). Murine tumor models 
      should combine low folates and low thymidine rescue to optimize preclinical 
      testing of antifolates.
FAU - van der Wilt, C L
AU  - van der Wilt CL
AD  - Department of Medical Oncology, University Hospital Vrije Universiteit, 1007 MB 
      Amsterdam, the Netherlands.
FAU - Backus, H H
AU  - Backus HH
FAU - Smid, K
AU  - Smid K
FAU - Comijn, L
AU  - Comijn L
FAU - Veerman, G
AU  - Veerman G
FAU - Wouters, D
AU  - Wouters D
FAU - Voorn, D A
AU  - Voorn DA
FAU - Priest, D G
AU  - Priest DG
FAU - Bunni, M A
AU  - Bunni MA
FAU - Mitchell, F
AU  - Mitchell F
FAU - Jackman, A L
AU  - Jackman AL
FAU - Jansen, G
AU  - Jansen G
FAU - Peters, G J
AU  - Peters GJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Folic Acid Antagonists)
RN  - 0 (Glutamates)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 5Z93L87A1R (Guanine)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - EC 2.7.1.21 (Thymidine Kinase)
RN  - FCB9EGG971 (raltitrexed)
RN  - Q573I9DVLP (Leucovorin)
RN  - U3P01618RT (Fluorouracil)
RN  - VC2W18DGKR (Thymidine)
SB  - IM
MH  - Animals
MH  - Antimetabolites, Antineoplastic/administration & dosage/*pharmacology
MH  - Cell Division/drug effects
MH  - Colonic Neoplasms/drug therapy/metabolism/pathology
MH  - Diet
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Enzyme Inhibitors/*pharmacology
MH  - Female
MH  - Fluorouracil/administration & dosage/pharmacology
MH  - Folic Acid/administration & dosage/blood/*metabolism
MH  - Folic Acid Antagonists/*pharmacology
MH  - Glutamates/pharmacology
MH  - Guanine/*analogs & derivatives/pharmacology
MH  - Leucovorin/administration & dosage
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C3H
MH  - Pemetrexed
MH  - Quinazolines/pharmacology
MH  - Thiophenes/pharmacology
MH  - Thymidine/blood/*metabolism
MH  - Thymidine Kinase/metabolism
MH  - Thymidylate Synthase/*antagonists & inhibitors/metabolism
EDAT- 2001/04/28 10:00
MHDA- 2001/05/25 10:01
CRDT- 2001/04/28 10:00
PHST- 2001/04/28 10:00 [pubmed]
PHST- 2001/05/25 10:01 [medline]
PHST- 2001/04/28 10:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2001 May 1;61(9):3675-81.