PMID- 10663629
OWN - NLM
STAT- MEDLINE
DCOM- 20000223
LR  - 20141120
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 45
IP  - 2
DP  - 2000
TI  - Modulation of RTX cytotoxicity by thymidine and dipyridamole in vitro: 
      implications for chemotherapy.
PG  - 142-8
AB  - PURPOSE: The cytotoxicity of the thymidylate synthase (TS) inhibitor raltitrexed 
      (RTX) is reversed by supraphysiologic thymidine concentrations. Dipyridamole (DP) 
      blocks thymidine salvage (uptake) and potentiates several chemotherapeutic agents 
      in vitro. The purpose of this study was to determine whether DP is capable of 
      potentiating RTX cytotoxicity in the presence of physiologic thymidine 
      concentrations. METHODS: We examined the effect of DP on RTX cytotoxicity in the 
      presence of various physiologic thymidine concentrations in eight colorectal 
      adenocarcinoma cell lines by colony formation assay, and in p53-defective HL60 S 
      and p53-competent HL60 SN3 promyelocytic leukemia cells by a tetrazolium 
      reduction-based assay. RESULTS: In WiDr colon adenocarcinoma cells the 
      cytotoxicity of 1.0 microM RTX (4 h) varied from 0% to >99% within the reported 
      range of human serum thymidine concentrations from 500 to <50 nM, respectively. 
      DP potentiated RTX cytotoxicity 2- to >93-fold within this range. Free DP 
      concentrations of 10 to 20 nM, achievable with oral dosing, potentiated RTX at 
      thymidine concentrations up to 100 nM. Potentiation at higher physiologic 
      thymidine concentrations of >/=200 nM required DP concentrations of at least 50 
      nM, or about twice the steady-state DP concentration obtainable from oral and 
      intravenous dosing, but well within that obtainable by intraperitoneal infusion. 
      Maximal potentiation required 72 to 120 h of DP exposure. DP also potentiated RTX 
      in the absence of exogenous thymidine in six of eight colon cell lines and HL60 S 
      and SN3 cells suggesting a second, nonthymidine salvage-dependent mechanism of 
      potentiation. CONCLUSIONS: Clinically achievable free DP concentrations 
      potentiated RTX cytotoxicity within the range of physiologic serum thymidine 
      concentrations. RTX/DP or DP analogue-based combination therapy should, 
      therefore, be considered for clinical trial. Serum or tumor thymidine 
      concentration determinations may aid in identification of patients likely to 
      respond to TS and nucleoside salvage inhibitors versus alternate, non-TS-directed 
      therapies.
FAU - Lehman, N L
AU  - Lehman NL
AD  - Norris Comprehensive Cancer Center, University of Southern California Los 
      Angeles, CA 90033, USA. nlehman@pathology.creighton.edu
FAU - Danenberg, P V
AU  - Danenberg PV
LA  - eng
GR  - R01CA60859/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - 64ALC7F90C (Dipyridamole)
RN  - FCB9EGG971 (raltitrexed)
RN  - VC2W18DGKR (Thymidine)
SB  - IM
MH  - Antimetabolites, Antineoplastic/*adverse effects
MH  - Colorectal Neoplasms/*pathology
MH  - Dipyridamole/pharmacokinetics/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Genes, p53/genetics
MH  - Humans
MH  - Phosphodiesterase Inhibitors/*pharmacology
MH  - Quinazolines/*adverse effects
MH  - Thiophenes/*adverse effects
MH  - Thymidine/*pharmacology
MH  - Tumor Cells, Cultured/drug effects
EDAT- 2000/02/09 09:00
MHDA- 2000/02/26 09:00
CRDT- 2000/02/09 09:00
PHST- 2000/02/09 09:00 [pubmed]
PHST- 2000/02/26 09:00 [medline]
PHST- 2000/02/09 09:00 [entrez]
AID - 00450142.280 [pii]
AID - 10.1007/s002800050022 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2000;45(2):142-8. doi: 10.1007/s002800050022.