PMID- 8147906
OWN - NLM
STAT- MEDLINE
DCOM- 19940505
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 47
IP  - 6
DP  - 1994 Mar 15
TI  - Effect of purine synthesis inhibition on WiDr spheroids in vitro or on WiDr or 
      colon 38 tumors in vivo. Complete growth inhibition but not regression.
PG  - 1067-78
AB  - Clinical responses for anticancer agents are based upon tumor regression. We have 
      investigated the potential of glycineamide ribonucleotide transformylase (GAR 
      TFase) inhibitors to produce regressions in multiple preclinical models of colon 
      carcinoma. The growth of multicellular tumor spheroids of WiDr human colon 
      carcinoma was inhibited by the GAR TFase inhibitors 5-deazaacyclotetrahydrofolate 
      (5-DACTHF), its 2'-fluoro, 3'-fluoro, 10-deaza, and 10-thia analogs as well as 
      5,10-dideazatetrahydrofolate, but none of the compounds caused spheroid 
      regressions. By contrast, complete spheroid disruption was observed with exposure 
      to etoposide, m-AMSA (amsacrine), piritrexim, or 
      2-desamino-2-methyl-10-propargyl-5,8-dideazafolate (DMPDDF). Light microscopy of 
      the spheroids treated with either 5-DACTHF or DMPDDF suggested that the reason 
      for the difference is extensive cell kill throughout the spheroid in the presence 
      of DMPDDF compared with little or no kill, over that found in controls, with 
      5-DACTHF. Treatment of spheroids with 5-DACTHF in the presence of 1 microM 
      hypoxanthine resulted in no significant reversal of growth inhibition; 50% 
      reversal required 10 microM hypoxanthine. The spheroid studies were extended to 
      in vivo studies examining the effects of 5-DACTHF on established WiDr and colon 
      38 tumors. The results showed that, in contrast to melphalan, which produced 
      cures and tumor regressions, 5-DACTHF produced reversible growth inhibition with 
      no significant regression of tumors. The results predict that clinical response, 
      typically measured by tumor regression, may be rare following single agent 
      therapy with inhibitors of de novo purine biosynthesis.
FAU - Jansen, M
AU  - Jansen M
AD  - Wellcome Research Laboratories, Research Triangle Park, NC 27709.
FAU - Dykstra, M
AU  - Dykstra M
FAU - Lee, J I
AU  - Lee JI
FAU - Stables, J
AU  - Stables J
FAU - Topley, P
AU  - Topley P
FAU - Knick, V C
AU  - Knick VC
FAU - Mullin, R J
AU  - Mullin RJ
FAU - Duch, D S
AU  - Duch DS
FAU - Smith, G K
AU  - Smith GK
LA  - eng
PT  - Journal Article
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Purines)
RN  - 0 (Tetrahydrofolates)
RN  - 118252-44-1 
      (N-(4-((3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl)amino)benzoyl)glutamic 
      acid)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.1.2.- (Hydroxymethyl and Formyl Transferases)
RN  - EC 2.1.2.2 (Phosphoribosylglycinamide Formyltransferase)
RN  - EC 2.3.- (Acyltransferases)
RN  - N8VP1Y24AU (ICI 198583)
SB  - IM
MH  - Acyltransferases/antagonists & inhibitors
MH  - Adenocarcinoma/pathology
MH  - Animals
MH  - Cell Division/drug effects
MH  - Colonic Neoplasms/*pathology
MH  - Folic Acid/analogs & derivatives/pharmacology
MH  - Humans
MH  - *Hydroxymethyl and Formyl Transferases
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphoribosylglycinamide Formyltransferase
MH  - Purines/*metabolism
MH  - Tetrahydrofolates/pharmacology
MH  - Tumor Cells, Cultured
EDAT- 1994/03/15 00:00
MHDA- 1994/03/15 00:01
CRDT- 1994/03/15 00:00
PHST- 1994/03/15 00:00 [pubmed]
PHST- 1994/03/15 00:01 [medline]
PHST- 1994/03/15 00:00 [entrez]
AID - 0006-2952(94)90419-7 [pii]
AID - 10.1016/0006-2952(94)90419-7 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 1994 Mar 15;47(6):1067-78. doi: 10.1016/0006-2952(94)90419-7.