PMID- 8306336
OWN - NLM
STAT- MEDLINE
DCOM- 19940314
LR  - 20131121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 54
IP  - 3
DP  - 1994 Feb 1
TI  - Cellular pharmacology of N1- and N8-aziridinyl analogues of spermidine.
PG  - 742-8
AB  - We have previously described the synthesis and cytotoxic properties of 2 
      polyamine analogues in which either the N1- or N8-amino group of spermidine was 
      replaced by the alkylating moiety, aziridine. However, the mechanisms by which 
      these aziridinyl analogues of spermidine inhibit cell growth remain unknown. As a 
      result, we have studied: (a) the effect of pretreatment with difluoromethyl 
      ornithine (DFMO) and coincubation with exogenous spermidine on cytotoxicity 
      induced by the aziridinyl spermidines; (b) the reversibility of the cytotoxicity 
      induced by the aziridinyl spermidines; (c) the accumulation of N1- and 
      N8-aziridinyl spermidine by cells and the effects of DFMO on this process; and 
      (d) the impact of N1- and N8-aziridinyl spermidine on cellular polyamine pools 
      and on cellular accumulation of spermidine. The cytotoxicity induced by these 2 
      aziridinyl derivatives of spermidine [concentration required to inhibit cell 
      growth or incorporation of radiolabeled precursor into trichloroacetic 
      acid-precipitable material by 50% (IC50) N1 = 0.2 microM, IC50 N8 = 0.4 microM)] 
      was potentiated by pretreatment of L1210 cells for 24 h with 100 microM DFMO 
      (IC50 N1 = 0.05 microM, IC50 N8 = 0.15 microM) and was prevented by coincubation 
      with 3.7 microM spermidine (IC50 N1 = 1.1 microM, IC50 N8 = 2.4 microM). In 
      contrast, similar pretreatment with DFMO or coincubation with spermidine had no 
      effect on the cytotoxicity induced by the aziridine-containing alkylating agent, 
      N,N',N"-triethylenethiophosphoramide (thiotepa) (IC50 = 2.4 microM). The 
      cytotoxicity induced by 24-h incubation with either N1- or N8-aziridinyl 
      spermidine was not altered by removal of those compounds and incubating treated 
      cells in medium augmented with 3.7 microM spermidine. However, and as expected, 
      similar maneuvers did not reverse the cell growth-inhibitory effect induced by 
      24-h incubation with 100 microM DFMO. Cellular accumulation of both N1- and 
      N8-aziridinyl spermidine increased with increasing extracellular concentrations. 
      N1-Aziridinyl spermidine was accumulated to a greater degree than was the 
      N8-analogue, achieving up to 6-fold higher intracellular concentrations at the 
      same extracellular concentration. Cellular accumulation of both aziridinyl 
      compounds was greatly enhanced by 24-h pretreatment with DFMO. Both N1- and 
      N8-aziridinyl spermidine inhibited the uptake of spermidine in a dose-dependent 
      manner. The perturbation of polyamine biochemistry by the test compounds was 
      characterized by their ability to deplete cellular putrescine, as well as 
      spermidine and spermine. These results imply that the cytotoxic mechanism of the 
      aziridinyl spermidine analogues is, to a great extent, dependent on their 
      polyamine nature and may imply selectivity for rapidly growing and neoplastic 
      cells.
FAU - Yuan, Z M
AU  - Yuan ZM
AD  - Department of Biomedicinal Chemistry, University of Maryland School of Pharmacy, 
      Baltimore 21201.
FAU - Egorin, M J
AU  - Egorin MJ
FAU - Rosen, D M
AU  - Rosen DM
FAU - Simon, M A
AU  - Simon MA
FAU - Callery, P S
AU  - Callery PS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Alkylating Agents)
RN  - 0 (Aziridines)
RN  - 0 (Polyamines)
RN  - 154264-46-7 (N(1)-aziridinylspermidine)
RN  - 154264-47-8 (N(8)-aziridinylspermidine)
RN  - U87FK77H25 (Spermidine)
RN  - ZQN1G5V6SR (Eflornithine)
SB  - IM
MH  - Alkylating Agents/pharmacokinetics/pharmacology/toxicity
MH  - Animals
MH  - Aziridines/pharmacokinetics/*pharmacology/toxicity
MH  - Eflornithine/pharmacology
MH  - Leukemia L1210/drug therapy/metabolism
MH  - Mice
MH  - Polyamines/metabolism
MH  - Spermidine/*analogs & derivatives/pharmacokinetics/pharmacology/toxicity
MH  - Time Factors
MH  - Tumor Cells, Cultured
EDAT- 1994/02/01 00:00
MHDA- 1994/02/01 00:01
CRDT- 1994/02/01 00:00
PHST- 1994/02/01 00:00 [pubmed]
PHST- 1994/02/01 00:01 [medline]
PHST- 1994/02/01 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1994 Feb 1;54(3):742-8.