Clinical Cancer Research Vol. 6, 17-23, January 2000
© 2000 American Association for Cancer Research
Effects of the Polyamine Analogues N1 -Ethyl-N11-((cyclopropyl)methyl)-4,8-diazaundecane and N1-Ethyl-N11-((cycloheptyl)methyl)-4,8- diazaundecane in Human Prostate Cancer Cells1
Diane E. McCloskey,
Patrick M. Woster,
Robert A. Casero, Jr. and
Nancy E. Davidson2
The Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231 [N. E. D., R. A. C.]; Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 [D. E. M.]; and Wayne State University, Detroit, Michigan 48202 [P. M. W.]
 |
ABSTRACT
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The
high levels of polyamines maintained in the prostate suggest that these
compounds are important to prostate cell function and that disruption
of polyamine metabolism may be an effective way to stop the growth of
prostate cancer cells. The unsymmetrically alkylated polyamine
analogues
N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaundecane
(CPENSpm) and
N1-ethyl-N11-((cycloheptyl)methyl)-4,8-diazaundecane
(CHENSpm) have been shown pre-viously to have cytotoxic effects in
breast and non-small cell lung cancer cells. We have now investigated
the responses of three human prostate cancer cell lines, LNCaP, PC3,
and Du145, to these polyamine analogues and to the symmetrically
alkylated analogue
N1,N11-bis(ethyl)norspermine
(BE 3-3-3). The Du145 cell line, in which IC50
values ranged from 0.65 to 0.8 µM, was the most sensitive
to each of the polyamine analogues, although significant growth
inhibition resulted in the other cell lines as well. CPENSpm and BE
3-3-3 but not CHENSpm caused significant decreases in the intracellular
spermine and spermidine pools, although all three analogues accumulated
to high levels in each of the cell lines. Spermidine/spermine
N1-acetyltransferase activity was induced
23–250-fold in response to CPENSpm and BE 3-3-3, but it was not
affected by CHENSpm. None of the analogues had significant effects on
the activities of ornithine decarboxylase or
S-adenosylmethionine decarboxylase. Quantitation of DNA
fragmentation indicative of programmed cell death (PCD) showed that
both CPENSpm and CHENSpm were effective inducers of PCD in all three
prostate cell lines. In contrast, BE 3-3-3 led to PCD only in LNCaP
cells. The ability to induce PCD was the only parameter measured that
correlated with cell line sensitivity to these polyamine analogues.
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Introduction
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Development of polyamine analogues that are similar in structure
to the natural polyamines but that cannot mimic their functions that
are essential for cellular growth and differentiation has led to
interest in these compounds as cancer chemotherapeutic agents. The
symmetrically substituted bis(ethyl)polyamine analogues have been
shown to have cell type-specific cytotoxic effects in a select group of
important human solid tumors, including non-small cell lung carcinoma,
breast cancer, melanoma, and pancreatic tumors (1, 2, 3, 4, 5)
.
Effects attributed to these analogues include down-regulation of
polyamine biosynthesis, depletion of intracellular pools of the natural
polyamines, and induction of the polyamine catabolic enzyme
SSAT.3
Additionally, as we
have reported previously, BE 3-4-3 is able to activate PCD pathways
(6)
. Because the bis(ethyl)polyamine analogues produce
only a cytostatic effect in some cell lines, several unsymmetrically
alkylated polyamine analogues have been synthesized in an effort to
identify those that would result in greater cytotoxicity in a wider
variety of tumor types (7)
. We have shown that one of
these unsymmetrically substituted analogues, CPENSpm (Fig. 1)
, is more cytotoxic than BE 3-4-3 in
the H157 non-small cell lung cell line and that the variable
sensitivity of the H157 cell line to these analogues appears to be
related to their differential ability to activate PCD (6)
.
We have also demonstrated that the ability of polyamine analogues to
induce PCD is not limited to the lung cancer cell lines, as CPENSpm can
activate PCD in six human breast cancer cell lines (8)
.
The relative ability of the polyamine analogues to activate PCD is also
cell type-specific because, in the non-small cell lung cells, the
entire population was ultimately killed, whereas in the breast cancer
cell lines, PCD was activated only in a subpopulation of the cells,
leading to an overall cytostatic response.
The observation of cell type- and analogue-specific effects resulting
from treatment with the alkyl substituted polyamine analogues
demonstrates the importance of evaluating the response of different
tumor types to a variety of these agents. The normal prostate is known
to maintain naturally high levels of polyamines (9)
. This
suggests that polyamines are important for prostate cell function and
that disruption of polyamine metabolism may be an effective way to halt
prostate cancer cell growth. We have now investigated the responses of
three human prostate cancer cell lines, LNCaP, PC3, and Du145, to the
unsymmetrically alkylated polyamine analogues CPENSpm and CHENSpm (Fig. 1)
, as well as the symmetrical polyamine analogue BE 3-3-3 (Fig. 1)
.
Our studies show that the unsymmetrically alkylated analogues result in
significant cytotoxicity that is greater than that observed from BE
3-3-3 in two of the three cell lines. Furthermore, the level of
cytotoxicity in each cell line appears to correlate with the ability to
activate PCD pathways.
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Materials and Methods
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Compounds and Cell Culture.
CPENSpm and CHENSpm were synthesized as described previously
(7)
. BE 3-3-3 was kindly supplied by Parke-Davis
Pharmaceuticals (Ann Arbor, MI). For all experiments, concentrated
solutions of CPENSpm, CHENSpm (10 and 5 mM, respectively,
in water, stored at -20°C) and BE 3-3-3 (10 mM in 0.1
M HCl) were diluted with medium to the desired
concentrations. As a control for the BE 3-3-3 vehicle, 0.1
mM HCl was diluted similarly in the untreated controls.
PC3, Du145, and LNCaP cells were maintained in RPMI 1640 supplemented
with 10% fetal bovine serum (Biofluids, Rockville, MD) and 2
mM glutamine. Cells were incubated at 37° in a 5%
CO2 atmosphere and passaged every 5–7 days.
Mycoplasma testing was routinely negative.
Growth Inhibition Assay.
Exponentially growing cells were plated in triplicate at 1–3 x
104 cells/cm2 in 24-well
plates. After a 12–18-h period for the cells to attach to the growth
surface, the medium was changed, and cells were incubated in the
absence or presence of at least six drug concentrations. After 120 h, the cells were detached by trypsinization and counted using a
Coulter counter. IC50 values were determined from
plots of percent of untreated control cell growth versus the
logarithm of the drug concentration. All experiments were carried out
at least twice, and values reported are mean ± SD of all
experiments.
Analysis of Intracellular Polyamine Pools, SSAT, ODC, and AdoMetDC
Activities.
The polyamine content of treated and untreated cells was determined by
precolumn dansylation and reverse-phase high-performance liquid
chromatography using 1,7-diaminoheptane as the internal standard
(10)
. SSAT, ODC, and AdoMetDC activities were measured
using cellular extracts as reported previously (1
, 11)
.
SSAT activity is expressed as pmol
N1
-[14C]acetylspermidine
formed/mg protein/min. Protein concentrations were determined by the
method of Bradford (12)
.
DNA Fragmentation Assays.
Exponentially growing cells were plated at 1–3 x
104 cells/25-cm2 culture
flask. After attachment, cells were labeled with
[methyl-14C]thymidine (0.05 mCi/ml
medium, specific activity 56 mCi/mmol, Amersham Pharmacia
Biotech, Arlington Heights, IL) for 24 h. After 24 h, the
[14C]thymidine-containing medium was removed,
and cells were incubated in normal growth medium with or without
drug for the desired exposure time. The time of drug addition was
considered time 0. At the time of harvest, cultures were processed, and
DNA fragmentation was quantitated as described previously
(13)
.
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Results
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Sensitivity of Human Prostate Cancer Cell Lines to CPENSpm,
CHENSpm, and BE 3-3-3.
The sensitivity of LNCaP, PC3, and Du145 prostate cancer cell lines to
the polyamine analogues BE 3-3-3, CPENSpm, and CHENSpm was assessed by
the measurement of growth inhibition after continuous exposure to
0.1–30 µM concentrations of each drug (Fig. 2)
. These cell lines were chosen because
they represent a spectrum of androgen-dependent and
androgen-independent prostate cancers. Concentration-dependent growth
inhibition resulted in all three cell lines in response to each of
these polyamine analogues. Determination of IC50
values indicated that the DU 145 cell line was the most sensitive to
each analogue, with IC50 values ranging from 0.65
to 0.8 µM, whereas those for the LNCaP cell line ranged
from 1.5 to 3 µM, and those for the PC3 cell line ranged
from 1.5 to 5 µM. Determination of the final cell number
relative to the initial cell number
(N1/N0),
where cytotoxicity is defined by an
N1/N0
value <1 and cytostasis is defined by an
N1/N0
value 
1, provides another indication of the sensitivity of a cell
line to a given agent. Using the
N1/N0
measurement, the Du145 cells were again the most sensitive to CPENSpm
and CHENSpm, with cytotoxicity resulting from concentrations 3
µM. Treatment with CHENSpm was also cytotoxic
to the LNCaP and PC3 cell lines, but only at a concentration of 30
µM. BE 3-3-3 treatments resulted in
cytotoxicity only to the LNCaP cell line and only at 30
µM.
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Fig. 2. Concentration dependence of growth inhibition of
LNCaP, PC3, and Du145 prostate cancer cells by BE 3-3-3, CPENSpm, and
CHENSpm. Exponentially growing cells of the indicated cell lines were
incubated in the absence or presence of the indicated drug
concentrations for 120 h as described in "Materials and
Methods." N0 is the initial cell number at
time 0, and N1 is the final cell number at
120 h. Values reported are the mean ± SD
(n = 6).
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Intracellular Accumulation of the Polyamine Analogues and Effects
on Intracellular Polyamine Pools.
The ability of cells to accumulate polyamine analogues and the ability
of the analogues to alter the normal polyamine pools are both
parameters that have been related to the sensitivity of a particular
cell line to structural polyamine analogues. Therefore, intracellular
concentrations of the analogues and the natural polyamines were
determined following a 24-h exposure of LNCaP, PC3, and Du145 cells to
a 10 µM concentration of each analogue (Table 1)
. All three analogues were accumulated
to high levels in each of the cell lines, indicating that the different
sensitivities of the three prostate cell lines to these agents were not
a result of differences in intracellular accumulation of the analogues.
BE 3-3-3 and CPENSpm treatments both led to significant decreases in
the spermidine and spermine pools of each cell line (Table 1)
. However,
treatment with CHENSpm, the analogue that produced the greatest
cytotoxicity, resulted in no decrease in spermine concentration and
small decreases in the spermidine pools of each cell line. These
results suggest that differences in the abilities of BE 3-3-3, CPENSpm,
and CHENSpm to deplete the natural polyamine pools of each cell line do
not correlate with the differential effects on the growth of the three
cell lines.
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Table 1 Exponentially growing cells were incubated in
the absence or presence of a 10 µM concentration of the
indicated analogue for 24 h, and the intracellular polyamine
concentrations were determined as described in "Materials and
Methods."
Values reported are the mean ± SE (n 7).
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Effects of BE 3-3-3, CPENSpm, and CHENSpm on SSAT, ODC, and
AdoMetDC Activities of the Prostate Cancer Cells.
Other possible effects of the structural polyamine analogues include
inhibition of the polyamine synthetic enzymes, ODC and AdoMetDC, and
induction of the polyamine catabolic enzyme, SSAT. The activities of
ODC, AdoMetDC, and SSAT were determined following a 24-h exposure of
each prostate cancer cell line to10 µM BE 3-3-3, CPENSpm,
or CHENSpm (Table 2)
. The analogues had
minimal effect on ODC and AdoMetDC activities of the three cell lines.
There was significant induction of the polyamine catabolic enzyme SSAT
in all three cell lines in response to both BE 3-3-3 and CPENSpm.
However, these effects did not correlate with the differential
sensitivity of the cell lines to the analogues because CHENSpm did not
induce SSAT in any of the cell lines, although it resulted in the
greatest cytotoxicity.
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Table 2 SSAT, AdoMetDC, and ODC activities of prostate
cancer cells exposed to the polyamine analogues BE 3-3-3, CPENSpm, and
CHENSpm
SSAT, AdoMetDC, and ODC activities were measured in LNCaP, PC3, and
Du145 cells incubated for 24 h in the absence or presence of 10
µM concentrations of the polyamine analogues 3-3-3,
CPENSpm, and CHENSpm. Values are reported as the ratios of activities
in the presence of analogue to the activity under control conditions,
when no analogue is present. Values are reported as the mean ± SE
(n 3).
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Induction of PCD by BE 3-3-3, CPENSpm, and CHENSpm.
We have demonstrated previously that the sensitivity of breast cancer
cell lines and non-small cell lung cancer cell lines to BE 3-4-3 and
CPENSpm correlates with the ability of these analogues to induce PCD
(6
, 8)
. To assess whether sensitivity to CPENSpm, CHENSpm,
and BE 3-3-3 correlates to PCD induction in the prostate cancer cell
lines, DNA fragmentation characteristic of PCD induction
(14)
was quantitated (13)
. The amount of DNA
fragmentation that resulted from treatment of the prostate cancer cell
lines with 10 µM BE 3-3-3, CPENSpm, or CHENSpm over a
period of 168 h is shown in Fig. 3
,
as are the corresponding cell numbers, expressed as
N1/N0.
The greatest effect resulted from CHENSpm, where DNA fragmentation
increased by 24 to 48 h and ultimately reached 39, 47, and 73% in
LNCaP, PC3, and Du145 cells, respectively, compared to 
20% in
untreated control cells. The corresponding
N1/N0
values indicate that CHENSpm treatment resulted in cytotoxicity of
Du145 cells at times 96 h. CHENSpm-treated LNCaP and PC3 cells
exhibited a slight increase in cell number through 96 h, followed
by a decrease in cell number, although neither reached a
N1/N0
value that indicated net cytotoxicity.
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Fig. 3. Time dependence of effects of BE 3-3-3, CPENSpm,
and CHENSpm on DNA fragmentation and cell number of LNCaP, PC3, and
Du145 cells. A, the time dependence of DNA fragmentation
resulting from continuous exposure to 10 µM of each
analogue was quantitated for LNCaP, PC3, and Du145 cells.
B, the time dependence of the ratio of the final cell
number (N1) to the initial cell number
(N0) resulting from 10 µM BE
3-3-3, CPENSpm, or CHENSpm was quantitated for each cell line. DNA
fragmentation and cell numbers were quantitated as described in
"Materials and Methods." Values shown are individual determinations
from a representative experiment. The doubling times of untreated
control cells were as follows: LNCaP, 37.5 h; PC3, 40.8 h;
Du145, 42.4 h.
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CPENSpm treatment also resulted in significant DNA fragmentation in all
three cell lines at times 96 h with final amounts of 45, 50, and 49%
in LNCaP, PC3, and Du145 cells, respectively. The corresponding
N1/N0
values indicate that CPENSpm treatment resulted in net cytotoxicity in
both the Du145 and PC3 cell lines. Treatment with BE 3-3-3 resulted in
significant DNA fragmentation only in the LNCaP cells, in which the
final 35% DNA fragmentation was only slightly less than that observed
from CHENSpm treatment. Although growth of LNCaP cells was not
initially inhibited by BE 3-3-3, at times 96 h, there was a
significant decrease in cell number to a level similar to that
resulting from treatment with the other two analogues. These results
indicated that the PCD-associated DNA fragmentation that resulted from
polyamine analogue treatment correlated with the sensitivity observed
for each cell line in response to these agents.
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Discussion
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There has been increasing interest in the use of structural
polyamine analogues as cancer chemotherapeutic agents recently, as a
greater variety of analogues have been synthesized and shown to be
active against several tumor types. Our interest has been in the
unsymmetrically alkylated polyamine analogues CPENSpm and CHENSpm,
which are related to the symmetrically substituted bis(ethyl)polyamine
analogues. We have previously demonstrated the effects of these
analogues against breast cancer and non-small cell lung carcinoma cell
lines (6
, 8
, 15
, 16)
, in which both cell type-specific and
analogue-specific effects were observed. The varying effects of this
category of analogue in different cell lines have clearly demonstrated
that it is difficult to predict the effects that will result from
treatment of a specific cell type. It is possible that the importance
of polyamine-related functions to the particular cell type may play a
role in the response to these analogues. The high levels of polyamines
maintained in the prostate suggest that they may be important to normal
functioning of this organ and may provide a good target for the
polyamine analogues. The objective of the present study was to examine
the effects of CPENSpm and CHENSpm in three human prostate cancer cell
lines, LNCaP, PC3, and Du145, and compare the effects to those of BE
3-3-3, the symmetrically substituted analogue that is currently in
clinical trials.
The results demonstrate that CPENSpm, CHENSpm, and BE 3-3-3 produced
significant concentration-dependent growth inhibitory effects against
all three prostate cancer cell lines tested, although some differential
effects were observed. The cause of the differential sensitivity
between these prostate cell lines currently is not clear, and further
work on this aspect will be necessary. However, one possible
explanation may be the difference in the total polyamine pools of each
cell line with the least sensitive LNCaP line maintaining the greatest
total polyamine content. The induction of PCD was the only parameter
measured that correlated with the sensitivity of these prostate cell
lines to these polyamine analogues. Both the amount of PCD induction
and the rapidity of that induction were determinants of the overall
response of each cell line to the polyamine analogues. In Du145 cells,
in which CHENSpm induction of PCD was more rapid and profound than that
resulting from CPENSpm, the decrease in cell numbers to
N1/N0
values <1, indicating net cytotoxicity, was also more rapid, and the
ultimate amount of cytotoxicity was greater. In LNCaP cells, in which
the ultimate PCD induction was similar for each analogue, the ultimate
growth inhibition was also similar. However, the timing of the decrease
in cell number reflected the timing of PCD induction by each analogue.
BE 3-3-3 induction of PCD and a reduction of cell number were observed
only after 120 h of treatment, whereas the more rapidly acting
CPENSpm and CHENSpm produced greater retardation of cell growth at
earlier times.
The current finding that the unsymmetrically alkylated polyamine
analogues cause more rapid induction of PCD than do the symmetrically
substituted analogues is consistent with our previous observations with
H157 non-small cell lung tumor cells (6)
. Whereas both
CPENSpm and BE 3-4-3, a symmetrical analogue similar to BE 3-3-3,
induced PCD and resulted in overall cytotoxicity to the lung cells, the
earliest detection of CPENSpm-induced PCD preceded that resulting from
BE 3-4-3 by 24 h. In a recent report, Zagaja et al.
(17)
concluded that the cytotoxic mechanisms of BE 3-3-3
and BE 4-4-4-4 did not involve PCD because they found no evidence of
PCD induction after 72 h treatment of Dunning rat prostate cancer
cell lines AT3.1 and AT6.1 with those analogues. Our studies
demonstrate that longer time points should be assessed when evaluating
PCD induction by alkylated polyamine analogues in prostate cell lines.
However, our results also indicate that the ability of a given analogue
to induce PCD can vary between prostate cell lines, and not all
polyamine analogues will induce PCD in all prostate cell lines.
Investigations of the mechanisms of polyamine analogue-induced PCD in
non-small cell lung cancer cells have demonstrated that different
pathways that lead to PCD contribute to the effects of CPENSpm and
CHENSpm. SSAT induction and the subsequent polyamine catabolism that
leads to hydrogen peroxide production have been shown to be involved
with but not totally responsible for the PCD resulting from CPENSpm
treatment in H157 cells (15)
. However, for CHENSpm, a
caspase-independent pathway that results in PCD induction has been
identified (16)
. Furthermore, CHENSpm demonstrates a
significant G2-M cell cycle block (15
, 18)
that appears to be associated with interference in the
processing of tubulin polymerization (18)
. Because
different cell lines exhibit varied relative sensitivity to these
analogues, one can speculate that the multiple paths that ultimately
lead to PCD may not be of equal importance to the functioning of each
cell type. PCD resulting from CHENSpm was greater in comparison to the
other analogues for Du145 cells, whereas CPENSpm and CHENSpm led to
similar PCD activation in LNCaP and PC3 cells. It is possible that the
caspase-independent pathway to PCD and the antimitotic effects are more
easily activated in Du145 cells than in the others, or that Du145 cells
are more resistant to the oxidative damage of CPENSpm. Although
additional studies will be needed to investigate these possibilities,
it is reasonable to suggest that combinations of these polyamine
analogues with other treatments that trigger PCD may lead to
synergistic effects through the use of complementary pathways. Eiseman
et al. (19)
recently reported that a spermine
analogue, BIS, caused a dose-dependent cytotoxic response that resulted
from the rapid induction of PCD in PC3 and Du145 cells. They also
demonstrated that BIS was able to reduce the apoptotic threshold to
radiation and that combination of BIS and radiation treatment resulted
in additive cell killing. Jeffers et al. (20)
and Zagaja et al. (17)
have recently
demonstrated significant activity of the symmetrically substituted
polyamine analogues BE 4-4-4-4 and
1,15-bis(ethylamino)-4,12-diazapentadecane in prostate cancer
cell lines. Interestingly, where examined (17)
, there was
no detection of induction of PCD following BE 3-3-3 or BE 4-4-4-4.
Additional studies will be necessary to dissect the differences
exhibited by the unsymmetrically substituted analogues and the
structurally similar symmetric compounds to understand the molecular
basis for the apparent differences in mechanism of action. However, it
is clear from the current and previous studies that polyamine analogues
require serious consideration for clinical trials against human
prostate cancer. As one polyamine analogue, BE 3-3-3, has now completed
Phase I testing in humans, such trials should be possible in the near
future (21)
.
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FOOTNOTES
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by NIH Grants CA 58236,
CA 51085, CA 63552, and CA 58184. 
2 To whom requests for reprints should be
addressed, at the Johns Hopkins Oncology Center, Johns Hopkins
University School of Medicine, 422 North Bond Street, Baltimore,
MD 21231. Phone: (410) 955-8489; Fax: (410) 955-0840.
3 The abbreviations used are: SSAT,
spermidine/spermine N1-acetyltransferase; BE
3-3-3,
N1,N11-bis(ethyl)norspermine;
BE 3-4-3,
N1,N12-bis(ethyl)spermine;
ODC, ornithine decarboxylase; AdoMetDC,
S-adenosylmethionine decarboxylase; S; CPENSpm,
N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaundecane;
CHENSpm,
N1-ethyl-N11-((cycloheptyl)methyl)-4,8-diazaundecane;
PCD, programmed cell death; BE 4-4-4-4,
1,19-bis-(ethylamino)-5,10,15-triazanoadecane; BIS,
1,12-diaziridinyl-4,9-diazadodecane.
Received 6/30/99;
revised 10/ 6/99;
accepted 10/ 6/99.
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REFERENCES
|
|---|
-
Casero R. A., Ervin S. J., Celano P., Baylin S. B., Bergeron R. J. Differential response to treatment with the bis(ethyl)polyamine analogues between human small cell lung carcinoma and large cell undifferentiated lung carcinoma in culture. Cancer Res., 49: 639-643, 1989.[Abstract/Free Full Text]
-
Davidson N. E., Mank A. R., Prestigiacomo L. J., Bergeron R. J., Casero R. A. Growth inhibition of hormone-responsive and -resistant human breast cancer cells in culture by N1,N12-bis(ethyl)spermine. Cancer Res., 53: 2071-2075, 1993.[Abstract/Free Full Text]
-
Casero R. A., Celano P., Ervin S. J., Porter C. W., Bergeron R. J., Libby P. Differential induction of spermidine/spermine N1-acetyltransferase in human lung cancer cells by the bis(ethyl)polyamine analogues. Cancer Res., 49: 3829-3833, 1989.[Abstract/Free Full Text]
-
Porter C. W., Ganis B., Libby P. R., Bergeron R. J. Correlations between polyamine analogue-induced increases in spermidine/spermine N1-acetyltransferase activity, polyamine pool depletion, and growth inhibition in human melanoma cell lines. Cancer Res., 51: 3715-3720, 1991.[Abstract/Free Full Text]
-
Chang B. K., Bergeron R. J., Porter C. W., Liang Y. Antitumor effects of N-alkylated polyamine analogues in human pancreatic adenocarcinoma models. Cancer Chemother. Pharmacol., 30: 179-182, 1992.[CrossRef][Medline]
-
McCloskey D. E., Yang J., Woster P. M., Davidson N. E., Casero J. R. A. Polyamine analog induction of programmed cell death in human lung tumor cells. Clin. Cancer Res., 2: 441-446, 1996.[Abstract]
-
Saab, N. H., E., W. E., Bieszk, N. C., Preuss, C. V., Mank, A. R., Casero, R. A., and Woster, P. M. Synthesis and evaluation of unsymmetrically substituted polyamine analogues as modulators of human spermidine/spermine-Nl-acetyltransferase (SSAT) and as potential antitumor agents. J. Med. Chem., 36: 2998–3004, 1993.
-
McCloskey D. E., Casero R. A., Woster P. M., Davidson N. E. Induction of programmed cell death in human breast cancer cells by an unsymmetrically alkylated polyamine analogue. Cancer Res., 55: 3233-3236, 1995.[Abstract/Free Full Text]
-
Heston W. D. W. Prostatic polyamines and polyamine targeting as a new approach to therapy of prostatic cancer. Cancer Surv., 11: 217-238, 1991.[Medline]
-
Kabra P. M., Lee H. K., Lubich W. P., Marton L. W. Solid-phase extraction and determination of dansyl derivatives of unconjugated and acetylated polyamines by reversed-phase liquid chromatography. Improved separation systems for polyamines in cerebrospinal fluid, urine and tissue. J. Chromatogr. Biomed. Appl., 380: 19-32, 1986.[CrossRef]
-
Casero R. A., Celano P., Ervin S. J., Wiest L., Pegg A. E. High specific induction of spermidine/spermine N1-acetyltransferase in a human large cell lung carcinoma. Biochem. J., 270: 615-620, 1990.[Medline]
-
Bradford M. A rapid sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 72: 248-254, 1976.[CrossRef][Medline]
-
McCloskey D. E., Kaufmann S. H., Prestigiacomo L. J., Davidson N. E. Paclitaxel induces programmed cell death in MDA-MB-468 human breast cancer cells. Clin Cancer Res., 2: 847-854, 1996.[Abstract]
-
Oberhammer F., Wilson J. W., Dive C., Morris I. D., Hickman J. A., Wakeling A. E., Walker P. R., Sikorska M. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J., 12: 3679-3684, 1993.[Medline]
-
Ha H. C., Woster P. M., Yager J. D., Casero R. A., Jr. The role of polyamine catabolism in polyamine analogue-induced programmed cell death. Proc. Natl. Acad. Sci. USA., 94: 11557-11562, 1997.[Abstract/Free Full Text]
-
Ha H. C., Woster P. M., Casero R. A. J. Unsymmetrically substituted polyamine analogue induces caspase-independent programmed cell death in Bcl-2-overexpressing cells. Cancer Res., 58: 2711-2714, 1998.[Abstract/Free Full Text]
-
Zagaja G. P., Shrivastav M., Fleig M. J., Marton L. J., Rinker-Schaeffer C. W., Dolan M. E. Effects of polyamine analogues on prostatic adenocarcinoma cells in vitro and in vivo. Cancer Chemother. Pharmacol., 41: 505-512, 1998.[CrossRef][Medline]
-
Webb H. K., Wu Z., Sirisoma N., Ha H. C., Casero R. A., Woster P. M. 1-(N-Alkylamino)-11-(N-ethylamino)-4,8-diazaundecanes: simple synthetic polyamine analogues that differentially alter tubulin polymerization. J. Med. Chem., 42: 1415-1421, 1999.[CrossRef][Medline]
-
Eiseman J. L., Rogers F. A., Guo Y., Kauffman J., Sentz D. L., Klinger M. F., Callery P. S., Kyprianou N. Tumor-targeted apoptosis by a novel spermine analogue, 1,12-diaziridinyl-4,9-diazadodecane, results in therapeutic efficacy and enhanced radiosensitivity of human prostate cancer. Cancer Res., 58: 4864-4870, 1998.[Abstract/Free Full Text]
-
Jeffers L., Chruch D., Basu H., Marton L., Wilding G. Effects of the polyamine analogues BE-4-4-4-4, BE-3-7-3, and BE-3-3-3 on the proliferation of three prostate cancer cell lines. Cancer Chemother. Pharmacol., 40: 172-179, 1997.[CrossRef][Medline]
-
Ettinger D. S., Bowling K., Hoker B., Chen T. L., Zabelina Y., Casero R. A. Phase 1 study of N1,N11-diethylnorspermine (DENSPM) in patients with non-small cell lung cancer (NSCLC). Proc. Amer. Soc. Clin. Onc., 17: 190a 1998.
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ABSTRACT
Introduction
