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Molecular Oncology, Markers, Clinical Correlates |
Divisions of Medical Oncology [A. A. A., C. E.] and Oncology Research [J. N. D., P. A. S., S. H. K.], Mayo Clinic and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Graduate School [S. H. K.], Rochester, Minnesota 55905
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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30% of human cancers (3)
. As a result of early reports
indicating that farnesylation was required for maturation of ras
proteins, there has been extensive interest in FT as a potential target
of antineoplastic therapy (4, 5, 6, 7, 8)
. To date, at least five
different FTIs, SCH66336, R115777, L778123, BMS214662, and FTI-277 have
entered clinical testing. Because these compounds are among the first potential anticancer drugs that inhibit aberrantly activated signal transduction pathways in neoplastic cells, there is considerable interest in assessing their cellular and subcellular effects in the clinical setting. Conceptually, assays of FTI action could serve two purposes. In early clinical trials, these assays will be required to determine whether FT has been inhibited at drug concentrations that are achievable in the clinical setting. In later clinical trials, these assays could potentially provide an early marker of drug efficacy if a strong correlation between assay results and clinical outcome can be established. A variety of assays have been proposed for these purposes.
Because the posttranslational processing of ras provided the initial rationale for the clinical development of FTIs (7, 8, 9, 10) , many earlier studies focused on alterations in ras itself. FT inhibition results in altered mobility of H-ras on SDS-polyacrylamide gels, particularly when H-ras-transfected murine cells are examined (7 , 11, 12, 13, 14) . Unfortunately, the existence of alternative prenylation pathways makes it difficult to detect altered processing of other ras isoforms after FT inhibition in many cells (15 , 16) . Moreover, a number of different observations have raised the possibility that other FT substrates, notably RhoB, might be involved in the antiproliferative effects of FTIs (4 , 10 , 17, 18, 19) . These considerations have prompted investigators to search for other assays to monitor the effects of FTIs.
Conceptually, the simplest assay for FT inhibition involves preparing extracts from FTI-treated cells and measuring the remaining ability of FT to farnesylate a substrate polypeptide. In situations in which the inhibitor dissociates from the enzyme, however, these enzymatic assays are likely to underestimate the degree of FT inhibition. Moreover, these assays are difficult to implement in the setting of multi-institution clinical trials.
Other potential assays evaluate the inhibition of processing of other FT substrates. Several farnesylated polypeptides, including the chaperone protein HDJ-2 (20) , the peroxisomal protein Pxf (21) , and the intranuclear intermediate filament protein lamin A (22) , are known to undergo mobility shifts when FT is inhibited (23 , 24) . In the case of lamin A, this mobility shift reflects inhibition of proteolytic processing that removes a 13-amino acid peptide from the COOH terminus of prelamin A to yield the mature lamin (23) . Because this processing is absolutely dependent on farnesylation (25) , it has been suggested that the accumulation of prelamin A containing this unique COOH-terminal peptide might be a potential marker of FT inhibition (26) .
In addition to these assays, it has been proposed that certain downstream events might also be used to monitor the effects of FTIs. For example, treatment with the FTI L744832 has been shown to cause increases in levels of the cyclin-dependent kinase inhibitor p21waf1 in p53 wild-type cells (27) . In addition, the activity of downstream kinases such as raf-1, MEK, or ERK1 or the phosphorylation state of MEK and ERK1 could, in principle, be used as a readout of FT inhibition (12 , 28, 29, 30) .
Although a wide variety of assays have been used in previous studies, they have not been compared. Moreover, it is unclear whether some of the effects reported are specific for certain agents rather than reflecting the effects of FTIs in general. In the present study, several of these different approaches have been compared in tissue culture cell lines treated with two FTIs that have entered clinical testing, the nonpeptidomimetic FTI SCH66336 (31) and the peptidomimetic inhibitor FTI-277 (12) . These experiments were designed to compare various assays of FT inhibition with respect to sensitivity and potential ease of application in the clinical setting and to determine whether these assays detect inhibition of FT by agents that are actually undergoing clinical testing.
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MATERIALS AND METHODS |
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pMEV encoding the
mevalonic acid transporter was obtained from American Type Culture
Collection (Manassas, VA).
Antibodies.
Monoclonal antihuman lamin A (33)
was a kind gift
from Frank McKeon (Harvard Medical School, Boston, MA). A high-titer
polyclonal serum that recognizes the COOH-terminal domain of human
prelamin A was raised by immunizing rabbits with the peptide
CLLGNSSPRTQSPQN coupled to keyhole limpet hemocyanin, as described by
Sinensky et al. (26)
. Polyclonal rabbit
anti-ras antiserum (antibody #3) was from Calbiochem (Cambridge, MA).
Monoclonal anti-p21waf1 (antibody #11) and
anti-HDJ-2 were from Neomarkers (Fremont, CA). Polyclonal chicken sera
that recognize lamins A and C or lamin B were raised as described
previously (34)
. Affinity-purified peroxidase- and
fluorochrome-coupled secondary antibodies were from Kirkegaard & Perry
(Gaithersburg, MD).
Tissue Culture, Colony-forming Assays, and Immunoblotting.
A549 human non-small cell lung cancer cells, HCT116 colon carcinoma
cells, BxPC-3 pancreatic carcinoma cells, and MCF-7 breast cancer cells
were obtained from American Type Culture Collection and propagated in
the tissue culture media specified by the supplier. To assess the
effect of SCH66336 on colony formation in A549 cells, aliquots
containing 500 cells were plated in triplicate plates for each data
point. After a 14–18 h incubation to allow cells to adhere, the
indicated concentrations of SCH66336 (added from 1000-fold concentrated
stocks prepared in DMSO) or the corresponding volume of diluent was
added. Cells were incubated for 7–8 days to allow colonies to form.
Alternatively, cells were incubated with SCH66336 for 24 h, washed
twice in serum-free RPMI 1640, and incubated for 7 days in medium A
(RPMI 1640, 5% heat-inactivated fetal bovine serum, 100 units/ml
penicillin G, 100 µg/ml streptomycin, and 2 mM glutamine)
in the absence of SCH66336.
To prepare whole-cell lysates for immunoblotting, replicate 100-mm
dishes containing 30–40% confluent cells were treated with the
indicated concentrations of SCH66336 or diluent for 22–24 h.
Alternatively, A549 cells were allowed to reach confluence and
maintained in this state for 7 days prior to treatment with SCH66336
for 24 h. The highest concentration of SCH66336 used in these
assays, 400 nM, is at or below the trough concentration
achieved in patients on prolonged schedules of SCH66336
(35)
. Flow cytometry (36)
confirmed that
>95% of the cells were in
G0-G1 after culture under
confluent conditions. At the completion of the incubation, log phase or
confluent cells were washed three times with ice-cold RPMI 1640
containing 10 mM HEPES (pH 7.4) and solubilized in buffer
consisting of 6 M guanidine hydrochloride, 250
mM Tris-HCl (pH 8.5 at 21°C), 10 mM EDTA, 1%
(v/v) ß-mercaptoethanol, and 1 mM
-phenylmethylsulfonyl fluoride (freshly added from a 100
mM stock in anhydrous isopropanol). In some experiments,
SCH66336 was replaced with 20 µM FTI-277 (added from a
1000-fold concentrated stock prepared in DMSO containing 10
mM DTT), a concentration chosen because it inhibited ras
farnesylation and raf activation in tissue culture in a previous study
(12)
.
After the whole-cell lysates were dialyzed and lyophilized as described previously (37) , aliquots containing 50 µg of protein [assayed by the bicinchoninic acid method (38) ] were subjected to electrophoresis on SDS-polyacrylamide gels containing 8% (w/v) acrylamide (for lamins or HDJ-2) or 12% acrylamide (p21waf1, ras), transferred to nitrocellulose, and probed with the immunological reagents described above. Antigen-antibody complexes were detected using peroxidasecoupled secondary antibodies and ECL enhanced chemiluminescence reagents.
Transfection.
A549 cells (2 x 107; 50% confluent) were
transfected with 40 µg of plasmid pRc/CMV7pMEV (prepared using a
plasmid isolation kit; Qiagen, Valencia, CA) by electroporation using a
Bio-Rad Gene Pulser electroporator operating at 300 V, 960 µfarad and
infinite resistance. Cells were cultured at low density in medium A for
24 h. Stably transfected clones were selected in 2 mg/ml G418 and
isolated using cloning rings. After expansion, clones were examined for
ability to accumulate [3H]mevalonate during a
22–24 h incubation at 37°C. Of 25 clones examined, one with
substantial mevalonate uptake was identified and named A549pMEV.
Immunohistochemistry.
A549 cells grown on 20-mm glass coverslips were incubated in medium A
for a minimum of 1 week after reaching confluence. Cells were then
treated with 200 nM SCH66336 or diluent for 24 h as
described above. At the completion of the incubation, coverslips were
washed twice with ice-cold PBS and fixed in acetone for 15 min at
-20°C. Samples were then rehydrated with two to three changes of PBS
and blocked for a minimum of 1 h at 4°C in buffer B, which
consisted of 10% (w/v) powdered milk in 150 mM NaCl, 10
mM Tris-HCl (pH 7.4 at 21°C), 100 units/ml penicillin G,
100 µg/ml streptomycin, and 1 mM sodium azide. Cells were
treated with a mixture of murine monoclonal anti-lamin A (1:3000) and
rabbit anti-prelamin A (1:750) in buffer B at 4°C for 12–16 h. After
removal of the primary antibodies, samples were washed six times with
PBS over a 20-min period, incubated for 30 min with a mixture of
affinity-purified, rhodamine-conjugated antimouse IgG and
fluorescein-conjugated antirabbit IgG (20 µg/ml each), washed six
times with PBS over a 20-min period, mounted in Vectashield (Vector
Laboratories, Burlingame, CA), sealed with clear nail polish, and
examined on a Zeiss LSM 310 confocal microscope (Carl Zeiss, Inc., New
York, NY).
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RESULTS |
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•). In
contrast, a 24-h exposure to SCH66336 had a minimal effect on colony
formation (
), indicating that SCH66336 was not
killing the cells under these conditions. This model system provided
the opportunity to examine the effects FT inhibition without secondary
changes related to cytotoxic effects per se.
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. This
analysis revealed that SCH66336 caused a dose-dependent decrease in
prenylation of several different polypeptides with apparent molecular
weights between Mr 18,000 and
Mr 75,000 (Fig. 1B,
*). The prenylation of these polypeptides was detectably decreased at
250 nM SCH66336 (Fig. 1B,
Lane 2) and
completely inhibited at 1–2 µM (Lanes
4 and 5). These results confirm that SCH66336 inhibits
the prenylation of several polypeptide species in this model system. In
contrast, a number of polypeptides in the
Mr 20,000–30,000 region were
prenylated despite the presence of high concentrations of SCH66336
(Fig. 1B,
bracket). These polypeptides, which were
identified previously as small GTP-binding proteins, have been reported
to be prenylated in the presence of other FTIs as well
(11)
.
Examination of Altered Protein Mobility after FTI Treatment.
In additional experiments, whole-cell lysates prepared from A549 cells
after treatment with varying concentrations of SCH66336 were subjected
to SDS-PAGE, followed by immunoblotting with reagents raised against
polypeptides that are FT substrates. When blots were probed with a
serum that recognizes all ras species, altered mobility of the
predominant ras species in this cell line was not detectable (Fig. 2A,
top panel). In the same
samples, only a small percentage of the farnesylated nuclear protein
lamin B (41)
demonstrated altered mobility (Fig. 2B,
top panel). In contrast, increased amounts of a slower migrating
species of HDJ-2 were observed after SCH66336 treatment (Fig. 2A,
second panel). This slower migrating species was readily
detectable at drug concentrations as low as 6.25
nM and amounted to as much as half of the total
HDJ-2 at 400 nM SCH66336.
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second
panel). Probing of the same blot with an antiserum that
specifically recognizes the precursor polypeptide at the COOH terminus
of prelamin A (26)
revealed that the inhibition of
prelamin A processing could be detected at SCH66336 concentrations as
low as 6.25 nM (Fig. 2B,
bottom
panel).
To look for downstream markers that might be useful for examining FT
inhibition, blots were also probed with antibodies to
p21waf1. Although another FTI has been reported
to increase p21waf1 levels in certain cells
(27)
, levels of this polypeptide did not increase in A549
cells after treatment with SCH66336 (Fig. 2A,
bottom panel).
To rule out the possibility that these results were unique to A549
cells, three additional cell lines were treated with 200 nM
SCH66336 and subjected to the same analysis. The cell lines chosen for
this analysis were the pancreatic carcinoma line BxPC-3, which has
wild-type ras (42)
and displays an
IC50 of 200 nM upon continuous
exposure to SCH66336 in clonogenic
assays;4
the breast carcinoma
line MCF7, which has wild-type ras (43)
and displays an
IC50 of 50 nM upon continuous
exposure to SCH66336 in clonogenic assays;4
and the colon
carcinoma line HCT116, which has a mutant K-ras (42)
and
displays an IC50 of 100 nM upon
continuous exposure to SCH66336 in clonogenic assays.4
Treatment for 24 h with 200 nM SCH66336 again failed
to demonstrate any alteration in the mobility of detectable ras
proteins by immunoblotting (Fig. 3
,
top panel, Lane 2). In contrast, increased levels of the
slower migrating HDJ-2 species were readily detectable in all four cell
lines after FTI treatment (Fig. 3
, second panel, Lane 2).
Moreover, each of the FTI-treated cell lines contained a slower
migrating species of lamin A that reacted with the prelamin A antiserum
(Fig. 3
, third panel, Lane 2). As was the case in A549
cells, p21waf1 failed to reproducibly increase in
the other three cell lines after SCH66336 treatment (Fig. 3
,
bottom panel, Lane 2).
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, Lanes 3) demonstrated that FTI-277 altered
processing of HDJ-2 and prelamin A. In contrast, altered migration of
ras and altered levels of p21 were not observed. Identical results were
also obtained when the FTI R115777 was substituted for SCH66336 (data
not shown).
Effects of FT Inhibition on Noncycling Cells.
Because the vast majority of cells in clinical tumor specimens are not
cycling at any point in time, we evaluated these assays in noncycling
A549 cells. Seven days after reaching confluence, the vast majority of
these cells were in G0-G1
(Fig. 4A,
bottom panel). In
the confluence-arrested cells, increased levels of the slower migrating
species of HDJ-2 and the appearance of prelamin A were readily
demonstrated after SCH66336 treatment (Fig. 4A)
, although
the signals were slightly decreased in noncycling cells compared with
cycling A549 cells examined on the same blot.
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top row) but became readily
detectable in all of the cells by immunofluorescence after treatment
with SCH66336 (
middle row). The immunizing peptide
prevented labeling with this serum (
bottom row),
demonstrating specificity of this reaction. When combined with the
immunoblotting results in Fig. 3
, these observations not only confirm
that multiple FTIs inhibit prelamin A processing but also indicate
that this inhibition can be detected in noncycling cells by
immunoblotting (Fig. 4A)
or immunohistochemistry (Fig. 4B)
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DISCUSSION |
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Because the FTIs are among the first inhibitors of signal transduction to be widely tested in the clinic, there is considerable interest in assessing their effects in clinical material. An ideal marker for such studies would be one that is highly sensitive to inhibition of the targeted pathway, selective for inhibition of that pathway, and assayable in a wide variety of tumor types as well as potentially in surrogate normal tissues. Other features that would be desirable in a marker assay would be ease of performance and the ability to analyze samples in batches rather than individually. As signal transduction inhibitors are tested clinically, such assays will be particularly important in differentiating between compounds that successfully target the intended pathway but do not have clinical activity versus compounds that fail to target the intended pathway at concentrations where toxicity prohibits dose escalation. Distinguishing between these alternatives will be particularly important in clinical trials that do not have the classical end point of tumor shrinkage as well as in chemoprevention and adjuvant chemotherapy trials. In light of the potential importance of these types of studies, we have compared several of the assays that have been proposed for the assessment of FT inhibition in clinical material.
One potential approach would be to assay FT enzymatic activity in cell extracts after drug exposure. This approach suffers from the potential problem that reversible inhibitors such as SCH66336 and FTI-277 might dissociate from FT during cell purification and fractionation, thereby leading to underestimation of the degree of inhibition achieved in situ. In addition, current assays of FT activity in certain cell types are subject to interference by endogenous inhibitors.5 As a result, some investigators have resorted to partial purification of the enzyme prior to assaying its activity (44) , an approach that does not appear feasible in the context of multicenter clinical trials.
Immunoblotting and immunohistochemistry approaches appear to be better
suited for application in the clinical setting. FTIs were initially
developed to inhibit the posttranslational processing of the ras
oncoproteins (4
, 5
, 45)
. Several earlier studies
demonstrated that FTI treatment altered mobility of H-ras in
transfected murine cells. Nonetheless, immunoblotting experiments
failed to demonstrate altered migration of endogenous ras polypeptides
in a number of different cell lines after treatment with SCH66336 or
FTI-277 (Figs. 2
and 3)
. There are several potential explanations for
this result. It is possible that the predominant ras species in these
cell lines are isoforms of K-ras, which has been shown to be more
resistant to FTIs than H-ras (46)
. We note, however, that
prelamin A farnesylation is also more resistant to FTIs than H-ras
(47)
, yet we could readily detect inhibition of prelamin A
processing in each of the cell lines. Alternatively, it is possible
that geranylgeranylation of ras polypeptides in FTI-treated human cells
(16)
leads to processed ras species that have unaltered
mobility on SDS-polyacrylamide gels. In either case, it is possible
that immunoprecipitation of H-ras, followed by Western blotting (an
approach necessitated by low levels of endogenous H-ras in these cells
and many other tissue types), might demonstrate an effect of the FTIs
on migration of H-ras. However, it is difficult to envision that
immunoprecipitation followed by immunoblotting would be practical for
routine performance in the clinical setting.
Recent studies have suggested that RhoB might also be a critical
target for FTIs (4
, 10
, 17, 18, 19)
. These studies have
examined epitope-tagged RhoB that is expressed after transfection. In
our hands, experiments similar to those in Fig. 2
have revealed that
endogenous rho species are below the limit of detection with
commercially available monoclonal antibodies,4
making it
difficult to use this polypeptide as a marker of FTI action in the
clinical setting. Accordingly, we focused on other potential markers of
FT inhibition.
Consistent with recent results published in abstract form
(24)
, the prenylated protein HDJ-2 demonstrated a shift in
mobility upon treatment with SCH66336 (Figs. 2
and 3)
. The appearance
of the slower migrating species was detectable at concentrations of
SCH66336 as low as 6.25 nM (Fig. 2A)
. In
addition, a similar mobility shift was observed in noncycling cells
(Fig. 4A)
, indicating the potential usefulness of this assay
in clinical tumor specimens.
Work from several laboratories demonstrated previously that lamin B and
prelamin A are farnesylated polypeptides (23
, 41)
. In our
studies, only a small amount of lamin B displayed a mobility shift in
the presence of SCH66336 (Fig. 2B)
. In contrast, as much as
half of the lamin A demonstrated a mobility shift after the same
treatment
. Further analysis revealed that the
processing of prelamin A was extensively inhibited in all cell lines
examined (Figs. 2B
and 3
). Accumulation of prelamin A above
low basal levels was detectable at SCH66336 concentrations as low as
6.25 nM and increased in a dose-dependent manner
(Fig. 2B)
. Because prelamin A is ordinarily present in
limited amounts within the cell, the assay for prelamin A was suitable
for immunoblotting (Figs. 2
3
4)
or immunohistochemistry (Fig. 4B)
, either of which should be potentially useful in the
clinical setting. The widespread use of immunohistochemistry for other
purposes (e.g., assessment of estrogen and progesterone
receptors, HER2-neu status, and cytokeratin expression) suggests that
the immunohistochemical assay for prelamin A might be particularly
useful.
Finally, as a potential example of polypeptide changes downstream from
ras, we examined the up-regulation of p21waf1.
Although the FTI L744832 has been reported to induce accumulation of
p21waf1 in a p53-dependent manner, we could not
detect increased p21waf1 in any of the four cell
lines after treatment with SCH66336 (Figs. 2
and 3)
or FTI-277 (Fig. 3)
. In this context, it is important to note that A549, MCF-7, and
HCT116 cells all have wild-type p53. These observations not only raise
the possibility that up-regulation of p21waf1
after treatment with L744832 might be a drug- or cell line-specific
effect but also highlight the importance of examining potential markers
of FTI action with the compounds that are actually undergoing clinical
testing.
To rule out the possibility that some of the results described in the
present work might be unique to SCH66336 and FTI-277, experiments
depicted in Figs. 2
3
4
were repeated using R115777, another FTI that is
in Phase II clinical trials (10)
. All of the results
presented above were readily reproduced with
R115777.4
In summary, the current findings identify two different assays that appear to be sensitive and widely applicable markers of FT inhibition. HDJ-2 is present in a variety of tumor cell lines and undergoes a readily detectable mobility shift upon treatment with FTIs. Lamin A likewise undergoes a mobility shift in multiple cell lines after FTI treatment. The mobility shift of HDJ-2 and the accumulation of prelamin A are detectable at similar drug concentrations. The retention of a unique prepeptide in prelamin A after FTI treatment makes this polypeptide amenable to assay by both immunoblotting and immunohistochemistry. Because the effects on HDJ-2 and lamin A are observed in noncycling as well as cycling cells, one or both of these assays should be suitable for detecting inhibition of FT in the clinical setting.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by Grants K01 CA77112, U01
CA69912, and P30 CA15083. 
2 To whom requests for reprints should be
addressed, at Division of Medical Oncology, Mayo Clinic, 200 First
Street, S.W., Rochester, MN 55905. E-mail: Adjei.Alex{at}Mayo.edu
3 The abbreviations used are: FT,
farnesyltransferase; FTI, farnesyltransferase inhibitor.
4 D. End, personal communication.
5 J. N. Davis and A. A. Adjei, unpublished
observations.
Received 1/ 3/00; revised 3/28/00; accepted 3/30/00.
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 C. Capanni, E. Mattioli, M. Columbaro, E. Lucarelli, V. K. Parnaik, G. Novelli, M. Wehnert, V. Cenni, N. M. Maraldi, S. Squarzoni, et al. Altered pre-lamin A processing is a common mechanism leading to lipodystrophy Hum. Mol. Genet., June 1, 2005; 14(11): 1489 - 1502. [Abstract] [Full Text] [PDF]
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 C.-L. Gau, J. Kato-Stankiewicz, C. Jiang, S. Miyamoto, L. Guo, and F. Tamanoi Farnesyltransferase inhibitors reverse altered growth and distribution of actin filaments in Tsc-deficient cells via inhibition of both rapamycin-sensitive and -insensitive pathways Mol. Cancer Ther., June 1, 2005; 4(6): 918 - 926. [Abstract] [Full Text] [PDF]
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 G. K. Dy, L. M. Bruzek, G. A. Croghan, S. Mandrekar, C. Erlichman, P. Peethambaram, H. C. Pitot, L. J. Hanson, J. M. Reid, A. Furth, et al. A Phase I Trial of the Novel Farnesyl Protein Transferase Inhibitor, BMS-214662, in Combination with Paclitaxel and Carboplatin in Patients with Advanced Cancer Clin. Cancer Res., March 1, 2005; 11(5): 1877 - 1883. [Abstract] [Full Text] [PDF]
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Y. Kho, S. C. Kim, C. Jiang, D. Barma, S. W. Kwon, J. Cheng, J. Jaunbergs, C. Weinbaum, F. Tamanoi, J. Falck, et al. A tagging-via-substrate technology for detection and proteomics of farnesylated proteins PNAS, August 24, 2004; 101(34): 12479 - 12484. [Abstract] [Full Text] [PDF]
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M. Alsina, R. Fonseca, E. F. Wilson, A. N. Belle, E. Gerbino, T. Price-Troska, R. M. Overton, G. Ahmann, L. M. Bruzek, A. A. Adjei, et al. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma Blood, May 1, 2004; 103(9): 3271 - 3277. [Abstract] [Full Text] [PDF]
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J. Sun, J. Ohkanda, D. Coppola, H. Yin, M. Kothare, B. Busciglio, A. D. Hamilton, and S. M. Sebti Geranylgeranyltransferase I Inhibitor GGTI-2154 Induces Breast Carcinoma Apoptosis and Tumor Regression in H-Ras Transgenic Mice Cancer Res., December 15, 2003; 63(24): 8922 - 8929. [Abstract] [Full Text] [PDF]
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V. Ramamurthy, M. Roberts, F. van den Akker, G. Niemi, T. A. Reh, and J. B. Hurley AIPL1, a protein implicated in Leber's congenital amaurosis, interacts with and aids in processing of farnesylated proteins PNAS, October 28, 2003; 100(22): 12630 - 12635. [Abstract] [Full Text] [PDF]
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 C. P. Maske, M. S. Hollinshead, N. C. Higbee, M. O. Bergo, S. G. Young, and D. J. Vaux A carboxyl-terminal interaction of lamin B1 is dependent on the CAAX endoprotease Rce1 and carboxymethylation J. Cell Biol., September 29, 2003; 162(7): 1223 - 1232. [Abstract] [Full Text] [PDF]
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C. Selleri, J. P. Maciejewski, N. Montuori, P. Ricci, V. Visconte, B. Serio, L. Luciano, and B. Rotoli Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells Blood, August 15, 2003; 102(4): 1490 - 1498. [Abstract] [Full Text] [PDF]
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A. A. Adjei, G. A. Croghan, C. Erlichman, R. S. Marks, J. M. Reid, J. A. Sloan, H. C. Pitot, S. R. Alberts, R. M. Goldberg, L. J. Hanson, et al. A Phase I Trial of the Farnesyl Protein Transferase Inhibitor R115777 in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer Clin. Cancer Res., July 1, 2003; 9(7): 2520 - 2526. [Abstract] [Full Text] [PDF]
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Y. Shi, J. Gera, J.-h. Hsu, B. Van Ness, and A. Lichtenstein Cytoreductive Effects of Farnesyl Transferase Inhibitors on Multiple Myeloma Tumor Cells Mol. Cancer Ther., June 1, 2003; 2(6): 563 - 572. [Abstract] [Full Text] [PDF]
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A. A. Adjei, A. Mauer, L. Bruzek, R. S. Marks, S. Hillman, S. Geyer, L. J. Hanson, J. J. Wright, C. Erlichman, S. H. Kaufmann, et al. Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., May 1, 2003; 21(9): 1760 - 1766. [Abstract] [Full Text] [PDF]
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A. Nakajima, T. Tauchi, M. Sumi, W. R. Bishop, and K. Ohyashiki Efficacy of SCH66336, a Farnesyl Transferase Inhibitor, in Conjunction with Imatinib against BCR-ABL-positive Cells Mol. Cancer Ther., March 1, 2003; 2(3): 219 - 224. [Abstract] [Full Text] [PDF]
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R. B. Lobell, D. Liu, C. A. Buser, J. P. Davide, E. DePuy, K. Hamilton, K. S. Koblan, Y. Lee, S. Mosser, S. L. Motzel, et al. Preclinical and Clinical Pharmacodynamic Assessment of L-778,123, a Dual Inhibitor of Farnesyl:Protein Transferase and Geranylgeranyl:Protein Transferase Type-I Mol. Cancer Ther., July 1, 2002; 1(9): 747 - 758. [Abstract] [Full Text] [PDF]
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V. Smith, M. G. Rowlands, E. Barrie, P. Workman, and L. R. Kelland Establishment and Characterization of Acquired Resistance to the Farnesyl Protein Transferase Inhibitor R115777 in a Human Colon Cancer Cell Line Clin. Cancer Res., June 1, 2002; 8(6): 2002 - 2009. [Abstract] [Full Text] [PDF]
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B. Zhang, G. C. Prendergast, and R. G. Fenton Farnesyltransferase Inhibitors Reverse Ras-mediated Inhibition of Fas Gene Expression Cancer Res., January 1, 2002; 62(2): 450 - 458. [Abstract] [Full Text] [PDF]
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L. R. Kelland, V. Smith, M. Valenti, L. Patterson, P. A. Clarke, S. Detre, D. End, A. J. Howes, M. Dowsett, P. Workman, et al. Preclinical Antitumor Activity and Pharmacodynamic Studies with the Farnesyl Protein Transferase Inhibitor R115777 in Human Breast Cancer Clin. Cancer Res., November 1, 2001; 7(11): 3544 - 3550. [Abstract] [Full Text] [PDF]
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J. E. Karp, J. E. Lancet, S. H. Kaufmann, D. W. End, J. J. Wright, K. Bol, I. Horak, M. L. Tidwell, J. Liesveld, T. J. Kottke, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial Blood, June 1, 2001; 97(11): 3361 - 3369. [Abstract] [Full Text] [PDF]
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A. A. Adjei, J. N. Davis, L. M. Bruzek, C. Erlichman, and S. H. Kaufmann Synergy of the Protein Farnesyltransferase Inhibitor SCH66336 and Cisplatin in Human Cancer Cell Lines Clin. Cancer Res., May 1, 2001; 7(5): 1438 - 1445. [Abstract] [Full Text]
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