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Clinical Investigations |
Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905 [A. A. A., C. E., J. N. D., J. A. S., R. S. M., L. J. H., P. A. S., P. A., S. H. K.], and Schering-Plough Research Institute, Kenilworth, New Jersey 07033 [D. L. C., W. R. B., P. K.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This pathway initially attracted attention because of its role in the processing of ras proteins, membrane-localized guanine nucleotide-binding polypeptides that function as molecular switches linking receptor and nonreceptor tyrosine kinase activation to downstream cytoplasmic and nuclear events. Three mammalian ras proto-oncogenes encode four related and highly conserved proteins, H-ras, N-ras, and the splice variants K-ras 4A and K-ras 4B (5) . Activating mutations in these Ras polypeptides result in constitutive signaling, thereby stimulating cell proliferation and inhibiting apoptosis (6) . Oncogenic ras mutations have been identified in approximately 30% of human cancers (7) . K-ras mutations are frequent in non-small cell lung, colorectal, and pancreatic carcinomas; H-ras mutations are found in bladder, kidney, and thyroid carcinomas; and N-ras mutations are found in melanoma, hepatocellular carcinoma, and hematological malignancies (7) . Because of the role of farnesylation in ras maturation (8) , FT inhibition was envisioned as a strategy for interfering with ras-dependent transformation.
Whereas FTIs clearly inhibit ras farnesylation, it is unclear whether the antiproliferative effects of these compounds result exclusively from effects on ras. Geranylgeranylated forms of K-ras and N-ras, which are themselves capable of transforming cells, are observed in cells treated with FTIs (9) . Despite this alternative prenylation pathway, FTIs inhibit proliferation of many tumor cells expressing activated K-ras in vitro and in vivo. In addition, several cell types that lack ras mutations are also sensitive to FTIs in vivo and in vitro (10) . Collectively, these findings argue that inhibition of the farnesylation of other proteins might also contribute to the observed antitumor properties of FTIs (11 , 12) .
SCH66336, a novel nonpeptide tricyclic FTI, competes with the protein substrate for binding to FT (13) . Farnesylation of H-ras and K-ras-4B in vitro by purified human FT is inhibited by SCH66336 with IC50 values of 1.9 and 5.2 nM, respectively. No inhibition of the related geranylgeranyl protein transferase GGT-1 occurs at SCH66336 concentrations of up to 50 µM, confirming the selectivity of this agent for FT. In tissue culture, SCH66336 blocks the growth of human neoplastic cell lines and fibroblasts expressing activated K-ras proteins. SCH66336 induces significant tumor regressions in WAP-ras transgenic animals (14) . In addition, SCH66336 demonstrates potent antineoplastic activity in nude mice bearing human lung, prostate, pancreas, colon, and bladder cancer xenografts (14) . On the basis of these findings, a Phase I study of cyclic oral administration of SCH66336 was undertaken in patients with advanced solid tumors. The goals of this study were as follows: (a) to determine the MTD of SCH66336; (b) to determine the dose-limiting toxicity of SCH66336; (c) to determine the recommended dose for subsequent studies; (d) to seek preliminary evidence of antitumor activity; and (e) to demonstrate FT inhibition at doses achieved in vivo.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18 years, ECOG performance status
2 (moderate physical impairment from the effects of the disease),
prior radiation to 30% of bone marrow completed at least 3 weeks
before study enrollment, life expectancy of at least 12 weeks, and
adequate bone marrow (platelets 100 x 109/liter, ANC > 1.5 x 109/liter, and hemoglobin 10 g/dl), hepatic (total
bilirubin 1.5 x the upper limit of normal and
aspartate transaminase 2.5 x normal), and renal
(serum creatinine <1.5 x the upper limit of normal)
functions.
Experimental Treatment.
SCH66336 was supplied by Schering-Plough Research Institute,
(Kenilworth, NJ) in solid gelatin capsules containing 25, 100, or 200
mg of SCH66336. This agent was administered orally twice daily for 7
days out of a 21-day cycle. Antiemetic prophylaxis was not given.
One new patient was entered at each dose level until moderate organ toxicity (NCI CTC grade 2; Ref. 15 ) was observed. The schedule was then changed to three patients at each dose level. Dose escalation was not allowed in individual patients. The MTD was defined as one dose level below the dose that induced dose-limiting toxicity in more than one-third of patients (at least two of a maximum of six patients). Severe or life-threatening (NCI CTC grades 3 or 4) nonhematological toxicity (with the exception of nausea and vomiting) were considered dose limiting. NCI CTC grade 3 or 4 nausea and vomiting in patients who had received prophylactic treatment with an optimal antiemetic regimen were considered dose limiting. ANC <1.0 x 109/liter, platelet count <50 x 109/liter, or hemoglobin of 6.5 g/dl was also considered dose limiting.
Clinical Care of Patients.
Complete patient histories, physical examinations, complete blood cell
counts, serum electrolytes, chemistries, urinalysis, and
electrocardiograms were performed at baseline and before each course of
treatment. Laboratory studies were repeated weekly while patients were
on study. Ophthalmologic examination, including retinal photography,
was performed at baseline and before every second cycle. Radiological
studies (roentgenograms, computed axial tomographic scans, and magnetic
resonance imaging) were performed at baseline and after every two
courses of therapy to assess tumor response.
Standard response criteria were utilized. A PR was defined as a
50% reduction in the sum of the products of the largest
perpendicular diameters of indicator lesion(s), single or multiple,
chosen before therapy. A CR was the total disappearance of all evidence
of tumor. For a patient to qualify for CR or PR, none of the factors
constituting progression could be present. Tumor progression was
defined as the appearance of new lesion(s) or a 25% increase in size
of indicator lesion(s). Stable disease was documented when there was a
failure to meet the criteria for CR, PR, or progression. All objective
responses were required to last for at least 4 weeks.
Antibodies.
Monoclonal antihuman lamin A (16)
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 limpit hemocyanin as described by
Sinensky et al. (17)
. Generation and
characterization of the monoclonal anti-PxF antibody will be described
in greater detail
elsewhere.4
Affinity-purified peroxidase- and fluorochrome-coupled secondary
antibodies were from Kirkegaard & Perry (Gaithersburg, MD).
Immunoblotting.
Replicate 100-mm dishes containing 30–40% confluent A549 human
non-small cell lung cancer cells (American Type Culture Collection,
Manassas, VA) grown in RPMI 1640 containing 5% (v/v) heat-inactivated
fetal bovine serum, 100 units/ml penicillin G, 100 µg/ml
streptomycin, and 2 mM glutamine were treated with the
indicated concentrations of SCH66336 (added from 1000x concentrated
stocks prepared in DMSO) or the corresponding volume of diluent. After
a 24-h incubation, cells were washed three times with ice-cold RPMI
1640 supplemented with 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). Samples were prepared
for electrophoresis as described previously (18)
. Aliquots
containing 50 µg of protein [assayed by the method of Smith et
al. (19)
] were subjected to electrophoresis on
SDS-polyacrylamide gels containing 8% (w/v) acrylamide (for lamins) or
12% acrylamide (for Pxf), transferred to polyvinylidene difluoride
membrane, and probed with the antibodies or sera described above.
Antigen-antibody complexes were detected using peroxidase-coupled
secondary antibodies and an enhanced chemiluminescence kit (Amersham
Pharmacia Biotech, Piscataway, NJ).
Immunohistochemistry.
A549 cells grown on 20-mm glass coverslips were 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 A, 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 A 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). Control experiments indicated that the epitope recognized by
the prelamin A serum was attenuated when samples were exposed to air
for 24–48 h before fixation but was stable for at least 3 months when
samples were fixed and then stored in buffer A.
Buccal smears obtained before therapy and again on day 8 (12 h after the last dose of SCH66336) were air-dried and fixed in acetone within 3 h of harvest. Samples were stored in buffer A and subjected to the immunohistochemical assay in batches. With each batch, A549 cells treated with SCH66336 or diluent were included as positive and negative controls, respectively. Sensitivity of the photomultiplier tubes on the confocal microscope was adjusted so that the signal for prelamin A in diluent-treated A549 cells was just below the limit of detection, a result consistent with the appearance of the specimens by conventional fluorescence microscopy. With the sensitivity of the confocal microscope fixed at this level, all other specimens were then examined in the conventional and laser scanning modes. When images were subsequently imported into Adobe Photoshop 3.0, any adjustments to brightness or contrast were applied identically to paired samples harvested before and after therapy with SCH66336.
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RESULTS |
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, 8 females and 12 males, received 92 assessable courses of therapy
through seven dosage levels (Table 2)
. The median number of courses administered per patient was 2.5 (range,
1–21 courses). The median age of study participants was 58.5 years
(range, 43–72 years). Patients were minimally symptomatic from their
cancer, with only two patients being significantly impaired in their
daily activities. Four patients had received no prior chemotherapy, and
16 patients had received up to two prior chemotherapy regimens. Six
patients had received prior radiation therapy to <30% of bone marrow.
The tumor types treated on this study are shown in Table 1
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. Brief and mild noncumulative leukopenia (CTC grade 1) was the most
common hematological toxicity. This toxicity was seen in 5 of 92
treatment courses. The leukopenia was associated with neutropenia in
four of the five episodes, with ANCs dropping to 
60% of baseline
values during the first cycle. Brief and mild thrombocytopenia was the
next most common hematological toxicity, occurring in 4 of 92 treatment
courses (one grade 2 and three grade 1). Anemia was not observed in
this study. The incidence and severity of hematological toxicity did
not appear to be related to SCH66336 dose.
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In addition to diarrhea, nausea and vomiting were observed. Nausea was reported by 11 of the 20 patients, and vomiting was reported by 6 patients. Nausea and vomiting were sporadic and mild at doses of SCH66336 up to 350 mg b.i.d. Above this dose, nausea and vomiting were frequent and severe. In all instances, nausea and vomiting resolved quickly and completely with antiemetic therapy.
Fatigue.
Fatigue precluded dose escalation above 350 mg b.i.d. Both patients
treated at 400 mg b.i.d. experienced severe fatigue, necessitating bed
rest for most of the day; neither patient could complete the 7-day
course of treatment. The fatigue, which was constitutional in nature,
led to a two-grade decline of performance status on the ECOG scale.
This fatigue was worsened by dehydration from GI toxic effects but
slowly resolved after discontinuation of SCH66336. Twenty-five episodes
of less severe fatigue (23 grade 1 and 2 grade 2 episodes) were
reported at lower doses.
Other Toxicities.
Moderate reversible renal insufficiency (serum creatinine = 2–4 mg/dl, representing a 2–4-fold elevation above baseline)
occurred in both patients receiving 400 mg b.i.d. In both instances,
serum creatinine normalized in 24 h with hydration, suggesting
that the renal effects reflected dehydration-associated prerenal
azotemia secondary to nausea, vomiting, and diarrhea. One patient at
the 400 mg b.i.d. dose level (subsequently reduced to 200 mg b.i.d.)
developed hypokalemia with each treatment and required potassium
supplementation. No other possible etiological factors for the
hypokalemia could be identified.
Because the visual proteins rhodopsin kinase and transducin are farnesylated, ophthalmologic examinations were performed at regular intervals. No evidence of ocular toxicity was found.
Based on the results of this study, the MTD and recommended dose of SCH66336 for subsequent clinical testing on this schedule is 350 mg orally twice a day.
Antitumor Activity.
One patient with metastatic NSCLC who had previously received combined
modality treatment with radiation and chemotherapy achieved a PR after
two courses of treatment. This patient remained on study for 14 months.
Eight patients had stable disease for 5–10 treatment cycles, and 10
patients progressed on therapy after 1–3 treatment cycles.
FT Inhibition: Development of an Assay Suitable for Clinical
Material.
As indicated in the "Introduction," a number of intracellular
polypeptides are farnesylated. In principle, any one of these could
serve as an indicator for FT inhibition. Our studies focused on PxF
(Hk33), a peroxisomal protein of unknown function that is widely
expressed (20)
, and lamin A, a major structural protein of
the nuclear envelope. Processing of both of these polypeptides involves
farnesylation followed by further posttranslational modifications
(20, 21, 22, 23)
.
When A549 lung cancer cells [which contain mutated K-ras
(24)
] were treated with increasing concentrations of
SCH66336, evidence for inhibited farnesylation of both polypeptides was
observed. Twenty-four h after the addition of 400 nM
SCH66336 to the cells, levels of the Mr
33,000 PxF polypeptide (Fig. 2A
,top) decreased by 50%, accompanied by appearance of a
new Mr 35,000 species (see Lanes 1
and 2) that has previously been reported to represent
unprocessed PxF. This species was observed at SCH66336 concentrations
as low as 12.5 nM (Lane 7). Likewise, 24 h
after the addition of 400 nM SCH66336, a slower migrating
species of lamin A (Fig. 2A
, middle) was detected
(see Lanes 1 and 2). This species, which was the
sole antigen that reacted with antiserum raised against the lamin A
prepeptide (Fig. 2A
, bottom and B),
was detected after exposure of A549 cells to SCH66336 concentrations as
low as 6 nM (bottom, Lane 8). In
additional studies, this serum was used to develop a
histochemistry-based assay for prelamin A. As indicated in Fig. 3
(right), prelamin A was detected at the periphery of the
nucleus in SCH66336-treated cells (middle) but not in
control cells (top). Binding of the antibody was inhibited
by the immunizing peptide (lower panels). Binding of an
antibody that recognizes mature lamin A polypeptide was unaffected by
these experimental manipulations (Fig. 3
, left). These
observations form the basis for the histochemical assay used to detect
prelamin A in clinical samples.
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). The lack of unprocessed PxF in these specimens might reflect slow cell
turnover with a concomitant low synthesis rate of PxF or altered
prenylation and processing of PxF in these cells (Pxf, like K- and
N-ras, can be alternatively prenylated by geranylgeranyl protein
transferase in FTI-treated
cells).5
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). Examination of the relationship between dose and inhibition of
lamin processing revealed that prelamin A was detected in 60% of
buccal mucosa samples from patients treated with 200 mg of SCH66336, in
67% of patients treated with 300 mg of SCH66336, in 75% of patients
treated with 350 mg of SCH66336, and in 100% of patients treated with
400 mg of SCH66336, indicating the possibility of a dose-dependent
trend. These results provide evidence that FT is inhibited at
clinically achievable doses and also suggest that the degree of FT
inhibition at any particular dose level might vary from patient to
patient. Whereas the sample sizes are too small to be tested
statistically with any degree of accuracy, these results are worthy of
further study in a larger group of patients.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Because of the large number of farnesylated mammalian proteins, FTIs were expected to have serious toxicities. The present Phase I study, however, demonstrates that SCH66336 is well tolerated, with reversible and manageable GI toxicity. Rigorous physical examination and laboratory tests did not identify any other significant toxicities. Several factors might account, in part, for the relative lack of toxicity of SCH66336. First, SCH66336 is highly selective for FT as compared with GGT-1. As a result, several farnesylated proteins might be geranylgeranylated if farnesylation is inhibited, providing an alternative pathway for generating active forms of the proteins. Second, it is possible that survival pathways in normal cells might be less dependent on ras-containing signal transduction pathways than those in ras-transformed cells. Additional studies in preclinical models and clinical specimens are required to determine the basis for the selectivity of FTIs.
Despite the growing literature on FTIs, there is only limited evidence
that FT is inhibited in animals at therapeutic doses. Accordingly, we
set out to determine whether clinically achievable doses of SCH66336
inhibited FT in patients. Mammalian cells contain at least 20 FT
substrates, several of which require prenylation for further processing
(1, 2, 3, 4)
. These include prelamin A, which is farnesylated
before proteolytic removal of the COOH-terminal peptide (Fig. 2B
; Refs. 21
, 23
, and 32 ), and the ras proteins. Recent work
has shown that N-ras and K-ras can undergo geranylgeranylation when
farnesylation is inhibited by SCH66336 (9)
. This
alternative prenylation makes these ras isoforms unsuitable as
biochemical markers for FT inhibition. Although H-ras is not
alternatively prenylated, this isoform is difficult to detect in normal
tissue such as peripheral blood mononuclear cells. Moreover, as
indicated in the "Introduction," there is evidence that
antiproliferative effects of FTIs might result from effects on
farnesylated substrates other than ras.
In this study, we examined processing of prelamin A in buccal mucosa cells as a potential marker of in vivo activity of SCH66336. Removal of the COOH-terminal peptide occurs only if prelamin A is farnesylated (21 , 23 , 32) . We observed a dose-dependent increase in the frequency of unprocessed prelamin A when accessible lamin A-expressing tissue was examined. These data provide the first evidence of successful FT inhibition in humans. Because prelamin A is more resistant than ras to the effects of FT inhibition (33) , the ability of clinically achievable levels of SCH66336 to inhibit prelamin A farnesylation suggests that the modification of several FT substrates has very likely been inhibited in vivo.
A >50% shrinkage of a metastatic NSCLC lesion in the adrenal gland was noted in a patient previously treated with radiation and chemotherapy. This patient received 21 treatment cycles (14 months). Seven additional patients with refractory tumors had stable disease for 5–10 treatment cycles. Thus, the present Phase I study in a pretreated population provides a hint that this class of agents might have anti-neoplastic activity in humans. Phase II studies of this agent are currently in progress.
In summary, the present study establishes that the FTI SCH66336 has a toxicity profile different from that of most conventional anticancer agents and identifies a suitable dose (350 mg orally twice a day) for subsequent clinical trials on this 7-day schedule. In addition, this study provides the first demonstration that protein farnesylation can be safely inhibited in vivo in humans and the first evidence of clinical activity of this class of agents. These findings not only encourage the future clinical development of FTIs but also establish a paradigm for the study of other small molecule inhibitors of signal transduction.
ACKNOWLEDGMENTS
We gratefully thank Dr. Michael Sinensky for an aliquot of
anti-prelamin A and advice on the prelamin A assay, Dr. Robert Patton
for an aliquot of anti-prelamin A raised by the Schering Plough
Research Institute, Kim Jensen for data management, Michelle Daiss for
protocol development, and Gail Prechel and Deb Strauss for secretarial
assistance.
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FOOTNOTES |
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1 Supported in part by NIH Grants CA77112 and
RR00585. 
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, farnesyl protein
transferase; ANC, absolute neutrophil count; CR, complete response;
CTC, Common Toxicity Criteria; FTI, farnesyl transferase inhibitor;
MTD, maximum tolerated dose; PR, partial response; GI,
gastrointestinal; NCI, National Cancer Institute; ECOG, Eastern
Cooperative Oncology Group; b.i.d., twice a day; NSCLC, non-small cell
lung cancer.
4 P. Kirschmeier et al., manuscript in
preparation.
5 P. Kirschmeier and W. Robert Bishop, unpublished
observations.
6 P. A. Svingen and S. H. Kaufmann,
unpublished observations.
Received 10/11/99. Accepted 2/18/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-carboxyl methylation for full enzymatic activity of rhodopsin kinase. J. Biol. Chem., 267: 1422-1425, 1992.
subunit of transducin is farnesylated. Proc. Natl. Acad. Sci. USA, 87: 7673-7677, 1990.This article has been cited by other articles:
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  S. H. Oh, Q. Jin, E. S. Kim, F. R. Khuri, and H.-Y. Lee Insulin-like Growth Factor-I Receptor Signaling Pathway Induces Resistance to the Apoptotic Activities of SCH66336 (Lonafarnib) through Akt/Mammalian Target of Rapamycin-Mediated Increases in Survivin Expression Clin. Cancer Res., March 1, 2008; 14(5): 1581 - 1589. [Abstract] [Full Text] [PDF]
|
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|
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|
|
M. Loprevite, M. Tiseo, M. Chiaramondia, M. Capelletti, C. Bozzetti, B. Bortesi, N. Naldi, R. Nizzoli, P. Dadati, A. Kunkl, et al. Buccal Mucosa Cells as In vivo Model to Evaluate Gefitinib Activity in Patients with Advanced Non Small Cell Lung Cancer Clin. Cancer Res., November 1, 2007; 13(21): 6518 - 6526. [Abstract] [Full Text] [PDF]
|
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 |
|
 T. Raz, V. Nardi, M. Azam, J. Cortes, and G. Q. Daley Farnesyl transferase inhibitor resistance probed by target mutagenesis Blood, September 15, 2007; 110(6): 2102 - 2109. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 M. W. Kieran, R. J. Packer, A. Onar, S. M. Blaney, P. Phillips, I. F. Pollack, J. R. Geyer, S. Gururangan, A. Banerjee, S. Goldman, et al. Phase I and Pharmacokinetic Study of the Oral Farnesyltransferase Inhibitor Lonafarnib Administered Twice Daily to Pediatric Patients With Advanced Central Nervous System Tumors Using a Modified Continuous Reassessment Method: A Pediatric Brain Tumor Consortium Study J. Clin. Oncol., July 20, 2007; 25(21): 3137 - 3143. [Abstract] [Full Text] [PDF]
|
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|
 |
|
 S.-Y. Sun, X. Liu, W. Zou, P. Yue, A. I. Marcus, and F. R. Khuri The Farnesyltransferase Inhibitor Lonafarnib Induces CCAAT/Enhancer-binding Protein Homologous Protein-dependent Expression of Death Receptor 5, Leading to Induction of Apoptosis in Human Cancer Cells J. Biol. Chem., June 29, 2007; 282(26): 18800 - 18809. [Abstract] [Full Text] [PDF]
|
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|
|
J. E. Lancet, I. Gojo, J. Gotlib, E. J. Feldman, J. Greer, J. L. Liesveld, L. M. Bruzek, L. Morris, Y. Park, A. A. Adjei, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia Blood, February 15, 2007; 109(4): 1387 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. X. Ma, P. Steen, K. M. Rowland, R. D. Niedringhaus, T. R. Fitch, J. W. Kugler, D. W. Hillman, E. A. Perez, J. N. Ingle, and A. A. Adjei A phase II trial of a combination of pemetrexed and gemcitabine in patients with metastatic breast cancer: an NCCTG study Ann. Onc., February 1, 2006; 17(2): 226 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Basso, P. Kirschmeier, and W. R. Bishop Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors J. Lipid Res., January 1, 2006; 47(1): 15 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Murthy, H. Tong, and R. J. Hohl Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate J. Biol. Chem., December 23, 2005; 280(51): 41793 - 41804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. David, S.-Y. Sun, E. K. Waller, J. Chen, F. R. Khuri, and S. Lonial The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT Blood, December 15, 2005; 106(13): 4322 - 4329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M.G.M. Appels, J. H. Beijnen, and J. H.M. Schellens Development of Farnesyl Transferase Inhibitors: A Review Oncologist, September 1, 2005; 10(8): 565 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Bruzek, J. N. Poynter, S. H. Kaufmann, and A. A. Adjei Characterization of a Human Carcinoma Cell Line Selected for Resistance to the Farnesyl Transferase Inhibitor 4-(2-(4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide (SCH66336) Mol. Pharmacol., August 1, 2005; 68(2): 477 - 486. [Abstract] [Full Text] [PDF]
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D. Ferguson, L. E. Rodriguez, J. P. Palma, M. Refici, K. Jarvis, J. O'Connor, G. M. Sullivan, D. Frost, K. Marsh, J. Bauch, et al. Antitumor Activity of Orally Bioavailable Farnesyltransferase Inhibitor, ABT-100, Is Mediated by Antiproliferative, Proapoptotic, and Antiangiogenic Effects in Xenograft Models Clin. Cancer Res., April 15, 2005; 11(8): 3045 - 3054. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tabernero, F. Rojo, I. Marimon, M. Voi, J. Albanell, M. Guix, F. Vazquez, J. Carulla, M. Cooper, J. Andreu, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of Weekly 1-Hour and 24-Hour Infusion BMS-214662, a Farnesyltransferase Inhibitor, in Patients With Advanced Solid Tumors J. Clin. Oncol., April 10, 2005; 23(11): 2521 - 2533. [Abstract] [Full Text] [PDF]
|
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|
|
|
S. L. Moulder, J. J. Mahany, R. Lush, C. Rocha-Lima, M. Langevin, K. J. Ferrante, L. M. Bartkowski, S. M. Kajiji, D. A. Noe, S. Paillet, et al. A Phase I Open Label Study of the Farnesyltransferase Inhibitor CP-609,754 in Patients with Advanced Malignant Tumors Clin. Cancer Res., November 1, 2004; 10(21): 7127 - 7135. [Abstract] [Full Text] [PDF]
|
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 |
|
 H.-J. Na, S.-J. Lee, Y.-C. Kang, Y.-L. Cho, W.-D. Nam, P. K. M. Kim, K.-S. Ha, H.-T. Chung, H. Lee, Y.-G. Kwon, et al. Inhibition of Farnesyltransferase Prevents Collagen-Induced Arthritis by Down-Regulation of Inflammatory Gene Expression through Suppression of p21ras-Dependent NF-{kappa}B Activation J. Immunol., July 15, 2004; 173(2): 1276 - 1283. [Abstract] [Full Text] [PDF]
|
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|
 |
|
 W. R. Parulekar and E. A. Eisenhauer Phase I Trial Design for Solid Tumor Studies of Targeted, Non-Cytotoxic Agents: Theory and Practice J Natl Cancer Inst, July 7, 2004; 96(13): 990 - 997. [Abstract] [Full Text] [PDF]
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 H. Mo and C. E. Elson Studies of the Isoprenoid-Mediated Inhibition of Mevalonate Synthesis Applied to Cancer Chemotherapy and Chemoprevention Experimental Biology and Medicine, July 1, 2004; 229(7): 567 - 585. [Abstract] [Full Text] [PDF]
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Y. Takada, F. R. Khuri, and B. B. Aggarwal Protein Farnesyltransferase Inhibitor (SCH 66336) Abolishes NF-{kappa}B Activation Induced by Various Carcinogens and Inflammatory Stimuli Leading to Suppression of NF-{kappa}B-regulated Gene Expression and Up-regulation of Apoptosis J. Biol. Chem., June 18, 2004; 279(25): 26287 - 26299. [Abstract] [Full Text] [PDF]
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F. R. Khuri, B. S. Glisson, E. S. Kim, P. Statkevich, P. F. Thall, M. L. Meyers, R. S. Herbst, R. F. Munden, C. Tendler, Y. Zhu, et al. Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Solid Tumors Clin. Cancer Res., May 1, 2004; 10(9): 2968 - 2976. [Abstract] [Full Text] [PDF]
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 V. Chhokar and A. L. Tucker Angiogenesis: Basic Mechanisms and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 253 - 280. [Abstract] [PDF]
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