Current
Cancer Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 8, Number 3, May 2008
Contents
The Gene Expression Profiles of Medulloblastoma Cell
Lines Resistant to Preactivated Cyclophosphamide
Pp. 172-179
M.D. Bacolod, S.M. Lin, S.P. Johnson, N.S. Bullock, M.
Colvin, D.D. Bigner and H.S. Friedman
[Abstract]
Genetically Modified Cellular Vaccines for Therapy of Human
Papilloma Virus Type 16 (HPV 16)-Associated Tumours
Pp. 180-186
J. Bubenik
[Abstract]
The PTEN/PI3K/AKT Signalling Pathway in Cancer, Therapeutic
Implications Pp. 187-198
Amancio Carnero, Carmen Blanco-Aparicio, Oliver Renner,
Wolfgang Link and Juan F.M. Leal
[Abstract]
Circulating Levels of VCAM and MMP-2 May Help
Identify Patients with More Aggressive Prostate Cancer
Pp. 199-206
Concetta De Cicco, Laura Ravasi, Laura Zorzino, Maria
Teresa Sandri, Edoardo Botteri, Fabrizio Verweij, Donatella
Granchi, Ottavio de Cobelli and Giovanni Paganelli
[Abstract]
Deregulation of the Mitochondrial Apoptotic Machinery
and Development of Molecular Targeted Drugs in Acute Myeloid
Leukemia Pp. 207-222
G. Del Poeta, A. Bruno, M.I. Del Principe, A. Venditti,
L. Maurillo, F. Buccisano, R. Stasi, B. Neri, F. Luciano,
A. Siniscalchi, P. de Fabritiis and S. Amadori
[Abstract]
Phosphorylation-Specific Prolyl Isomerase Pin1
as a new Diagnostic and Therapeutic Target for Cancer
Pp. 223-229
Greg Finn and Kun Ping Lu
[Abstract]
Ramammary Application of Non-Methylated-CpG Oligodeoxynucleotides
(CpG) Inhibits both Local and Systemic Mammary Carcinogenesis
in Female BALB/c Her-2/neu Transgenic Mice Pp. 230-242
Cristina Mastini, Pablo D. Becker, Manuela Iezzi, Claudia
Curcio, Piero Musiani, Guido Forni, Federica Cavallo and Carlos
A. Guzmán
[Abstract]
Abstracts
[Back to top]
The Gene Expression Profiles of Medulloblastoma Cell
Lines Resistant to Preactivated Cyclophosphamide
M.D. Bacolod, S.M. Lin, S.P. Johnson, N.S. Bullock, M.
Colvin, D.D. Bigner and H.S. Friedman
The total expression profiles of two medulloblastoma
cell lines resistant to the preactivated form of cyclophosphamide
(4-hydroperoxycyclophosphamide, 4-HC) were examined using
the Affymetrix GeneChip U133A array. Our primary objective
was to look for possible genes, other than the well-studied
aldehyde dehydrogenases (ALDH) that may be involved in cyclophosphamide
(CP) resistance in medulloblastomas. We present here the lists
of the most highly upregulated [30 for D341 MED (4-HCR); 20
for D283 MED (4-HCR)] and downregulated [19 for D341 MED (4-HCR);
15 for D283 MED (4-HCR)] genes which may be involved in conferring
CP-resistance to the two medullobalstoma cell lines. The lists
of genes from the two sublines almost had no overlap, suggesting
different mechanisms of CP-resistance. One of the most noteworthy
upregulated gene is TAP1 [ 90-fold increase in D341 MED (4-HCR)
relative to D341 MED ]. TAP1, a protein belonging to the ABC
transporter family is normally involved in major histocompatibility
class I (MHC I) antigen processing. This suggests the possible
role of multidrug resistance (MDR), albeit atypical (which
means it does not involve the usual MDR1 and MRP glycoproteins),
in medulloblastoma’s CP-resistance. Apart from TAP1,
a number of other genes involved in MHC1 processing were upregulated
in D341 MED (4HCR). D341 MED (4-HCR) also had a 20-fold increase
in the expression of the aldo-keto reductase gene, AKR1B10,
which may deactivate the reactive cyclophosphamide metabolite,
aldophosphamide. For D283 MED (4-HCR), the most notable increase
in expression is that of ALDH1B1, a member of the aldehyde
dehydrogenase (ALDH) family of proteins.
[Back to top]
Genetically Modified Cellular Vaccines for Therapy
of Human Papilloma Virus Type 16 (HPV 16)-Associated Tumours
J. Bubenik
Therapeutic strategies based on the insertion of cytokine
or other immunostimulatory genes into the genome of tumour
cells followed by vaccination with the resulting, genetically
modified, cytokine-producing vaccines represent a new potential
prospect for the treatment of cancer patients. HPV 16 is the
aetiological agent of more than 60 percent human cervical
carcinomas (CC). At present, two prophylactic vaccines against
HPV 16 are available (GlaxoSmithKline "Cervarix"
and Merck "Gardasil"). These vaccines can almost
completely protect the immunized individuals against both,
persistent HPV 16 infection and HPV 16-related pathological
findings in cervical cytology. In contrast, no clinically
utilizable therapeutic vaccines against CC are available.
During the last decade animal models have substantially contributed
to the development of the therapeutic vaccines against HPV
16-associated tumours. It has been demonstrated that the HPV
16 E6/E7 oncoproteins can serve as tumour rejection antigens
(TRA) and that the HPV 16-associated tumour cells can be genetically
modified with DNA encoding immunostimulatory cytokines (IL-2,
IL-12, GM-CSF) or other immunostimulatory molecules, used
for vaccination, and inhibit tumour growth. To improve the
HPV 16 antigen presentation in tumour-bearing individuals,
dendritic cell-based vaccines loaded with HPV 16 E6/E7 DNA
or hybrids of the dendritic and tumour cells have also been
successfully employed. Unfortunately, when these encouraging
approaches used in animal models were translated into clinical
trials, the results were less optimistic. The problems that
are still to be faced before the therapeutic vaccines against
high-risk HPV-associated tumours can be approved for clinical
purposes are discussed.
[Back to top]
The PTEN/PI3K/AKT Signalling Pathway in Cancer,
Therapeutic Implications
Amancio Carnero, Carmen Blanco-Aparicio, Oliver Renner,
Wolfgang Link and Juan F.M. Leal
PTEN/PI3K/AKT constitutes an important pathway regulating
the signaling of multiple biological processes such as apoptosis,
metabolism, cell proliferation and cell growth. PTEN is a
dual protein/lipid phosphatase which main substrate is the
phosphatidyl-inositol,3,4,5 triphosphate (PIP3), the product
of PI3K. Increase in PIP3 recruits AKT to the membrane where
it is activated by other kinases also dependent on PIP3. Many
components of this pathway have been described as causal forces
in cancer. PTEN activity is lost by mutations, deletions or
promoter methylation silencing at high frequency in many primary
and metastatic human cancers. Germ line mutations of PTEN
are found in several familial cancer predisposition syndromes.
Activating mutations which have been reported for PI3K and
AKT, in tumours are able to confer tumourigenic properties
in several cellular systems. Additionally, the binding of
PI3K to oncogenic ras is essential for the transforming
properties of ras. In summary, the data strongly
support the view of the PTEN/PI3K/AKT pathway as an important
target for drug discovery.
[Back to top]
Circulating Levels of VCAM and MMP-2 May Help
Identify Patients with More Aggressive Prostate Cancer
Concetta De Cicco, Laura Ravasi, Laura Zorzino, Maria
Teresa Sandri, Edoardo Botteri, Fabrizio Verweij, Donatella
Granchi, Ottavio de Cobelli and Giovanni Paganelli
Background: Prostate adenocarcinoma is generally characterized
by slow progression although some phenotypes have a more aggressive
behavior with tendency to local invasion and distant metastases,
mainly to bones. Better specific care could be provided to
the aggressive phenotype-group of patients if pre-surgical
identification were available.
Material and Methods: Correlations between pre-surgical
levels of 6 blood molecules and pathological tumour staging,
post-surgical Gleason score and disease-free survival have
been observed.
Plasma and sera from 162 men affected by prostate adenocarcinoma
were analysed with ELISA to assess levels of neovascularization-related
molecule (VEGF), endothelial cell adhesion molecule (VCAM),
extracellular matrix destruction-related molecules (MMP-2,
MMP-9), and tissue inhibitors of metalloproteinase (TIMP-1
and TIMP-2).
Results: The median values of serum determinations
were for VEGF 279 pg/ml, VCAM 633 ng/ml, MMP-2 206 ng/ml and
MMP-9 614 ng/ml. Plasma medians (ng/ml) were 94 for TIMP-1
and 90 for TIMP-2. Patients with VCAM values > 633 ng/ml
had a worse disease-free survival than patients with values
<633 ng/ml with an adjusted Hazard Ratio of 2.1, significant
(95% confidence interval 0.8-5.6). Patients with levels of
MMP-2 < 206 ng/ml showed an increased risk of progression
(adjusted HR 1.7; 95% C.I. 0.6-4.8).
Conclusions: Levels of VCAM and MMP-2 should be checked
in patients with prostate adenocarcinoma, because distant
spread is more likely to occur in patients with high levels
of VCAM and low levels of MMP-2. The scientific community
should further investigate impact on prognosis of VCAM and
MMP-2.
[Back to top]
Deregulation of the Mitochondrial Apoptotic Machinery
and Development of Molecular Targeted Drugs in Acute Myeloid
Leukemia
G. Del Poeta, A. Bruno, M.I. Del Principe, A.
Venditti, L. Maurillo, F. Buccisano, R. Stasi, B. Neri, F.
Luciano, A. Siniscalchi, P. de Fabritiis and S. Amadori
Apoptosis plays a key role in the control of rapidly
renewing tissues, such as the hematopoietic system and leukemia
cells invariably have abnormalities in one or more apoptotic
pathways, determining a survival advantage of these cells
and the development of drug resistance. These defects are
also frequently associated with a low rate of response to
standard chemotherapy and with a poor survival in acute myeloid
leukemia (AML). The major form of apoptosis proceeds through
the mitochondrial pathway, with the mitochondrial outer membrane
permeabilization, leading to the release of proteins normally
found in the space between the inner and outer mitochondrial
membranes (cytochrome C, AIF and others). Higher levels of
anti-apoptosis proteins bcl-2, bcl-xL,
Mcl-1 block permeabilization of the membrane and are reported
in AML patients presenting a poor outcome. On the contrary,
activated pro-apoptotic bax or bad proteins allow this permeabilization
and are correlated to a good prognosis in AML. Defects in
the mitochondrial pathway induce multidrug-resistance and
confer important prognostic information in AML. High ratios
of bcl-2 to bax protein confer a poor prognosis with decreased
rates of complete remission and overall survival. The prognostic
information from the ratio of the proteins is greater than
bcl-2 levels alone. Recently, we confirmed the impressive
impact of the bax/bcl-2 ratio, determined by flow cytometry,
on AML prognosis (complete remission and overall survival)
in 255 AML patients. Bcl-2 down regulation might lower the
apoptotic threshold of leukemic cells and, through this mechanism,
favor response to chemotherapy. Phase II studies of oblimersen
(antisense Bcl-2), cytarabine and daunorubicin or oblimersen
plus gentuzumab, a cytotoxic antibody directed against CD33+
cells in relapsed AMLs, showed promising results. Defects
in apoptosome proteins, such as APAF-1, are frequent in AML
and treatment with 5-aza-2’-deoxycytidine, a specific
inhibitor of DNA methylation, restored APAF-1 expression in
leukemic cells. In conclusion, targeted therapies that are
designed to induce apoptosis in leukemic cells, are the most
promising anti-leukemia strategies. The elucidation of the
apoptotic machinery and of its defects in AML lays the basis
for developing new drugs able to trigger apoptosis and overcome
therapy resistance.
[Back to top]
Phosphorylation-Specific Prolyl Isomerase Pin1 as
a new Diagnostic and Therapeutic Target for Cancer
Greg Finn and Kun Ping Lu
Proline directed phosphorylation is a key regulatory
mechanism controlling the function of fundamental proteins
involved in cell proliferation and oncogenic transformation.
Recently, the identification of the phosphorylation dependent
prolyl isomerase Pin1 has uncovered a distinct regulatory
mechanism controlling protein function. Specifically, Pin1
controls the conversion of peptidyl proline bond conversion
from cis to trans, only when the preceding serine or threonine
is phosphorylated. The intrinsic inter-conversion of such
bonds is rather slow and is further inhibited by phosphorylation.
As a consequence catalysis by Pin1 is required to overcome
this restriction. Importantly, structural evidence has now
demonstrated that Pin1-catalyzed prolyl isomerization can
have significant effects on the global structure of substrate
proteins. Furthermore, Pin1 overexpression is found in several
types of cancer where it functions to not only promote tumorigenesis
induced by oncogenes such as Ras and Neu, but also to regulate
molecules that facilitate persistent proliferative capacity.
Consequently, Pin1-mediated phosphorylation-dependent isomerization
represents a unique regulatory mechanism in cell signaling
whose deregulation during tumorigenesis adds to the pro-proliferative
capacity of tumor cells and therefore Pin1 represents a novel
tumor marker and potential therapeutic target.
[Back to top]
Ramammary Application of Non-Methylated-CpG Oligodeoxynucleotides
(CpG) Inhibits both Local and Systemic Mammary Carcinogenesis
in Female BALB/c Her-2/neu Transgenic Mice
Cristina Mastini, Pablo D. Becker, Manuela Iezzi,
Claudia Curcio, Piero Musiani, Guido Forni, Federica Cavallo
and Carlos A. Guzmán
CpG are powerful drugs activating the innate immune system.
In this study, the ability of their intramammary administration
in impeding the devastating progression of carcinogenesis
in all the mammary glands of female BALB/c mice transgenic
for the rat neu transforming oncogene was assessed.
Starting when in situ carcinomas were scattered over
all their mammary glands (week 10), mice received CpG injections
in the stroma of the fourth left gland. Local neoplastic progression
was inhibited by six monthly administrations. CpG not only
delayed the onset of carcinomas in the injected gland, but
also hampered their progression. Extended latency was observed
for tumors in glands both close to and far from the injection
site. When the experiment ended (week 45), no tumors were
palpable in 67% of the injected glands and a markedly impaired
tumor growth was evident in the others. An impressive local
infiltrate of CD11b+ cells
with the morphologic features of macrophages, plasma cells,
B220+ B cells, and CD4+
and CD8+ T cells was quickly
recruited to the CpG-treated glands. High quantities of IFN-γ
producing cells were only present in the ipsilateral axillary
draining lymph nodes of the treated glands. Enhanced natural
killer (NK) lytic activity was also detected in the spleens.
Inhibition of progression was weaker when only four injections
were given, and abolished by in vivo depletion of
NK cells. CpG monotherapy is thus effective in an aggressive
model of autochthonous cancer. The results strongly support
the administration of CpG as a local monotherapy of multiple
invasive microscopic lesions.
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