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Current Cancer
Therapy Reviews
ISSN: 1573-3947
Current Cancer Therapy Reviews
Volume 3, Number 3, August 2007
Contents
Control of Protein Synthesis in Malignant Transformation
- the Role of eIF4E and the eIF4E Binding Proteins in the
Regulation of Apoptosis Pp. 151-163
Michael J. Clemens, Androulla Elia and Constantina Constantinou
[Abstract]
Fluoroquinolones Prophylaxis of Bacterial Infections
in Neutropenic Patients: Time to Re-Evaluate Pp.
164-173
Mario Cruciani
[Abstract]
Anticancer Drug-Induced Immunomodulation and Cancer
Therapeutics Pp. 174-193
Enrico Mihich
[Abstract]
Genetic Engineering – A New Era for Cancer Immunotherapy?
Pp. 194-198
Angelica Loskog and Thomas H. Tötterman
[Abstract]
Macroautophagy as a Target of Cancer Therapy Pp.
199-208
Séverine Lorin, Patrice Codogno and Mojgan Djavaheri-Mergny
[Abstract]
Sentinel Lymph Node Identification in Patients with
Stage IB1 Invasive Cervical Carcinoma Pp. 209-214
Ricardo dos Reis, Eduardo Belmonte Tavares, Beatriz Amaral,
Heleusa Ione Monego, Márcia Binda, Valentino Magno,
Waldemar Rivoire, Maria Isabel Edelweiss and Edison Capp
[Abstract]
Update on the Rheumatologic Manifestations of Malignancy
Pp. 215-222
Lianne Marks, Clifton D. Fuller, Parag Sanghvi, Melva
Pinn and Charles R. Thomas, Jr.
[Abstract]
Abstracts
[Back to top]
Control of Protein Synthesis in Malignant Transformation
- the Role of eIF4E and the eIF4E Binding Proteins in the
Regulation of Apoptosis
Michael J. Clemens, Androulla Elia and Constantina Constantinou
Tumour cells are frequently characterized by over-expression
of the polypeptide chain initiation factor eIF4E and current
evidence supports the view that this factor contributes to
malignant transformation. The availability of eIF4E for protein
synthesis is regulated by the 4E binding proteins. The ability
of these proteins to bind eIF4E is inhibited by multi-site
phosphorylation, catalysed by the mammalian target of rapamycin
(mTOR) and other protein kinases. This phosphorylation is
stimulated by growth factors and nutrients whereas dephosphorylation
is activated by a variety of cellular stresses. Over-expression
of eIF4E promotes resistance to apoptosis, most likely as
a result of enhanced synthesis of growth-promoting and anti-apoptotic
proteins. Conversely, increased levels of the 4E binding proteins
can promote apoptosis and suppress tumourigenicity. Consistent
with this, the mTOR inhibitor rapamycin can enhance cell death,
especially in cells in which signal transduction pathways
that activate mTOR are hyperactive, and analogues of rapamycin
are now in clinical use against a number of human cancers.
Recent evidence suggests that phosphorylation may also reduce
the stability of the 4E binding proteins, as a consequence
of increased susceptibility to ubiquitination and subsequent
degradation. Such accelerated degradation would result in
greater availability of eIF4E for translation and the inhibition
of apoptosis.
[Back to top]
Fluoroquinolones Prophylaxis of Bacterial Infections
in Neutropenic Patients: Time to Re-Evaluate
Mario Cruciani
Fluoroquinolones have been studied extensively as prophylaxis
in neutropenic cancer patients. There is a large body of evidence
suggesting that fluoroquinolones are a valuable choice for
preventing bacterial infections in neutropenic cancer patient.
As yet, there is no question that prophylaxis with fluoroquinolones
has led to a decrease in the occurrence of gram-negative infections
in neutropenic patients. By contrast, the benefits of fluoroquinolone
prophylaxis on other parameters of infection-related morbidity
and on the occurrence of infection-related mortality are not
clear. Moreover, the use of fluoroquinolones is not without
risk. Reports of fluoroquinolone-resistant Escherichia
coli causing bacteremia among cancer patients are matter
of concern. Recent well conducted, large clinical trials confirm
the long lasting interest in the use of fluoroquinolones prophylaxis.
Moreover, a reduction in mortality has been demonstrated in
recent meta-analyses, though the generalizability of this
finding is uncertain. Reports from cancer centers in Europe
have shown a re-bound of gram-negative bacteremias after discontinuation
in the use of prophylaxis with fluoroquinolones. In light
of the these findings, prophylaxis with a quinolone during
granulocytopenia, where resistance permits, is still appropriate.
[Back to top]
Anticancer Drug-Induced Immunomodulation and Cancer
Therapeutics
Enrico Mihich
In the light of increasing knowledge on the regulation of
the efferent and afferent branches of antitumor immunity,
on tumor-induced imbalances of immune response and on tumor
escape mechanisms, it seem important to review the information
available on the immunomodulating effects of anticancer drugs
and their possible exploitation in cancer therapeutics.
The immunomodulation induced by several antitumor antibiotics
is considered with particular emphasis on the effects of Doxorubicin
and their therapeutic exploitation. The immunomodulating effects
of anticancer drugs considered include those of cyclophosphamide
and other alkylating agents, of 6—mercaptopurine and
other antimetabolities, of Vinca alkaloida, Taxanes, Thalidomide,
Gleevec and Difluoromethyl ornithine. The positive effects
on tumor immunity are discussed with reference to their potential
exploitation in the therapeutics. The effects of certain anticancer
drugs on tumor antigen expression are also discussed as a
mechanism by which these agents increase tumor immunogenicity
with consequent advantages for therapeutic exploitation and
vaccine effectiveness. The need for increased molecular and
clinical studies of anticancer drugs–induced immunomodulation
is emphasized.
[Back to top]
Genetic Engineering – A New Era for Cancer Immunotherapy?
Angelica Loskog and Thomas H. Tötterman
Cancer patients often exhibit immunosuppression that is caused
by the expanding tumor mass. This fact has severely compromised
many efforts to develop effective cancer vaccines in the past.
However, a new generation of immunotherapies takes focus on
both activating the effector cells of the immune system as
well as reverting the immunosuppression. This two-step process
has lead to impressive anti-tumor effects both in experimental
settings as well as in initial clinical trials. With new and
powerful techniques for genetic engineering, the transfer
of immunostimulating genes has gained interest. Genetic engineering
of the tumor micromilieu has, for example, shown to be an
effective means for breaking tumor-induced immunosuppression
in an experimental model of bladder cancer. Genetic engineering
can also be used to modify the immune effector cells to efficiently
target tumor cells and to simultaneously resist immune inhibition.
This review will discuss the immunological status of cancer
patients with focus on T regulatory cells and their inhibitory
cytokines as well as offer a survey of novel immune strategies
for cancer gene therapy.
[Back to top]
Macroautophagy as a Target of Cancer Therapy
Séverine Lorin, Patrice Codogno and Mojgan Djavaheri-Mergny
Macroautophagy (hereafter referred as to autophagy) is a vacuolar
lysosomal degradative pathway for cytoplasmic macromolecules
and organelles. There is growing evidence that autophagy is
controlled by tumor-regulating molecules, and that it is downregulated
during the early stages of tumorigenesis. Nevertheless, the
relationship between autophagy and tumor progression seems
to be complex, since in response to various stress situations,
cancer cells are able to trigger autophagy either as a survival
mechanism or conversely as a mechanism leading to cell death.
Therefore, depending on the context, autophagy may trigger
opposite outcomes in cancer cell fate. These two aspects of
autophagy should be further taken into account in view of
its possible modulation for cancer treatment.
[Back to top]
Sentinel Lymph Node Identification in Patients with
Stage IB1 Invasive Cervical Carcinoma
Ricardo dos Reis, Eduardo Belmonte Tavares, Beatriz Amaral,
Heleusa Ione Monego, Márcia Binda, Valentino Magno,
Waldemar Rivoire, Maria Isabel Edelweiss and Edison Capp
Background and Objectives: To establish the
feasibility of sentinel lymph node (SLN) identification in
patients with stage IB1 invasive cervical cancer. Methods:
Selected patients with cervical cancer scheduled for radical
hysterectomy with bilateral pelvic lymphadenectomy underwent
SLN detection. Preoperatively, 1 mCi of technetium-99 (99Tc)
was injected into four points of the superficial cervical
stroma around the tumor. Intraoperatively, the patients underwent
gamma-probe-guided lymphatic mapping, and patent blue dye
was injected into the same points as the 99Tc.
Results: Of the 12 eligible patients, 11
(92%) had at least one SLN detected. Seven (64%) patients
had SLNs detected by intraoperative lymphoscintigraphy and
the blue-dye technique, 3 (27%) by intraoperative lymphoscintigraphy,
and 1 (9%) by the blue-dye technique only. Intraoperatively,
22 SLNs were detected: 9 (41%) by lymphoscintigraphy, 7 (32%)
by lymphoscintigraphy and the blue-dye technique, and 6 (27%)
by the blue-dye technique only. Six patients (54.5%) had bilateral
SLNs. Sensitivity, specificity, positive predictive value,
and negative predictive value for SLN detection were 100%,
80%, 33%, and 100%, respectively. There were no false-negative
results. Conclusions: In this small cohort
of patients, the combination of 99Tc
and patent blue dye was safe and feasible for the detection
of SLNs in early-stage cervical cancer.
This study investigates the sentinel lymph node technique
in patients with stage IB1 cervical cancer.
[Back to top]
Update on the Rheumatologic Manifestations of Malignancy
Lianne Marks, Clifton D. Fuller, Parag Sanghvi, Melva
Pinn and Charles R. Thomas, Jr.
Malignancy can be accompanied by rheumatologic clinical
findings, and these can occur prior to, concurrently with,
or after a diagnosis of cancer. Certain clinical information
helps to differentiate paraneoplastic symptoms from those
more characteristic of classic rheumatologic disorders such
as rheumatoid arthritis or systemic lupus erythematosus. Clinicians
need to have a higher level of suspicion for malignancy in
a patient with rheumatologic manifestations in certain populations.
This may be the case in patients with a personal or family
history of malignancy, atypical presentations of rheumatologic
disorders, and certain clinical situations (such as hypertrophic
osteoarthropathy, carcinoma polyarthritis, dermatomyositis,
and unilateral sacroiliitis). The current standard of care
for patients with a rheumatologic disorder with a known paraneoplastic
association (i.e., dermatomyositis) is age-appropriate cancer
screening. This review is designed to guide the physician
to musculoskeletal signs and symptoms that may be paraneoplastic
in origin. Additionally, when the clinician understands current
information regarding malignant associations, it will help
them decide when it may be appropriate to pursue further investigative
work-up or evaluate for recurrence of a known primary tumor.
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