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Current Cancer
Therapy Reviews
ISSN: 1573-3947
Current Cancer Therapy Reviews
Volume 2, Number 3, August 2006
Contents
Biological Basis of Novel Therapies for Myelodysplastic
Syndrome Pp. 199-209
Eyal C. Attar and Karen K. Ballen
[Abstract]
Current Treatment of Relapsed Ovarian Carcinoma
Pp. 211-221
Aristotle Bamias, Alexandros Rodolakis and Meletios A.
Dimopoulos
[Abstract]
Lenalidomide: Cancer Therapy via Antiangiogenesis
and Immunomodulation Pp. 223-229
Tanyifor M. Tohnya, Jürgen Venitz, Alex Sparreboom
and William D. Figg
[Abstract]
A Role for Tumor Suppressor Protein p53 in the
Fidelity of DNA Synthesis and Resistance Towards Nucleoside
Analogs Pp. 231-241
Mary Bakhanashvili and Galia Rahav
[Abstract]
Molecular Profiles of Sentinel and Non-Sentinel
Lymph Nodes in Breast Cancer Progression and Prognosis
Pp. 243-253
Gajanan V. Sherbet
[Abstract]
Testicular Germ Cell Tumors: A Paradigm for the
Successful Treatment of Solid Tumor Stem Cells Pp.
255-270
Caryl J. Giuliano, Sarah J. Freemantle and Michael J.
Spinella
[Abstract]
Cancer Therapy-Induced Residual Bone Marrow Injury:
Mechanisms of Induction and Implication for Therapy
Pp. 271-279
Yong Wang, Virginia Probin and Daohong Zhou
[Abstract]
Abstracts
[Back to top]
Biological Basis of Novel Therapies for Myelodysplastic
Syndrome
Eyal C. Attar and Karen K. Ballen
Myelodysplastic syndrome (MDS) represents a group of malignant
clonal disorders characterized by ineffective hematopoiesis
and an accumulation of hematopoietic precursors in the bone
marrow, frequently resulting in transformation to acute leukemia
and death. However, recent understanding of MDS pathophysiology
has provided novel treatment approaches with pharmacologic
agents capable of manipulating pathways intrinsic and extrinsic
to the malignant hematopoietic clone. These advances provide
new therapeutic options for patients and provide a basis for
further understanding and treatment of this disease.
[Back to top]
Current Treatment of Relapsed Ovarian Carcinoma
Aristotle Bamias, Alexandros Rodolakis and Meletios A.
Dimopoulos
Ovarian cancer is a leading cause of death from gynecological
cancer. Although most patients will experience remission of
their disease, following cytoreductive surgery and platinum
(±
paclitaxel) chemotherapy, relapse will occur in about 80%
of cases with FIGO stages III and IV disease. Treatment of
recurrent ovarian cancer represents a challenge. Cure is rare
but long-term survival can be achieved in a significant proportion
of patients.
Treatment-free interval after first-line platinum-based chemotherapy
determines sensitivity to platinum rechallenge. Nevertheless,
other factors, such as symptoms, tumor bulk, ECOG PS and patients’
preferences can also aid decision making in this setting.
The recent ICON4/AGO and GCIC studies showed that combination
of carboplatin with paclitaxel or gemcitabine are superior
to carboplatin monotherapy in patients with platinum-sensitive
disease, but at the expense of additional toxicity. Platinum
refractory disease is associated with poor prognosis and monotherapy
with a non-platinum agent, such as liposomal doxorubicin,
topotecan or a taxane is recommended.
Biological agents targeting various components on cancer cells,
such as vascular endothelial growth factor (VEGF), growth
factors and stromal elements, are under investigation as adjuncts
to chemotherapy. In addition, selected patients may benefit
from surgery at recurrence, but they represent the minority
of patients with relapsed ovarian cancer.
[Back to top]
Lenalidomide: Cancer Therapy via Antiangiogenesis
and Immunomodulation
Tanyifor M. Tohnya, Jürgen Venitz, Alex Sparreboom
and William D. Figg
Our rapidly expanding understanding of the molecular pathogenesis
of a variety of cancers is providing new molecular targets
for drug development; specifically, immunomodulatory and antiangiogenic
agents are poised to become essential in novel cancer therapeutics.
Rationale for the development of such therapies rest in the
observation that these immune and angiogenic targets (e.g.
TNF-α,
VEGF, IL-6, IL-2 and IFN-γ)
are at the core of cancer growth and progression, and are
aberrant and deregulated in many human malignancies. Successful
immunomodulation and inhibition of aberrant angiogenesis pathways
are essential for malignant tumor cells. Herein we present
an overview of immune modulation and angiogenesis in cancer.
We will also review preclinical and clinical development,
pharmacology and clinical trials of lenalidomide (Revlimid®,
formerly CC-5013; Celgene Corporation), and agent that alters
both pathways.
[Back to top]
A Role for Tumor Suppressor Protein p53 in the
Fidelity of DNA Synthesis and Resistance Towards Nucleoside
Analogs
Mary Bakhanashvili and Galia Rahav
The tumor suppressor protein p53 plays an important role in
maintaining genomic integrity. p53 possesses an intrinsic
3' →
5'
exonuclease activity. The presence of exonuclease activity
has been implicated in the prevention of mutator phenotype
and in acquired resistance to chemotherapeutic agents. p53
may act as proofreading exonuclease for DNA polymerases during
DNA replication. The recombinant wild-type p53 can proofread
for various exonuclease-deficient cellular and viral DNA polymerases.
The preferential excision of mismatched nucleotides from DNA
by 3'-->5' exonuclease activity enhances the fidelity of
DNA synthesis, thus providing a biochemical mechanism to reduce
mutations caused by incorporation of mismatched nucleotides.
P53 exonuclease activity for different mismatches is dependent
upon the nature of the mispair. The observed specificity of
mismatch excision indicates that p53 exonucleolytic proofreading
preferentially repairs transversion mutations. Interestingly,
p53 exonuclease activity preferentially removes the same base
that is less efficiently incorporated and extended by the
DNA polymerase. Hence, the proofreading activity of p53 may
limit the transversion mutations, indicating that the mutation
spectra might be affected by the actions of DNA polymerase
and p53-exonuclease. p53 was found in the nucleus and in the
cytoplasm of the cell. In cytoplasmic extracts, non-induced
p53, displays high level of 3'
→
5'
exonuclease activity in comparison to nuclear extracts. P53
may recognize and remove incorporated nucleoside analogs from
DNA in vitro, in whole cells and in cytoplasm. These
findings raise the possibility that resistance to anti-cancer
and anti-viral nucleoside analogs, in part, may involve the
excision of incorporated drug during DNA synthesis.
[Back to top]
Molecular Profiles of Sentinel and Non-Sentinel
Lymph Nodes in Breast Cancer Progression and Prognosis
Gajanan V. Sherbet
Sentinel lymph nodes (SLN) receive lymphatic drainage from
the primary tumour and have been regarded as sensitive and
reliable indicators of disease progression. It has been postulated
that absence of metastatic tumour in SLN might obviate the
exigency of axillary clearance and avoid the associated morbidity.
But debate continues about the need for complete axillary
dissection in SLN positive breast cancer patients, and whether
SLN positivity might reflect the involvement of non-SLN. In
essence, SLN positivity might be an invaluable aid in patient
management. Albeit fraught with much debate, it would be worthwhile
examining importance of the presence of micrometastases in
patient management and disease outcome. Some of these considerations
have led to the identification of molecular markers and measurement
of their expression in SLN and non-SLN using sensitive, specific
and precise molecular biological techniques. Several molecular
markers of cancer progression have been employed in this way.
These are related to the state of differentiation, and cell
proliferation and apoptosis of tumours. Tumour suppressor
genes and oncogenes have also been seen as ideal markers of
SLN involvement. Significant advances have also been made
in the elucidation of pathways of signalling that angiogenic
and lymphangiogenic factors use and these have also contributed
to the identification of potential markers of lymphangiogenesis.
The availability of such a wide spectrum of markers requires
not only that their expression is assessed objectively but
also that potential difficulties of interpreting the complex
interactions and inter-relationships between these markers
and their bearing on disease progression and prognosis are
addressed and assessed, which robustly advocates the use of
artificial intelligence systems for this purpose. Construction
of molecular profiles of primary tumours and disseminated
tumour in SLN and body fluids would be invaluable for assessing
cancer progression, for the prediction of prognosis and in
designing therapeutic clinical trials.
[Back to top]
Testicular Germ Cell Tumors: A Paradigm for the
Successful Treatment of Solid Tumor Stem Cells
Caryl J. Giuliano, Sarah J. Freemantle and Michael J.
Spinella
Treatment of testicular germ cell tumors (TGCTs) has been
a success primarily due to the exquisite responsiveness of
this solid tumor to cisplatin-based therapy. Despite the promise
of cure for the majority of TGCT patients, the effectiveness
of therapy for some patients is limited by toxicity and the
problem of resistance. There is compelling rationale to further
understand the biology of TGCTs in order to better treat other
solid tumors and to address the shortcomings of present TGCT
therapies. TGCTs contain undifferentiated pluripotent stem
cells, known as embryonal carcinoma, that share many properties
with human embryonic stem cells. The importance of cancer
stem cells in the initiation, progression and treatment of
solid tumors is beginning to emerge. We discuss TGCTs in the
context of solid tumor curability and targeted cancer stem
cell therapy.
[Back to top]
Cancer Therapy-Induced Residual Bone Marrow Injury:
Mechanisms of Induction and Implication for Therapy
Yong Wang, Virginia Probin and Daohong Zhou
Bone marrow (BM) suppression is an important dose-limiting
side effect of chemotherapy and radiotherapy for cancer. Although
acute myelosuppression is an immediate concern for patients
undergoing cancer therapy, its management has been improved
significantly in recent years by the use of various hematopoietic
growth factors. However, many patients receiving chemotherapy
and/or ionizing radiation (IR) also develop residual (or long-term)
BM injury (a sustained decrease in HSC reserves due to an
impairment in HSC self-renewal) after the recovery from acute
myelosuppression. Unlike acute myelosuppression, residual
BM injury is latent and long lasting and shows little tendency
for recovery. Following additional hematopoietic stress such
as subsequent cycles of consolidation cancer treatment or
autologous BM transplantation, residual BM injury can deteriorate
to become a hypoplastic or myelodysplastic syndrome. This
article review some of the new developments in elucidating
the cellular and molecular mechanisms whereby chemotherapy
and radiotherapy cause residual BM injury. Particularly, we
discuss the role of induction of hematopoietic stem cell (HSC)
senescence via the p53-p21Cip1/Waf1
and/or p16Ink4a-RB
pathways in the induction of the injury and the therapeutic
potential of molecularly targeting these pathways for amelioration
of chemotherapy- and radiotherapy-induced long-term BM toxicity.
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