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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 20, 2006
Contents
Development of WT1 Peptide Cancer Vaccine Against Hematopoietic
Malignancies and Solid Cancers Pp. 2345-2352
Y. Oka, A. Tsuboi, M. Kawakami, O.A. Elisseeva, H. Nakajima,
K. Udaka, I. Kawase, Y. Oji and H. Sugiyama
[Abstract]
Human Terminal Deoxynucleotidyl Transferases
as Novel Targets for Anticancer Chemotherapy Pp.
2353-2368
Roberto Di Santo and Giovanni Maga
[Abstract]
A Novel Antiretroviral Class (Fusion Inhibitors)
in the Management of HIV Infection. Present Features and Future
Perspectives of Enfuvirtide (T-20) Pp. 2369-2384
Roberto Manfredi and Sergio Sabbatani
[Abstract]
Inhibitors of Protein: Geranylgeranyl Transferases
Pp. 2385-2427
Farid El Oualid, Louis H. Cohen, Gijs A. van der Marel
and Mark Overhand
[Abstract]
Designing HIV Integrase Inhibitors-Shooting the Last
Arrow Pp. 2429-2441
Mahindra T. Makhija
[Abstract]
Vitamin D and Cardiovascular Disease Pp.
2443-2447
Khanh Vinh Quoc Luong and Lan Thi Hoang Nguyen
[Abstract]
Peptides and Peptidomimetics in Medicine, Surgery
and Biotechnology Pp. 2449-2466
Luca Gentilucci, Alessandra Tolomelli and Federico Squassabia
[Abstract]
Abstracts
[Back to top]
Development of WT1 Peptide Cancer Vaccine Against
Hematopoietic Malignancies and Solid Cancers
Y. Oka, A. Tsuboi, M. Kawakami, O.A. Elisseeva, H. Nakajima,
K. Udaka, I. Kawase, Y. Oji and H. Sugiyama
Wild-type Wilms’ tumor gene WT1 is highly
expressed not only in hematopoietic malignancies, including
leukemia and myelodysplastic syndromes (MDS), but also in
various kinds of solid tumors. Human cytotoxic T lymphocytes
(CTLs) which could specifically lyse WT1-expressing tumor
cells with HLA class I restriction were generated in vitro.
We have also demonstrated that mice immunized with the WT1
peptide or WT1 cDNA rejected challenges by WT1-expressing
tumor cells and survived with no signs of auto-aggression
to normal organs which physiologically expressed WT1
in prophylactic and therapeutic models. Furthermore, we and
others detected IgM and IgG WT1 antibodies in the patients
with hematopoietic malignancies, indicating that WT1 protein
was highly immunogenic, and that immunoglobulin class-switch-inducing
WT1-specific cellular immune responses were elicited in the
patients. CD8+
WT1-specific CTLs were also detected in peripheral blood or
tumor-draining lymph nodes of cancer patients. These results
provided us with the rationale for elicitation of CTL responses
targeting the WT1 product for cancer immunotherapy. On the
basis of the findings mentioned above, we performed a phase
I clinical trial of WT1 peptide cancer vaccine for the patients
with malignant neoplasms. These results strongly suggested
that WT1 peptide cancer vaccine had efficacy in the clinical
setting, because clinical responses, including reduction of
leukemic blast cells or regression of tumor masses, were observed
after the WT1 vaccination in patients with hematopoietic malignancies
or solid cancers. The power of TAA-derived cancer vaccine
may be enhanced by combination with stronger adjuvants, helper
peptide, or conventional treatments such as molecular-target-based
drugs.
[Back to top]
Human Terminal Deoxynucleotidyl Transferases
as Novel Targets for Anticancer Chemotherapy
Roberto Di Santo and Giovanni Maga
Mammalian terminal deoxyribonucleotidyl transferase (TDT)
catalyzes the non-template-directed polymerization of deoxyribonucleoside
triphosphates and has a key role in V(D)J recombination during
lymphocyte and repertoire development. Over 90% of leukemic
cells in acute lymphocytic leukemia and approximately 30%
of leukemic cells in the chronic myelogenous leukemia crisis
show elevated TDT activity. This finding is connected to a
poor prognosis and response to chemotherapy and reduced survival
time. On the other hand, recent data indicated that TDT is
not the only terminal deoxyribonucleotidyl transferase in
mammalian cells. Its close relative, DNA polymerase (pol)
pol  can synthesize
DNA both in a template dependent (DNA polymerase) and template-independent
(terminal deoxyribonucleotidyl transferase) fashion. Pol
might be involved in the nonhomologous end-joining (NHEJ)
recombinational repair pathway of DNA double strand breaks
(DSBs). Specific inhibitors of these enzymes hold the potential
to be developed into a novel class of antitumoral agents.
In this review, we will summarize the recent advances in the
synthesis and characterization of the first classes of specific
inhibitors of mammalian terminal transferases and their potential
applications.
[Back to top]
A Novel Antiretroviral Class (Fusion Inhibitors)
in the Management of HIV Infection. Present Features and Future
Perspectives of Enfuvirtide (T-20)
Roberto Manfredi and Sergio Sabbatani
Enfuvirtide (Fuzeon®,
Roche), is the first member of a novel class of antiretroviral
agents, the so-called fusion inhibitors, which act against
HIV with a completely novel (extra cellular) mechanism of
action, and can therefore be easily added to all anti-HIV
association therapies including all other antiretroviral agents
belonging to nucleoside/nucleotide reverse transcriptase inhibitors,
non-nucleoside reverse transcriptase inhibitors, and protease
inhibitors, since no interactions of any type are expected
with enfuvirtide. Despite the need of a twice-daily parenteral
(subcutaneous) delivery due to the polypeptide structure of
the drug, and its proportionally short elimination lifetime,
two extensive multicentre randomized clinical trials and a
huge amount of other clinical and laboratory experiences confirmed
the elevated potency and the safety profile of enfuvirtide
in appropriate samples of HIV-infected patients (both adults
and children), who failed and/or became intolerant to all
previously available anti-HIV regimens, and had a very restricted
choice of antiviral compounds showing residual activity. As
a consequence, enfuvirtide is recommended as an adjunct to
an “optimized background” containing at least
one or two antiretroviral drugs, which are still active against
the isolated viral strain, as assessed by resistance testing.
The extremely promising profile of this novel anti-HIV drug
and the reduced potential for the development of viral resistance
(with no possibility of cross-resistance with the other anti-HIV
classes) however warrant further pharmacokinetic, pharmacodynamic,
pharmacogenomic, and pharmacoeconomic investigation. Also
more extensive and prolonged clinical and quality of life
studies are strongly needed to establish the best positioning
of enfuvirtide in the current therapeutic guidelines of HIV
disease and its future role, besides its current approval
for salvage therapy of adult and pediatric HIV-infected patients
with limited therapeutic options.
[Back to top]
Inhibitors of Protein: Geranylgeranyl Transferases
Farid El Oualid, Louis H. Cohen, Gijs A. van der Marel
and Mark Overhand
The enzyme protein:geranylgeranyl transferase-1 (PGGT-1
or GGTase-I) catalyzes the geranylgeranylation of cysteine
residues near the C-termini of a variety of proteins,
including most monomeric GTP binding precursor proteins belonging
to the Rho, Rac and Rap subfamilies. These proteins are involved
in signaling pathways controlling important processes such
as cell differentiation and growth. In the framework of the
development of therapeutics against disorders associated with
aberrant cell proliferation, the interference with these signal
transduction cascades has been a major focus of investigation.
For instance inhibitors of PGGT-1 have shown promise in the
treatment of cancer, smooth muscle hyperplasia as well as
parasitic infections, such as malaria. In this review, structural
and mechanistic aspects of the protein:geranylgeranyl transferases
are discussed as well as their importance with respect to
the terpene metabolism. An extensive summary of reported inhibitors
of PGGT-1, classified as natural products, peptide substrate
(Ca1a2L
box), terpene substrate (geranylgeranyl pyrophosphate) and
others, is presented. The few known inhibitors of the other
geranylgeranylating enzyme, protein:geranylgeranyl transferase-2
(PGGT-2), are also included.
[Back to top]
Designing HIV Integrase Inhibitors-Shooting the Last
Arrow
Mahindra T. Makhija
The arsenal of drugs in the fight against AIDS is rapidly
diminishing as the HIV becomes resistant to the available
reverse transcriptase and protease inhibitors. After killing
millions all over the world, the virus is still on the rampage
and hence the pharmaceutical industry is resorting to the
development of inhibitors of integrase. This seems to be the
last arrow in the quiver of potential drug leads to combat
the deadly infection. Several classes of HIV integrase inhibitors
have been reported to date; however, none is clinically useful.
This review details the existing knowledge of the biological
functions of the HIV-1 integrase with the focus on its available
inhibitors, their disadvantages, and the current trends in
designing novel compounds as anti-integrase.
[Back to top]
Vitamin D and Cardiovascular Disease
Khanh Vinh Quoc Luong and Lan Thi Hoang Nguyen
Cardiovascular disease (CVD) is the leading cause of
death among patients with end-stage renal disease (ESRD).
Vitamin D deficiency accompanies the loss of kidney function
and is extremely common. Treatment with active vitamin D has
improved survival rate in dialysis patients. The relationship
between vitamin D and CVD has been reported in the literature.
Genetic factors have been known to cause both vitamin D deficiency
and CVD. Vitamin D receptor is found in the heart muscle.
Vitamin D is reported to be involved in the pathogenesis of
many cardiovascular problems. Certainly, vitamin D has an
important role in modulating CVD.
[Back to top]
Peptides and Peptidomimetics in Medicine, Surgery
and Biotechnology
Luca Gentilucci, Alessandra Tolomelli and Federico Squassabia
Despite the fact that they have been used for a century to
treat several kinds of diseases, peptides and short proteins
are now considered the new generation of biologically active
tools. Indeed, recent findings suggest a wide range of novel
applications in medicine, biotechnology, and surgery. The
efficacy of native peptides has been greatly enhanced by introducing
structural modifications in the original sequences, giving
rise to the class of peptidomimetics. This review gives an
overview of both classical applications and promising new
categories of biologically active peptides and analogs. Besides
the new entries in well known peptide families, such as antibiotic
macrocyclic peptides, integrin inhibitors, as well as immunoactive,
anticancer, neuromodulator, opioid, and hormone peptides,
a number of novel applications have been recently reported.
Outstanding examples include peptide-derived semi-synthetic
vaccines, drug delivery systems, radiolabeled peptides, self-assembling
peptides, which can serve as biomaterials in tissue engineering
for creating cartilage, blood vessels, and other tissues,
or as substrates for neurite outgrowth and synapse formation,
immobilized peptides, and proteins. Finally, peptide-based
biomaterials can find applications in bio-nanotechnology for
bio-microchips, peptide nanorods and nanotubes, bio-sensors,
bio-electronic devices, and peptide-metal wires.
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