|
Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 9, Number 3, March 2009
Contents
Synthesis of Quinazolines as Tyrosine Kinase Inhibitors
Pp. 246-275
S.K. Srivastava, V. Kumar, S.K. Agarwal,
R. Mukherjee and A.C. Burman
[Abstract] [Purchase
Article] [PMID: 19275520 PubMed - indexed for MEDLINE]
A Trojan Horse in Drug Development: Targeting
of Thapsigargins Towards Prostate Cancer Cells Pp.
276-294
S.B. Christensen, D.M. Skytte, S.R. Denmeade,
C. Dionne, J.V. Møller, P. Nissen and J.T.
Isaacs
[Abstract]
[Purchase Article] [PMID: 19275521 PubMed - indexed for MEDLINE]
Quantification Techniques and Biodistribution of Semiconductor
Quantum Dots Pp. 295-303
E. Pic, L. Bezdetnaya, F. Guillemin and
F. Marchal
[Abstract] [Purchase
Article] [PMID: 19275522 PubMed - indexed for MEDLINE]
Novel Analogues of CC-1065 and the Duocarmycins for the Use
in Targeted Tumour Therapies Pp. 304-325
L.F. Tietze and B. Krewer
[Abstract]
[Purchase Article] [PMID: 19275523 PubMed - indexed for MEDLINE]
The Management of Metastatic Bone Disease with the Combination
of Bisphosphonates and Radiotherapy: From Theory to Clinical
Practice Pp. 326-335
V. Vassiliou and D. Kardamakis
[Abstract] [Purchase
Article] [PMID: 19275524 PubMed - indexed for MEDLINE]
Antimitotic Chalcones and Related Compounds as Inhibitors
of Tubulin Assembly Pp. 336-347
S. Ducki
[Abstract] [Purchase
Article] [PMID: 19275525 PubMed - indexed for MEDLINE]
Mechanisms of Trastuzumab Resistance
in Breast Cancer Pp. 348-355
S.M. Tolaney and I.E. Krop
[Abstract]
[Purchase Article] [PMID: 19275526 PubMed - indexed for MEDLINE]
Current Development of Pd(II) Complexes as Potential
Antitumor Agents Pp. 356-368
E. Gao, C. Liu, M. Zhu, H. Lin, Q. Wu and
L. Liu
[Abstract] [Purchase
Article] [PMID: 19275527 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[Purchase
Article] [PMID: 19275520 PubMed - indexed for MEDLINE]
Synthesis of Quinazolines as Tyrosine
Kinase Inhibitors
S.K. Srivastava, V. Kumar, S.K. Agarwal,
R. Mukherjee and A.C. Burman
In the present review, the discovery and development
of quinazoline as tyrosine kinase inhibitors has been described.
The synthesis of most potent quinazoline inhibitors of EGFR,
VEGFR and PDGRF has been discussed. Structure activity relationship
for quinazoline as tyrosine kinase inhibitors has been established.
It was found that C-4, C-6 and C-7 positions in quinazoline
are appropriate sites for designing new tyrosine kinase inhibitors.
This review should help the medicinal chemist in designing
more effective tyrosine kinase inhibitors.
[Back to top] [Purchase
Article] [PMID: 19275521 PubMed - indexed for MEDLINE]
A Trojan Horse in Drug Development: Targeting of Thapsigargins
Towards Prostate Cancer Cells
S.B. Christensen, D.M. Skytte, S.R. Denmeade,
C. Dionne, J.V. Møller, P. Nissen and J.T.
Isaacs
Available chemotherapeutics take advantage of the fast
proliferation of cancer cells. Consequently slow growth makes
androgen refractory prostate cancer resistant towards available
drugs. No treatment is available at the present, when the
cancer has developed metastases outside the prostate (T4 stage).
Cytotoxins killing cells irrespective of the phase of the
cell cycle will be able to kill slowly proliferating prostate
cancer cells. Lack of selectivity, however, prevents their
use as systemic drugs. Prostate cancer cells secrete characteristic
proteolytic enzymes, e.g. PSA and hK2, with unusual substrate
specificity. Conjugation of cytotoxins with peptides, which
are selective substrates for PSA or hK2, will afford prodrugs,
from which the active drug only will be released in close
vicinity of the cancer cells. Based on this strategy prodrugs
targeted at prostate cancer cells have been constructed and
evaluated as potential drugs for prostate cancer. The potency
of the thapsigargins as apoptotic agents make these naturally
occurring sesquiterpene lactones attractive lead compounds.
Intensive studies on structure-activity relationships and
chemistry of the thapsigargins have enabled construction of
potent derivatives enabling conjugation with peptides. Studies
on the mechanism of action of the thapsigargins have revealed
that the cytoxicity is based on their ability to inhibit the
intracellular sarco-/endoplasmtic calcium pump.
[Back to top]
[Purchase Article][PMID: 19275522 PubMed - indexed for MEDLINE]
Quantification Techniques and Biodistribution of Semiconductor
Quantum Dots
E. Pic, L. Bezdetnaya, F. Guillemin and
F. Marchal
Quantum dots (QDs) are fluorescent inorganic nanocrystals
with advantageous optical properties, which have been applied
for biomedical purposes including imaging, diagnostic, drug
delivery or therapy. Potential toxicity of QDs remains the
major barrier to clinical translation, and as such the precise
analysis of in vivo QDs distribution and pharmacokinetics
is of major importance. Biodistribution studies in animal
models are, however, sparse. The present review provides in
a first lieu a summary of different techniques, which are
currently used for relative quantification of QDs in vivo
or their absolute quantification ex vivo. Fluorescence
and radioactivity based techniques along with mass-spectrometry
detection at the elementary level are addressed in this review.
We further introduce biodistribution studies in animal models
and discuss the possibilities to modify quantum dots biodistribution
in function of different injection ways.
[Back to top] [Purchase
Article] [PMID: 19275523 PubMed - indexed for MEDLINE]
Novel Analogues of CC-1065 and the Duocarmycins for the Use
in Targeted Tumour Therapies
L.F. Tietze and B. Krewer
In recent years, a series of new and highly cytotoxic
analogues of CC-1065 and the duocarmycins have been developed
that can be transformed into much less toxic prodrugs for
the use in antibody-directed enzyme prodrug therapy (ADEPT),
gene-directed enzyme prodrug therapy (GDEPT) and prodrug monotherapy
(PMT) of cancer. In all these approaches, a relatively non-toxic
prodrug is applied and subsequently converted selectively
in the tumour tissue into a highly cytotoxic drug, thus reducing
undesired side effects accompanying conventional chemotherapy.
Here, the design and biological evaluation of prodrugs based
on analogues of CC-1065 and the duocarmycins for the use in
tumour selective cancer therapies is reviewed. The advantage
of this approach is the excellent therapeutic index of some
of the new prodrugs of over 5000 and the high cytotoxicity
of the corresponding drugs with IC50
values of as low as 16 pM (IC50:
concentration required for 50 % growth inhibition of target
cells). In addition, a novel method for the correlation of
the alkylation efficiency and the cytotoxicity based on mass
spectrometry is described.
[Back to top] [Purchase
Article] [PMID: 19275524 PubMed - indexed for MEDLINE]
The Management of Metastatic Bone Disease with the Combination
of Bisphosphonates and Radiotherapy: From Theory to Clinical
Practice
V. Vassiliou and D. Kardamakis
Bone metastases are common in the event of malignancy
and are inevitably associated with serious complications that
may deteriorate the quality of life (QOL) of patients and
threaten life. Both radiotherapy (RT) and bisphosphonates
(BPs) have an established role in the management of metastatic
bone disease. Many clinical trials have demonstrated their
effectiveness when used as sole treatment modalities, but
only a few have evaluated their therapeutic value when applied
concomitantly. We herein discuss the pathophysiology of bone
metastases and the potential interactions between RT and BPs.
Moreover, the results of both animal models and clinical studies
are presented in detail.
Apart from aspects of normal tissue tolerance, other interactions
include spatial cooperation and additive or super-additive
effects. The latter brings about a synergistic activity that
results in an enhanced reossification, improved bone stability
and microarchitecture, and increased mechanical strength,
as documented through animal model studies. The results of
published clinical studies investigating the effectiveness
of concomitant application of RT and BPs are promising, reporting
a significant clinical and radiologic response. More specifically,
a significant reduction of pain scores and a worth noticing
improvement in QOL and performance status (PS) were noted,
accompanied by a considerable increase in bone density. Pain
relief was accompanied by a marked reduction in analgesic
opioid need. The enhanced reossification may be responsible
for the improved therapeutic response, since it was shown
that the correlation between pain and bone density is negative
and strong. Although promising and encouraging, the results
of such studies should be corroborated by larger, randomized
trials.
[Back to top] [Purchase
Article] [PMID: 19275525 PubMed - indexed for MEDLINE]
Antimitotic Chalcones and Related Compounds as Inhibitors
of Tubulin Assembly
S. Ducki
The development of chalcones as antimitotic agents has
led to the design of other analogues able to interact with
tubulin and inhibit its assembly into microtubules. This activity
has also been associated with their anti-vascular activity.
This review focuses on the development of chalcones and related
analogues as antimitotic agents.
[Back to top] [Purchase
Article] [PMID: 19275526 PubMed - indexed for MEDLINE]
Mechanisms of Trastuzumab Resistance in Breast Cancer
S.M. Tolaney and I.E. Krop
Amplification of the HER2/neu gene occurs in approximately
20-25% of invasive breast cancers and is associated with poor
patient outcome. The development of trastuzumab, a humanized
monoclonal antibody that binds to the extracellular domain
of HER2, has led to a significant improvement in outcomes
of patients with HER2-positive breast cancer. However, many
patients with HER2-positive metastatic breast cancer do not
respond to trastuzumab, or eventually become resistant to
it. In addition, approximately 15% of patients treated with
trastuzumab-based therapy in the adjuvant setting relapse.
In this review, we discuss the mechanisms of antitumor activity
of trastuzumab, potential mechanisms contributing to its resistance,
and novel therapeutic agents that may provide a means to overcome
trastuzumab resistance.
[Back to top] [Purchase
Article] [PMID: 19275527 PubMed - indexed for MEDLINE]
Current Development of Pd(II) Complexes as Potential Antitumor
Agents
E. Gao, C. Liu, M. Zhu, H. Lin, Q. Wu and
L. Liu
Research has proven that the most effective and widely
used metal-containing chemotherapy anticancer drugs are cisplatin
([cis-PtCl2(NH3)2])
and many platinum complexes, however, these compounds have
significant disadvantages including poor water solubility
and serious side effects. Thus researches in order to overcome
these shortcomings have never interrupted. Many non-platinum
complexes have been synthesized and tested, in which some
palladium complexes show significant antitumor activity in
normal tumor cells and lower resistance of tumor cells to
clinical treatments as well as lower side effects. Mononuclear
palladium complexes with aromatic N-containing ligands, amino
acid ligands, S-donor ligands, and P-containing ligands have
respective qualities and properties due to the different structures
and properties of the ligands; some dinuclear palladium complexes
possess interesting steric structures and good antitumor activity;
a try to modify natural medicines with Pd2+
leads the research to a new route. In this review, medicinal
chemistry, the development status and interactions of palladium
complexes with DNA are discussed in order to provide guidance
and determine structure and antitumor activity relationships
for continuing studies of these systems.
|
