Design of Selectively Activated Anticancer Prodrugs: Elimination and
Cyclization Strategies
Pp-155-185
S. Papot,
I. Tranoy, F. Tillequin, J.-C. Florent and J.-P. Gesson
[Abstract]
Porphyrins in Photodynamic
Therapy - A Search for Ideal Photosensitizers Pp-187-207
S.K.
Pushpan, S. Venkatraman, V.G. Anand, J. Sankar, D. Parmeswaran, S. Ganesan and
T.K. Chandrashekar
[Abstract]
Herbal Medicine in the
Treatment of Cancer
Pp-209-214
John W.
Ho, Yuet Kin Leung and Chun Pong Chan
[Abstract]
Recent Developments in the
Design, Synthesis and Structure-Activity Relationship Studies of
Pyrrolo[2,1-c][1,4]benzodiazepines as DNA-Interactive Antitumour Antibiotics Pp-215-254
Ahmed
Kamal, Maddamsetty V. Rao, N. Laxman, G. Ramesh and G.S.K. Reddy
[Abstract]
Discovery of Antitumor
Indolocarbazoles: Rebeccamycin, NSC 655649, and Fluoroindolocarbazoles Pp-255-266
Byron. H.
Long, William C. Rose, Dolatrai M. Vyas, James A. Matson and Salvatore Forenza
[Abstract]
The Prodrugs of
5-Fluorouracil
Pp-267-310
M.
Malet-Martino, P. Jolimaitre and R. Martino
[Abstract]
Protein-Protein
Interactions: Lessons Learned Pp-311-330
S.K.
Sharma, T.M. Ramsey and K.W. Bair
[Abstract]
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Design of Selectively Activated Anticancer Prodrugs:
Elimination and Cyclization Strategies
S. Papot,
I. Tranoy, F. Tillequin, J.-C. Florent and J.-P. Gesson
Cancer
chemotherapy is associated with severe side effects which may be reduced by
selective liberation, at the tumour site, of a cytotoxic agent from a non-toxic
prodrug. Several strategies are used to achieve the required selective
activation : with enzymes which are present in higher concentration in, or
close, to the tumour (b-glucuronidase,
plasmin), with enzymes covalently linked to a macromolecular carrier able to
recognize antigen positive cancer cells (ADEPT : Antibody Directed Enzyme
Prodrug Therapy) or with reductive processes which are favoured in an hypoxic
environment. Most of the prodrugs include a linker (or spacer) between the
trigger and the drug (or effector). The design of such linkers is crucial in
order to achieve a fast drug liberation under physiological conditions. The
linker groups may be classified in two categories based on elimination or
cyclization processes. The advantages and the limitations of each strategy are
discussed.
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Porphyrins in Photodynamic Therapy - A Search for Ideal
Photosensitizers
S.K. Pushpan,
S. Venkatraman, V.G. Anand, J. Sankar, D. Parmeswaran, S. Ganesan and T.K.
Chandrashekar
The
utility of light as a therapeutic agent can be traced back over thousands of
years when it was used in Ancient Egypt, India and China to treat a variety of
skin diseases like psoriasis, vitiligo, rickets, cancer and psychosis. The
isolation of porphyrins and their inherent tumor localizing properties coupled
with its ability to generate reactive singlet oxygen when activated by light of
particular wavelength which in turn results in cytotoxicity led to the
emergence of a new modality namely, photodynamic therapy (PDT) as a therapeutic
tool. The higher degree of selectivity offered by this modality and fewer side
effects when compared to chemotherapy and radiotherapy has prompted the
researchers around the globe to generate new photosensitizers. Porphyrins and
expanded porphyrins are one class of molecules under intense investigation due
to their photosensitizing ability for PDT application. Expanded porphyrins
result from the expansion of the p electron conjugation by increasing the number of
heterocyclic rings or bridging carbons of the existing porphyrin framework.
These chromophores show strong absorptions in the red region (650-800 nm)
compared to that of normal 18p porphyrins. The strong absorption of light by a water
soluble nontoxic photosensitizing molecule in the therapeutic window resulting
in maximum penetration of light into the tissues coupled with high singlet
oxygen production will conceptualize an ideal photosensitizer. This review
highlights various porphyrinoid sensitizers reported till date and their
photosensitizing ability both in vitro and in vivo studies. Furthermore, the
urgent need for developing ideal photosensitizer for PDT will also be
highlighted.
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Herbal Medicine in the Treatment of Cancer
John W.
Ho, Yuet Kin Leung and Chun Pong Chan
Many
of the classes of phytochemicals in herbal medicine are finding therapeutic use.
In particular, cancer patients are reported to benefit from treatment with
herbal medicine and survivability in many cases is significantly enhanced.
Recent studies showed the anti-oxidative and superoxide scavenging activities
of individual active components of herbal medicine for their inhibitory
activities on lipid peroxidation and anti-cancer properties. Individual herbal
medicines show antipyretic, analgesic and anti-inflammatory and anti-cancer
effects. In addition to sharing many therapeutic activities, herbal medicine is
also used in nutrient supplement for anti-cancer and anti-inflammatory
activity. Numerous in vitro studies of herbal medicine on different cell lines
and in vivo study of herbal medicine have been reported. However, the mechanisms
of actions remain unclear. This review aims to give an overview on the recent
development of herbal medicine in the prevention and treatment of cancer. The
report covers the possible mechanism of action of some of the herbal medicine.
In addition, the common properties of herbal medicine are described. Finally,
the study sheds lights on the pharmacological applications of herbal medicine
in the treatment of cancer and its potential use as anti-cancer agents.
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Recent
Developments in the Design, Synthesis and Structure-Activity Relationship
Studies of Pyrrolo[2,1-c][1,4]benzodiazepines as DNA-Interactive Antitumour
Antibiotics
Ahmed
Kamal, Maddamsetty V. Rao, N. Laxman, G. Ramesh and G.S.K. Reddy
Pyrrolo[2,1-c][1,4]benzodiazepines
(PBDs) are naturally occurring compounds isolated from various Streptomyces
species. The PBDs exert their biological activity through covalent binding and
exhibit cytotoxicity. Extensive studies have been carried out on the synthetic
strategies of PBDs, and a sound understanding of structure activity
relationships within this class of compounds has been developed. The PBDs have
shown to interfere with the interaction of endonuclease enzymes of DNA and block
the transcription by inhibiting RNA polymerase in a sequence specific manner.
These processes have been thought to account for the biological activity of
PBDs. The PBDs have also been used as a scaffold to attach different type of
moieties leading to novel sequence selective DNA cleaving and cross-linking
agents. The design and synthesis of C8-linked PBD dimers and other hybrids of
PBDs has given a new insight towards the development of molecules with enhanced
DNA binding affinity and sequence specificity compared to the naturally
occurring PBDs. This improvement in the biological profile has been explained
on the basis of certain factors like DNA cross-linking and doubling of DNA
binding sites. There seems to be enough potential for further changing the substitution
pattern and to design structurally modified PBDs by retaining the PBD core
intact. In this review both the synthetic strategies and the structure-activity
relationships, particularly the DNA binding and cytotoxicity studies of PBDs
have been discussed.
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Discovery of Antitumor Indolocarbazoles: Rebeccamycin, NSC 655649, and
Fluoroindolocarbazoles
Byron. H.
Long, William C. Rose, Dolatrai M. Vyas, James A. Matson and Salvatore Forenza
A
fermentation directed product search for potential anticancer drugs conducted
by Bristol-Myers in the 1970s and early 1980s resulted in the identification of
a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development
candidate. Subsequently, an analog program designed to impart distal site in
vivo antitumor activity resulted in the discovery of diethylaminoethyl analog
of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC
655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of
action of DEAE-RBM resulting in the potent catalytic inhibition of both
topoisomerases I and II. Precursor feeding fermentation experiments with
fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These
FICs were identified as targeting topoisomerase (topo) I in a mechanism-based
screen and their action on topo I was confirmed by production of topo
I-mediated single-strand breaks in DNA at sites essentially identical to those
induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for
specific FICs using a P388 and camptothecin-resistant P388/CPT45 pair of cell
lines, the latter expresses little or no functional topo I. For example, topo I
selectivity was greatest with 3,9-difluoro substituted FIC and was least
significant and least cytotoxic with 4,8-difluoro substituted FIC. The review
focuses on the discovery of the rebeccamycin class of compounds and their
structure-activity relationships leading to the development of the clinical candidate
BMY-27557 (NSC 655649), as well as the lead identification of the
fluoroindolocarbazole class of compounds.
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The Prodrugs of 5-Fluorouracil
M. Malet-Martino, P. Jolimaitre and R.
Martino
Although 5-fluorouracil (FU) was first introduced in 1957, it remains an essential part of the treatment of a wide range of solid tumors. FU has antitumor activity against epithelial malignancies arising in the gastrointestinal tract, breast as well as the head and neck, with single-agent response rates of only 10-30%. Although FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than a third of patients achieve objective responses. Recent research has focused on the biomodulation of FU to improve the cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer agents, FU leads to several toxicities. The toxicity profile of FU is schedule dependent. Myelotoxicity is the major toxic effect in patients receiving bolus doses. Hand-foot syndrome (palmar-plantar erythrodysesthesia), stomatitis, neuro- and cardiotoxicity are associated with continuous infusions. Other adverse effects associated with both bolus-dose and continuous infusion regimens include nausea and vomiting, diarrhea, alopecia and dermatitis. All these reasons explain the need of more effective and less toxic fluoropyrimidines.
In the first part of the review, we briefly present the metabolic pathways of FU responsible for the efficacy and toxicity of the drug. This knowledge is also necessary to understand the target(s) of the biomodulation.
The
second part is devoted to a review of the literature on the various prodrugs of
FU, including 5’-deoxy-5-fluorouridine, capecitabine, BOF-A2, ftorafur, UFT,
and S-1. The promising approach of gene directed enzyme-prodrug therapy is also
presented. A brief survey of antibody directed enzyme-prodrug therapy and some
new FU prodrugs concludes the paper. The pharmacological principles that have
influenced the development of these new drugs and our current knowledge of the
clinical pharmacology of these new agents, focusing on antitumor activity and
toxicity, are presented.
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Protein-Protein Interactions: Lessons Learned
S.K. Sharma, T.M. Ramsey and K.W. Bair
Protein-Protein (P-P) interactions play a pivotal role in determining cellular structure and in all cellular processes. The nature of P-P interactions is complex, and despite the large amount of research that has occurred in the field, is still poorly understood. Abnormal P-P interactions are particularly important because of their association with a variety of diseases, including cancer.
This
review examines P-P interactions with particular emphasis on the discovery of
new anti-tumor drugs, including underlying physical forces that determine
affinity and specificity and discusses classical and newer strategies used to
discover inhibitors of P-P interactions, providing a number of recent
cancer-related case studies and commentary.