L K. Seymour
Update
on Antifolate Drugs Targets Pp. 135-166
M.P. Costi and S. Ferrari
Targeting the Expression of Anti-Apoptotic Proteins by Antisense Oligonucleotides. Pp. 167-180
Nicholas Deliha
Human Leptin Regulation and Promise in Pharmacotherapy Pp-181-195
Samuel Dagogo-Jack
Immunomodulating Anticancer Alkylating Drugs: Targets and Mechanisms of Activity Pp. 197-212
S. Ben-Efraim
[Back to top] Epidermal Growth Factor Receptor as a Target: Recent Developments in the Search for Effective New Anti-Cancer Agents
A
number of cancer chemotherapeutics targeting the epidermal growth factor
receptor (EGFR) are in development. These compounds were designed to either
bind to the EGFR or inhibit signal transduction after receptor activation.
Classes of inhibitory compounds include small molecules and humanized
monoclonal antibodies. Many of these compounds are relatively far advanced in
development. Proof of principle, with evidence of anti-tumour activity and
inhibition of EGFR activation/phosphorylation, has already been demonstrated in
some instances. Although these new compounds offer exciting opportunities, they
bring with them real challenges in terms of the selection of appropriate trial
designs as well as surrogate endpoints.
[Back to top] Update on Antifolate Drugs Targets
Antifolate
drugs are molecules directed to interfere with the folate metabolic pathway at
some level. They can be recognized among the first rationally designed
compounds applying the principle of structural analogy with the substrate
developing the antimetabolite strategy. This strategy has taken advantage of
the basic different features of the microbial and human folate metabolism and
therefore allows targeting the pathway at different steps generating a
specificity tools for Medicinal Chemists. Two main problems are giving renewed
importance to such targets and therefore improving the efforts to discover new
targets in the folate metabolism area. The first one is the increasing
resistance to the present drugs due to different mechanisms such as the enzyme
modification and the increased production of enzymes with not well recognized
importance. The second one is the development of techniques directed to
highlight the interference at genetic level of molecular probes as antifolate
drug to develop new enzymes previously unknown. This approach is defined as
genetic approach to drug discovery, from gene to drugs.
The present article describes the importance in drug design and discovery of some antifolate targets among the best known at the present status of research such as thymidylate synthase (TS), dhydrofolate reductases, (DHFR) serine hydroxymethyltransferase (SHMT), folyilpolyglutamyl synthetase (FPGS), g-glutamyl hydrolase (g-GH), glycinamide-ribonucleotide transformylase (GARTfase), amino-imidazole-carboxamide-ribonucleotide transformylase (AICARTfase) and Folate transporters. Discovery, known functions, structure/function studies and inhibition will be described.
[Back to top] Targeting the Expression of Anti-Apoptotic Proteins by Antisense Oligonucleotides
Antisense oligonucleotide (ASO) biotechnology has been widely used to inhibit the expression of proteins involved in human disease. ASOs are designed to bind messenger RNA transcripts via Watson-Crick base-pairing and inhibit synthesis of targeted proteins. These proteins include protein kinases, growth factors, glutamate receptors, anti-apoptotic proteins, and proteins involved in genetic disorders. Non-mRNA targets such as the RNA component of the telomerase enzyme are also being explored. Pre-clinical and clinical trials using ASO biotechnology have progressed with standard ASOs such as phosphorothioates, but newer ASO analogs are rapidly being developed with the idea of enhancing specificity and biological activity. A current major research thrust is the design and testing of antisense oligonucleotides as anti-cancer drugs. The primary focus of this review is an analysis of recent uses of ASO biotechnology to inhibit anti-apoptotic gene expression in tumor cells.
[Back to top] Human Leptin Regulation and Promise in Pharmacotherapy
Samuel Dagogo-Jack
In
rodents leptin inhibits food intake, stimulates energy expenditure, reverses
obesity, ameliorates insulin resistance, and accelerates sexual maturation.
These potent and diverse effects have stimulated interest in exploring a role
for leptin in the treatment of human metabolic disorders. However, the
significance of leptin in human (patho)physiology is still being investigated.
The present review summarizes current knowledge of leptin regulation, provides
a critical assessment of initial experience with leptin therapy, and discusses
potential targets for recombinant leptin therapy in humans. The results of
numerous studies indicate that leptin is indeed a regulated human hormone: The
physiological factors that influence leptin secretion include gender,
adiposity, physical exercise, feeding, and caloric restriction. Several
hormones, including insulin, glucocorticoids, estradiol, growth hormone,
testosterone, somatostatin, and insulin-like growth factor-I also modulate
leptin secretion. The results of initial trials of leptin therapy in humans
have become available. Treatment with recombinant human leptin (0.028 mg/kg)
induced a progressive weight loss (without evidence of tachyphylaxis) in a
morbidly obese patient with congenital leptin deficiency. The weight loss
averaged 1-2 kg/month, was associated with preservation of lean muscle mass,
and was almost exclusively accounted for by depletion of body fat.
Administration of recombinant leptin (0.01-0.3 mg/kg) also resulted in a
dose-dependent weight loss among lean and obese humans with presumably normal
leptin genotype. Thus leptin may have a therapeutic role in humans, but its
physiological functions and regulation first need to be fully unravelled.
[Back to
top] Immunomodulating Anticancer
Alkylating Drugs: Targets and Mechanisms of Activity
S.
Ben-Efraim
CY
and L-PAM potentiated specific anti-tumor response in addition to their killing
effect. The immunomodulating effect of a low dose of either CY or L-PAM was
expressed in mice bearing large s.c. MOPC-315 plasmacytoma tumors.Cured mice
were resistant to a challenge dose of the syngeneic tumor and their spleens
contained specific cytotoxic T cells. Induction of specific anti-tumor response
by a low dose of alkylating drugs was due to expression of “latent anti-tumor”
capability. This fitted with the conception that “suppressed concomitant
immunity” occurring in tumor-bearing animals can be activated. The
immunomodulating activity of alkylating drugs was related to enhancement of T-cell
functions:impairment of suppressor T-celll activity,enhancement of effector
T-cell activity and increase in production of cytokines at the tumor site. The
target tumor killing activity of a low dose alkylating drug was dissociated
from its immunomodulating activity by treating mice bearing a tumor resistant
to an alkylating drug.
A
low dose of CY had an immunomodulating effect in human cancer such as reduction
of ConA-induced suppressor cell activity in melanoma, some improvement in
addition to use of melanoma vaccine, and potentiation of DTH in cancer
patients.
The
immunomodulating effect of alkylating drugs suggest that their use might be
beneficial not only for killing tumor cells but also for promoting specific
anti-tumor immune response.