Rituximab: The First Monoclonal Antibody Approved for
the Treatment of Lymphoma Pp. 1-9
[Abstract] [Full text article]
Use of Recombinant Human
Erythropoietin as an Antianemic and Performance Enhancing Drug Pp. 11-31.
[Abstract] [Full text article]
Growth Velocity, Final Height and Bone Mineral
Metabolism of Short Children Treated Long Term with Growth Hormone Pp.
33-46
Roberto Lanes
[Abstract] [Full text article]
Advances in Biotechnology
for Tissue Engineering of Bone Pp. 48-55
U. Ripamonti, and J. R Tasker
[Abstract] [Full text article]
Transcription Factors as
Potential Targets for Therapeutic Drugs Pp.
57-61
David S. Latchman
[Abstract] [Full text article]
Modulation
of Metabolism Through Transcriptional Control has created New Treatment
Opportunities for Type 2 Diabetes Pp.
63-71.
Esper Boel, Tatjana Albrektsen, Jan
Fleckner, and Johan Selmer
[Abstract] [Full text article]
The Chick Embryo
Chorioallantoic Membrane as a Model for in
vivo Research on Anti-Angiogenesis Pp.
73-82
Domenico Ribatti, Angelo Vacca, Luisa
Roncali, Franco Dammacco
[Abstract] [Full text article]
Toward The Rational Design of Cell Fate Modifiers: Notch Signaling as a Target for Novel Biopharmaceuticals Pp. 83-106.
A. Zlobin, M.
Jang and L. Miele
[Abstract] [Full text article]
Inhibition of Cellular Proliferation by Drug Targeting of Cyclin-Dependent Kinases 107-116.
Ignacio Pérez-Roger, Carmen Ivorra, Antonio Díez, María José Cortés,
Enric Poch,
Silvia M. Sanz-González and Vicente
Andrés
[Abstract] [Full text article]
[Back to top] Rituximab: The First
Monoclonal Antibody Approved for the Treatment of Lymphoma
A.J. Grillo-López,
C.A. White, B.K. Dallaire, C.L. Varns, C.D. Shen, A. Wei, J.E. Leonard,
A. McClure, R. Weaver, S. Cairelli and J. Rosenberg
Rituximab, a genetically engineered monoclonal chimeric antibody, targets the CD20 antigen expressed on B cells. It was approved by the US Food and Drug Administration on November 26, 1997, for the indication of relapsed or refractory, CD20-positive, B‑cell, low-grade or follicular non-Hodgkin’s lymphoma (LG/F NHL), and by the European Agency for the Evaluation of Medicinal Products on June 2, 1998, for therapy of patients with Stage III/IV, follicular, chemoresistant or relapsed NHL. Eight Phase II or III clinical trials in LG/F NHL patients have been completed: five single‑agent studies and three combination studies. Rituximab has a favorable safety profile: most adverse events (AEs) are Grade 1 or 2, and the frequency of AEs decrease with subsequent infusions. AEs in the combination studies are consistent with those seen with individual agents. For evaluable patients in the single‑agent studies, overall response rates (ORR) ranged from 40% to 60%, median duration of response (DR) ranged from 5.9 to 15.0+ months, and median time to progression (TTP) ranged from 8.1 to 19.4+ months. For evaluable patients in the combination studies, the ORR ranged from 45% to 100%, median DR ranged from 11.7+ to 39.1+ months, and median TTP ranged from 12.9+ to 40.5+ months. Studies in intermediate- and high-grade NHL are ongoing. Long‑term development plans include evaluating the safety and efficacy of rituximab in various types of lymphoma and in combination with other lymphoma regimens. Future studies may explore ways to increase rituximab efficacy by upregulating CD20 or increasing effector function with different cytokines.
[Back
to top] Use of Recombinant
Human Erythropoietin as an Antianemic and Performance Enhancing Drug
W.
Jelkmann
The glycoprotein hormone erythropoietin is an essential viability and growth factor for the erythrocytic progenitors in the bone marrow. Tissue hypoxia is the main stimulus for the synthesis of the hormone in the kidneys and the liver. Endogenous erythropoietin and recombinant human erythropoietin (rHu-EPO) are similar with respect to their biological and chemical properties except for some microheterogeneities in their 4 carbohydrate chains. Generic products and alternatives to rHu-EPO are in development. Renal anemia can be corrected by rHu-EPO in a dose-dependent and predictable way without major side effects apart from a possible increase in arterial blood pressure. The optimal target hematocrit still needs to be defined. There are rare reports of antibody formation towards rHu-EPO in humans. Patients suffering from non-renal anemias may also benefit from the prescription of rHu-EPO. The drug has been approved for treatment of tumor patients with platinum-induced anemia. The cost-effectiveness and medical justification of the administration of rHu-EPO in tumor patients with respect to its positive effects on tumor oxygenation, tumor growth inhibition and support of chemo- and radiotherapy is still a matter of debate. In surgical patients, the pharmacological application of rHu-EPO can increase the yield of blood units in autologous blood donation programs and lower the severity and duration of postoperative anemia, if applicated some days prior to surgery. While rHu-EPO is a godsend in medical practice, its abuse as an performance enhancing drug by athletes in endurance sports is an unethical and potentially dangerous procedure. Unequivocal methods for detection of rHu-EPO doping still need to be established.
[Back
to top] Growth
Velocity, Final Height and Bone Mineral Metabolism of Short Children Treated
Long Term with Growth Hormone
Since human recombinant growth hormone (GH) became available a large number of short GH deficient and GH-sufficient children have been treated with growth hormone. Growth hormone deficient patients have been followed to final height and several studies have shown that even when treated with GH from very early on in life they tend to end up shorter than their target height. There is, however, a clear increase in their growth velocities particularly during the first 4 5 years of GH therapy so that patients end up with a height-SD score of aproximately -0.8. Recent studies have demonstrated decreased bone mineral densities (BMD) in children with growth hormone deficiency, both by areal and volumetric analysis. Therapy with growth hormone clearly increases their BMD with an increase in bone formation markers, as will be reviewed in detail. Growth hormone therapy of non-growth hormone deficient short children has increased their growth velocity short term, particularly in girls with Turner’s syndrome and in children with chronic renal insuficiency. Recent final height data by Rosenfeld et al. and by Sweedish and Dutch groups have demonstrated a gain of 8-12 cm in girls with Turner’s syndrome treated with GH or with a combination of GH and oxandrolone. Neely et al. and we have demonstrated that growth hormone treated prepubertal age girls and adolescents with Turner’s syndrome have normal BMD and Shaw et al. has suggested that they have normal BMD despite GH or estrogen therapy. However, we found the BMD of a group of previously GH treated young women with Turner’s syndrome on estrogen replacement to be decreased compared to both age and gender matched controls and to controls of the same weight and pubertal status. Growth hormone therapy increases the growth velocity and the final height of children with chronic renal insuficiency, particularly in prepubertal children treated with GH before dyalisis. We have demonstrated how the BMD of these patients, which at baseline is low when compared to healthy age matched controls, but normal when compared to height and bone age matched controls, increases with growth hormone treatment significantly, moreso than in untreated uremic controls or in untreated healthy controls paired for height and bone age.
Short,
slowly growing, non growth hormone deficient patients (idiopathic short
statature) have been treated for prolonged periods of time with GH. We and
others have demonstrated a clear increase in their growth velocity short term,
but improvement of their final height remains unclear and controversial. After
4-8 years of GH treatment, Hintz et al.
have found a 5-6 cm increase in final height compared to the predicted adult
height before beginning therapy, but most patients did not reach their target
heights. Other studies, however, have found no improvement in final height and
Kawai et al. even suggests that GH
therapy diminishes the final height of treated children due to an earlier
puberty and a shorter pubertal growth spurt. We, have found decreased BMD in
children with idiopathic short stature when compared to controls of their same
height and bone age with a significant increase in BMD following 12 months of
GH and with an increase in bone turnover as measured by bone formation and
resorption markers. Recent short term studies in patients with hypophosphatemic
rickets and osteogenesis imperfecta treated with rhGH have also yielded similar
results which will be specified in the review. Some 10-20% of children born
with intrauterine growth retardation (IUGR) end up short and we had already
demonstrated 20 years ago how 2 years of GH therapy were capable of increasing
their growth velocities significantly with an improvement of their height-SD
scores. Recent studies mainly from Europe have corraborated this data long
term, so that IUGR children have been shown by de Zegher et al. to increase their growth velocities and their height for age
after 6 years of treatment, entering into the low normal centiles of their
growth curves for age. Long term studies of these children to final height will
be necessary to determine the usefulness and safety of this form of therapy.
[Back
to top] Advances
in Biotechnology for Tissue Engineering of Bone
U.
Ripamonti*, and J. R Tasker
Tissue engineering is a rapidly developing field applying the disciplines of cell biology, developmental biology, molecular biology and biomimetic engineering to regenerate new tissues for replacement therapies in clinical contexts. To aid in the elicitation and reiteration of the processes of morphogenesis of tissues, the cascade of chemotaxis of progenitor cells, their differentiation and pattern formation is redeployed in postnatal tissues, effected by a variety of ever-increasing morphogens and biomaterials. The extensive recent progress in elucidating the molecular biology of BMPs and their receptors shall aid in promoting and extending the great operational future of this field. Although the BMP family of proteins and osteogenesis have been the subject of several recent reviews, we focus here on their activity in primates and on the novel localization of BMPs in the cerebellum and other areas of the nervous system, and the “mosaicism” of their localisation in the periodontal tissues followed by a discussion on the use of BMPs in periodontal regeneration. Lastly, we report on the unique osteoinductive activity of TGF-b proteins in heterotopic sites of primates and their synergistic interaction with a recombinant human BMP, and finally we present unique data on novel biomaterials endowed with intrinsic osteoinductive activity, capable of initiating de novo bone formation in heterotopic sites even in the absence of exogenously applied BMPs, and the results of a clinical trial in humans using naturally-derived BMPs.
[Back to top]
Transcription Factors as Potential
Targets for Therapeutic Drugs
David S. Latchman
Although drugs which target transcription are in wide therapeutic use, they were all identified on the basis of their effect on a specific biological process such as inflammation or hormone responses and were only subsequently shown to target transcription. Our recent progress in understanding the mechanism of action of these drugs and the mechanisms of transcriptional regulation in general offers hope for a new generation of drugs isolated on the basis of their ability to modulate either the synthesis of transcription factors, the regulation of their activity by ligands or phosphorylation events, their protein-protein interactions or their binding to DNA.
[Back
to top] Modulation of Metabolism Through Transcriptional
Control has created New Treatment Opportunities for Type 2 Diabetes
Esper Boel, Tatjana Albrektsen, Jan
Fleckner, and Johan Selmer
The discovery of the important metabolic and physiological role played by a family of transcription factors, the peroxisome proliferator activated receptors (PPAR), has opened up for a new understanding of the mode of action for the lipid lowering drugs known as fibrates and for the new glucose lowering compounds described as insulin sensitizers.
Both of these
classes of compounds have demonstrated significant efficacy in both animal
models of the metabolic derangements characteristic for type 2 diabetes and in human
clinical studies. The recognition of the role of these drugs as ligands for
PPAR transcription factors and the development of new molecular and cellular
tools to select and characterise new PPAR selective compounds will open up for
the development of even better new drug candidates for the treatment of
metabolic disorders associated with type 2 diabetes. With the combined strength
of new transcriptional mapping technologies developed in the field of molecular
biology, such as differential mRNA display and DNA microarray hybridisations,
it will be possible to perform a detailed molecular characterisation of the
transcriptional events involved in drug actions in cellular and tissue systems,
and information gathered from such types of analysis will lead to an enormous
amount of data, from which detailed knowledge of drug actions at the gene
regulatory level will emerge.
[Back
to top] The Chick
Embryo Chorioallantoic Membrane as a Model for in vivo Research on Anti-Angiogenesis
Domenico Ribatti, Angelo Vacca, Luisa
Roncali, Franco Dammacco
Anti-angiogenesis, i.e.inhibition of blood vessel growth,
is being investigated as a way to prevent the growth of tumors and other
angiogenesis-dependent diseases. Pharmacological inhibition interferes with the
angiogenic cascade or the immature neovasculature with synthetic or
semi-synthetic substances, endogenous inhibitors or biological antagonists. The
chick embryo chorioallantoic membrane (CAM) is an extraembryonic membrane
commonly used in vivo to study both
new vessel formation and its inhibition in response to tissues, cells, or
soluble factors. Angiogenesis or anti-angiogenesis is evaluated quantitatively
or semiquantitatively. The fields of application of CAM in the study of anti-angiogenesis,
including our personal experience, are illustrated in this paper.
[Back
to top] Toward The Rational Design of Cell Fate Modifiers: Notch Signaling
as a Target for Novel Biopharmaceuticals
A.Zlobin,
M. Jang and L. Miele
Recent advances in our understanding of highly conserved mechanisms that control cell fate determination are paving the way towards rationally designed biologics that modulate specific cell fate decisions. Cell fate decisions leading to proliferation, differentiation or apoptosis are crucial elements in the pathogenesis of countless human diseases. Biopharmaceuticals designed to regulate such processes in specific cell types in vivo or ex vivo have vast potential applications in oncology, stem cell technology, immunomodulation and neuropathology. One of the most conserved mechanisms controlling cell fate determination is based upon Notch-ligand interactions and subsequent signaling events. Recent studies have shown that this mechanism regulates cell differentiation, proliferation and apoptosis in a wide variety of cell maturation processes and in neoplastic cells. These observations identify the Notch signaling network as a promising drug target for numerous indications. In this review, we describe: 1) potential drug targets in the Notch signaling network; 2) the Notch agonists and antagonists developed so far, including recombinant proteins, antibody-based agents, synthetic peptides, antisense oligonucleotides and gene therapy approaches, as well as possible strategies to design novel Notch-targeting biopharmaceuticals; 3) the possible clinical applications of such biopharmaceuticals and 4) a model strategy for the selection and developement of a Notch-targeting biopharmaceutical.
[Back
to top] Inhibition
of Cellular Proliferation by Drug Targeting of Cyclin-Dependent Kinases
Ignacio Pérez-Roger, Carmen Ivorra, Antonio Díez,
María José Cortés, Enric Poch,Silvia
M. Sanz-González and Vicente Andrés
Abnormal cellular
proliferation is associated with the pathology of several diseases, including
cancer, atherosclerosis and restenosis post-angioplasty. Therefore,
anti-proliferative therapies may be a suitable approach to treat these
disorders. Candidate targets for such strategies include specific components of
the cell cycle machinery.
Progression through the cell cycle in mammalian cells requires the
activation of several cyclin-dependent protein kinases (CDKs) through their
association with regulatory subunits called cyclins. Active CDK/cyclin
holoenzymes phosphorylate cellular proteins including the retinoblastoma
susceptibility gene product (pRb) and the related pocket proteins p107 and
p130. Several
compounds have been described that directly or indirectly inhibit the activity
of CDKs, which results in a suppression of cell growth. In this review, we will
discuss the use of drugs targeting CDKs and their therapeutic application in
animal models and clinical trials.