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PubMed2005

Overview of monoclonal antibodies in cancer therapy: present and promise.

After 30 years of development, therapy with monoclonal antibodies has started to realize its promise. Clinical use is most widespread in the field of oncology, where half of the agents approved for routine clinical use are employed and a large number of molecules are currently undergoing clinical trials. In the past 2 years alone, three new compounds-the radiolabeled antibody (131)I-tositumomab and two antibodies targeting growth factor receptors (bevacizumab and cetuximab)-have received FDA approval for indications in oncology. This review summarizes the development of this exciting treatment modality over the last three decades, examines the outcome of treatment with these new antibodies and others available for routine clinical use (i.e. rituximab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, (90)Y-ibritumomab tiuxetan) in standard indications and in experimental settings, and gives a brief outlook on possible future developments.

Antibodies, Monoclonal↗

PubMed1994

Management of disseminated kidney cancer.

The approach to disseminate renal cell carcinoma (RCC) has evolved significantly in recent years, largely owing to the progress of biologic therapy development. With increasing knowledge of biologic therapy come several dilemmas, including the choice of cytokine therapy, the appropriate mode of delivery, the selection of candidates for given therapeutic options, and the role of cytoreductive nephrectomy in immunotherapy protocols. This article reviews the historical development of immunotherapy and the lessons learned from previous experience and offers a logical approach to the patient with disseminated RCC.

Carcinoma, Renal Cell↗

PubMed2006

Development of gene therapies for cardiovascular and renal diseases by nucleic acid medicines.

Nucleic acid medicines such as antisense DNA, antisense peptide nucleic acid (PNA), ribozyme, and decoy are expected to be novel therapeutic strategy for sever diseases which are resistant to present therapy. We have developed antisense DNA, antisense PNA and ribozyme targeting platelet-derived growth factor (PDGF) A-chain and transforming growth factor-beta1 (TGF-beta1) for arterial proliferative diseases such as coronary artery stenosis after angioplasty or stent implantation, hypertensive vascular diseases and atherosclerosis, and progressive renal diseases. Antisense DNA to PDGF A-chain inhibited arterial growth in spontaneously hypertensive rats without lowering blood pressure and inhibited the neointima formation of pig coronary artery after stent implantation. Ribozymes to PDGF A-chain and TGF-beta1 specifically inhibited the target transcripts and prevented the neointima formation. Ribozymes to TGF-beta1 improved renal damages in hypertensive rats. These nucleic acid medicines targeting PDGF A-chain and TGF-beta1 will be feasible gene therapies for the arterial proliferative diseases and progressive renal diseases. Pyrrole-imidazole polyamides are novel gene silencing compound, which bind to minor grove of double strand DNA by base-specific manner to inhibit gene expression. We developed pyrrole-imidazole polyamide to TGF-beta1 and confirmed that the polyamide binds to the TGF-beta1 promoter. The polyamide inhibited TGF-beta1 promoter activity and decreased expression of TGF-beta1 in vitro and in vivo. The polyamide markedly improved the renal injury in hypertensive rats. The pyrrole-imidazole polyamide will be a novel gene silencing agent for cardiovascular and renal diseases.

Amides↗

PubMed1988

Development of resistance to a long-acting somatostatin analogue during treatment of two patients with metastatic endocrine pancreatic tumours.

UNLABELLED: Two patients with metastatic endocrine pancreatic tumours initially responded well to therapy with the long-acting somatostatin analogue SMS 201-995. In the first patient with an insulinoma both the number of hypoglycemic attacks and the increased insulin levels decreased initially, but returned to pretreatment intensity and concentrations within 9 days after the start of therapy with 200-300 micrograms SMS 201-995 daily. After a short interruption, no effect was observed of re-institution of therapy at a dose of 400 micrograms SMS 201-995 daily. In the other patient with a metastatic vipoma both diarrhea, hypokalemia and plasma VIP levels reacted initially well to SMS 201-995 treatment with 300 micrograms per day, but resistance to therapy developed after 2 weeks. An increase in the dose of the analogue to maximally 600 micrograms/day was followed by a transient improvement, but finally both the volume of diarrhea and the levels of vasoactive intestinal polypeptide were higher than those before the start of therapy. CONCLUSIONS: Development of resistance to SMS 201-995 both with regard to the clinical effect and to the inhibitory effect on tumour hormone secretion can be expected in some patients with metastatic endocrine pancreatic tumours. On the basis of our clinical observations down-regulation of somatostatin receptors is suggested to be one of the mechanisms of this development.

Adenoma, Islet Cell↗

PubMed2004

[Education of laboratory technicians at graduate school contributes to development of advanced medical sciences and therapeutics].

Translational research for novel cell and molecular therapy requires high scientific and ethical standards throughout the manufacturing of clinical trial material according to ICH-GCP (International Conference on Harmonization-Good Clinical Practice) guidelines. Advanced cellular therapy development such as cell transplantation, adoptive immunotherapy, gene therapy and regenerative therapy mandate cGMP (current good manufacturing practices)-grade cell processing to assure the safety and quality of manipulated cell products. One of the first steps in cGMP conversion from the bench to the clinic is the design of a facility for the preparation of clinical material for use in human trials. The establishment of regulatory guidelines for cell processing to develop advanced cellular therapies is clearly needed. In addition, one of the important matters in the organization and management of advanced cell therapeutic centers for academia, is how to educate and train sophisticated technicians specialized for GMP regulations and GMP-graded cell processing. Such technicians should be educated at a graduate school of medicine for health science. GMP-cell processing is an active field for such graduates.

Bone Marrow Transplantation↗

PubMed1984

[Control of regressive processes in therapy groups].

At the outset a delineation is made of the concept of regression in the context of psychoanalysis. It is shown that partial and reversible regressive changes are a necessary pre-condition in order for progredient therapy developments to take place in a patient. This applies to the therapeutic process in the treatment of individuals as well as to group therapy. In analytic group therapy the development of a more mature personality structure can be facilitated by means of the carefully controlled use of such destructing measures as minimal structuring, abstinence, anonymity and rule of free interaction as well as the interpretation of the group analyst. In this way, the development and maintenance of psychoneurotic, functional somatic and character symptoms gradually become superfluous and psychic energies are liberated for more constructive forms of behavior. Some attention is given to the reciprocity between specifically psychoanalytic perception and a conclusion formation of an explanatory- hermeneutic nature. On the basis of the insights obtained in this way, the psychoanalytic group therapist designs his interventions which should, if possible, apply to all group participants. This approach is illustrated by means of a clinical case study.

Adult↗

PubMed1998

Human immunodeficiency virus type 1 protease genotypes and in vitro protease inhibitor susceptibilities of isolates from individuals who were switched to other protease inhibitors after long-term saquinavir treatment.

An understanding of the mechanisms of virologic cross-resistance between human immunodeficiency virus type 1 protease inhibitors is important for the establishment of effective treatment strategies for patients who no longer respond to their initial protease inhibitor. Protease gene sequencing results from patients treated with saquinavir showed significant increases in the frequency of the G48V protease mutation in patients receiving higher doses of the drug. In addition, all six patients who developed the G48V mutation during saquinavir therapy developed the V82A mutation either on continued saquinavir or after a switch to nelfinavir or indinavir. In vitro susceptibility assays showed that all 13 isolates with reduced susceptibilities to two or more protease inhibitors had either the G48V or L90M mutation, along with an average of six other protease mutations. Reduced susceptibility to nelfinavir was found in 14 isolates, but only 1 possessed the D30N mutation. These results suggest that mutations selected in vivo by initial saquinavir therapy may provide more cross-resistance to the other protease inhibitors than has been previously reported.

Genome, Viral↗

PubMed2004

Regulatory nodes that integrate and coordinate signaling as potential targets for breast cancer therapy.

Blockade of the estrogen receptor (ER) with antiestrogens and aromatase inhibitors is effective in the treatment of breast cancer. Why ER plays such a dominant role in breast cancer and represents such an excellent target remains to be defined. The ability of ER to respond to multiple inputs and to control expression of multiple downstream genes may be one of the reasons why ER is such a powerful target for breast cancer treatment. The recent modest performance of a number of targeted therapies in breast cancer has raised the question whether we will ever develop therapies that have such success as antiestrogens. Targeted therapies tend to inhibit a single pathway that is probably altered in only a subset of patients. Even within this subset, only a limited number of patients respond. The evidence that virtually all pathways can cross-talk and that they exhibit several layers of redundancy reveals a complexity of signaling networks that may defy the generation of targeted therapies with efficacy similar to antiestrogens. However, there are clearly regulatory nodes that can integrate multiple upstream inputs and elicit diverse downstream outputs. We provide evidence and rationales for integrins, insulin receptor substrates (IRSs), and cyclin D1 as potential therapeutic targets. These proteins, similar to ER, can integrate and coordinate multiple signals in breast cancer cells and thus mediate diverse aspects of breast cancer progression. New treatment targets will emerge in light of more global models of signal transduction that fully integrate all aspects of cell biology such as the role of the extracellular matrix and will hopefully result in the development of targeted therapies that show efficacy similar to antiestrogens.

Breast Neoplasms↗

PubMed2002

Tumour angiogenesis pathways: related clinical issues and implications for nuclear medicine imaging.

Tumour angiogenesis is essential for growth, invasion and metastasis. Retrospective studies suggest that it is an independent prognostic factor that merits prospective validation. Furthermore, as tumour blood vessels show many differences from normal vessels and are not genetically unstable, they form a key area for therapy development. However, as anti-angiogenic therapy is primarily cytostatic and not cytotoxic, novel tailor-made specific end-points for treatment monitoring are required. In this regard, suitable molecular parameters for imaging tumour angiogenesis by means of nuclear medicine are being explored. Here we review current knowledge on the multiple pathways controlling tumour angiogenesis and try to assess which are the most clinically relevant for nuclear medicine imaging. Parameters that may influence the imaging potential of radiopharmaceuticals for angiogenesis imaging such as molecular weight and structure, their targeted location within the tumour and their usefulness in terms of specificity and constancy of the targeted molecular pathway are discussed.

Angiogenesis Inhibitors↗

PubMed2004

Isoniazid-induced hyperacute liver failure in a young patient receiving carbamazepine.

A 16-year-old female under long-term carbamazepine and clobazam therapy developed fulminant liver failure after initiating therapy with isoniazid, rifampin, and pirazinamide for intestinal tuberculosis. Liver failure was hyperacute (with a minimal interval between jaundice and encephalopathy) and occurred very shortly (5 days) after the start of antituberculous therapy. The patient recovered completely with conservative measures. Later, she tolerated carbamazepine, clobazam, rifampin, and pirazinamide without problems, thus confirming that liver failure was isoniazid-induced. Drug interaction between isoniazid and carbamazepine could explain the atypical presentation of this case.

Journal Article↗

PubMed2005

Developments in glucocorticoid therapy.

Recent evidence for a disease-modifying potential of low-dose glucocorticoids (GCs) in the treatment of rheumatoid arthritis has renewed the debate on the risk benefit ratio with this therapy. Two recent developments are described that might have a positive influence on these risk benefit ratios. One is the improvement in new GC compounds--designer GCs, alterations in bioactivity, and alterations in formulations. The other is a better understanding and management of the toxicity of GCs.

Animals↗

PubMed2004

Gene therapy meets vaccine development.

Therapeutic vaccines such as those used to combat cancer or persistent viral infection are required to reprogramme a downregulated immune system. This presents a difficult challenge for vaccine design and merits the development of novel immunization protocols. Currently, we know that mobilization of dendritic cells (DCs) to present antigens to T lymphocytes is crucial for effective immunization. Our increasing understanding of DC biology, coupled with the growing sophistication of viral vectors developed for gene therapy, makes more rational vaccine design an exciting possibility. Here we propose that engineering viral vectors to express antigens in activated DCs will provide the most effective vaccines for priming an immune response.

Animals↗

PubMed2004

The impact of cyclosporine on the development of immunosuppressive therapy for pediatric liver transplantation.

Since the introduction of cyclosporine into pediatric liver transplantation remarkable progress in patient and graft survival has been observed: survival rates 60%; acute (60%), steroid-resistant (22%) and chronic rejection (4%); infections (60%); and side effects (20%). Individualization of cyclosporine therapy complements the development of new immunosuppressive agents such as tacrolimus, mycophenolate mofetil, and sirolimus for specific indications. The ultimate goal of transplantation to achieve immunotolerance a waits future progress.

Acute Disease↗

PubMed2002

Hypoxia as a target for combined modality treatments.

There is overwhelming evidence that solid human tumours grow within a unique micro-environment. This environment is characterised by an abnormal vasculature, which leads to an insufficient supply of oxygen and nutrients to the tumour cells. These characteristics of the environment limit the effectiveness of both radiotherapy and chemotherapy. Measurement of the oxygenation status of human tumours has unequivocally demonstrated the importance of this parameter on patient prognosis. Tumour hypoxia has been shown to be an independent prognostic indicator of poor outcome in prostate, head and neck and cervical cancers. Recent laboratory and clinical data have shown that hypoxia is also associated with a more malignant phenotype, affecting genomic stability, apoptosis, angiogenesis and metastasis. Several years ago, scientists realised that the unique properties within the tumour micro-environment could provide the basis for tumour-specific therapies. Efforts that are underway to develop therapies that exploit the tumour micro-environment can be categorised into three groups. The first includes agents that exploit the environmental changes that occur within the micro-environment such as hypoxia and reduced pH. This includes bioreductive drugs that are specifically toxic to hypoxic cells, as well as hypoxia-specific gene delivery systems. The second category includes therapies designed to exploit the unique properties of the tumour vasculature and include both angiogenesis inhibitors and vascular targeting agents. The final category includes agents that exploit the molecular and cellular responses to hypoxia. For example, many genes are induced by hypoxia and promoter elements from these genes can be used for the selective expression of therapeutic proteins in hypoxic tumour cells. An overview of the various properties ascribed to tumour hypoxia and the current efforts underway to exploit hypoxia for improving cancer treatment will be discussed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Host-pathogen interactions in mycoplasma pathogenesis: virulence and survival strategies of minimalist prokaryotes.

Despite their very small genomes mycoplasmas are successful pathogens of man and a wide range of animal hosts. Because of the lack of effective therapeutics and vaccines, mycoplasma diseases continue to be a significant problem for public health as well as livestock production with major socio-economic consequences worldwide. Recent outbreaks and epidemiological studies predict that the incidence of human and animal mycoplasma diseases might increase which indicates the urgent need to develop new approaches for prevention and therapy. Development of such reagents, however, requires a solid understanding of the molecular biology of mycoplasma infections. Knowledge in this field has considerably increased during the past decade since new techniques have been developed and adapted to mycoplasmas that allow these organisms to be studied at the molecular level. Research on the two human pathogens Mycoplasma pneumoniae and Mycoplasma genitalium of which the genome sequences have recently been completed as well as the substantial number of studies carried out on the AIDS-associated mycoplasmas, Mycoplasma penetrans and Mycoplasma fermentans, has led the way, but a number of animal mycoplasmas are becoming increasingly appreciated as models for the study of the molecular basis of mycoplasma diseases. This review summarizes and highlights some of the recent findings concerning the molecular interactions that occur between pathogenic mycoplasmas and their hosts, both the common strategies as well as some unique approaches evolved by particular mycoplasma pathogens, including adherence to and uptake into non-phagocytic host cells, as well as mechanisms of escaping the host immune system.

Animals↗

PubMed1999

[Psychotherapy in depression].

The field of psychotherapies has in general widely evolved for these ten last years in France and more in depressive disorders treatment, namely owing to short structured therapies development and especially cognitive-behaviour therapies well fitted for controlled studies assessment. Pyschoanalytically oriented psychotherapies have also changed but not so much and they still remain less efficacious in this area. Henceforth the numerous technicals of this kind of therapy will be modified in the eclective and integrative approach; they must not be compared in opposition one another but used in a collaborative way on the basis of scientific data in order to make them more effective. So some very exciting prospects are open in the future of that field of research. Practically, nowadays the best outcomes are obtained in the association of both antidepressant drugs and cognitive-behavior psychotherapy.

Antidepressive Agents↗

PubMed2000

Morphological and cytogenetic changes in therapy-related leukemia developed in a t(8;21)-acute myeloid leukemia (M2) patient: sequential cytogenetic and molecular analyses.

A patient with acute myeloid leukemia (AML)-M2 with t(8;21)(q22;q22) achieved complete remission with remission-induction chemotherapy followed by consolidation and intensification chemotherapies. T(8;21)(q22;q22) disappeared, but chimeric AML1/MTG8 was continuously detected in bone marrow cells. Following the development of therapy-related leukemia after 1 year, evolution of therapy-related AML-M4 with t(11;17)(q23;q25) and the rearrangement of the MLL gene were observed, while AML/MTG8 disappeared. After reinduction and following intermittent chemotherapies, a subsequent alternative transformation to AML-M2 occurred after detection of t(3;21)(q21;q22), with a break in the AML1 gene shown by interphase fluorescence in situ hybridization analysis. This leukemia transformed to AML-M4 after t(9;22)(q34;q11), with a minor BCR/ABL rearrangement, and then finally to AML-M2. This therapy-related leukemia was resistant to chemotherapy. These findings indicate that alterations in cytogenetic and molecular events caused by chemotherapeutic agents contribute to the sequential evolution of new leukemic clones with different morphology.

Adult↗

PubMed1993

[Wagner von Jauregg and development of malaria therapy].

In this history of psychiatric therapy the progressive paralysis deserves special interest: for the first time an organic psychosis was treatable successfully by a procedure found by scientific methods. This article describes life and work of Julius Wagner, Ritter von Jauregg (1857-1940) and remembers the introduction of the malaria-therapy, which was developed by Wagner 75 years ago.

Austria↗