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R Cowen

Publications and source records attributed to R Cowen.

7 recordsLinked to original sources
PubMed2003

Current and future strategies for the treatment of malignant brain tumors.

Glioblastoma (GB) is the most common subtype of primary brain tumor in adults. These tumors are highly invasive, very aggressive, and often infiltrate critical neurological areas within the brain. The mean survival time after diagnosis of GB has remained unchanged during the last few decades, in spite of advances in surgical techniques, radiotherapy, and also chemotherapy; patients' survival ranges from 9 to 12 months after initial diagnosis. In the same time frame, with our increasing understanding and knowledge of the physiopathology of several cancers, meaningful advances have been made in the treatment and control of several cancers, such as breast, prostate, and hematopoietic malignancies. Although a number of the genetic lesions present in GB have been elucidated and our understanding of the progressions of this cancer has increased dramatically over the last few years, it has not yet been possible to harness this information towards developing effective cures. In this review, we will focus on the classical ways in which GB is currently being treated, and will introduce a novel therapeutic modality, i.e., gene therapy, which we believe will be used in combination with classical treatment strategies to prolong the life-span of patients and to ultimately be able to control and/or cure these brain tumors. We will discuss the use of several vector systems that are needed to introduce the therapeutic genes within either the tumor mass, if these are not resectable, or the tumor bed, after successful tumor resection. We also discuss different therapeutic modalities that could be exploited using gene therapy, i.e., conditional cytotoxic approach, direct cytotoxicity, immunotherapy, inhibition of angiogenesis, and the use of pro-apoptotic genes. The advantages and disadvantages of each of the current vector systems available to transfer genes into the CNS are also discussed. With the advances in molecular techniques, both towards the elucidation of the physiopathology of GB and the development of novel, more efficient and less toxic vectors to deliver putative therapeutic genes into the CNS, it should be possible to develop new rationale and effective therapeutic approaches to treat this devastating cancer.

Animals↗
PubMed2000

Gene therapy strategies for intracranial tumours: glioma and pituitary adenomas.

Intracranial tumours such as brain gliomas and pituitary adenomas pose a challenging area of research for the development of gene therapy strategies, both from the point of view of the severity of the diseases, to the physiological implication of gene delivery into the central nervous system and pituitary gland. On the one hand, brain gliomas are very malignant tumours, with a life expectancy of six months to a year at the most after the time of diagnosis, in spite of advances in treatment modalities which involve chemotherapy, surgery and radiotherapy. Gene therapy for these tumours is therefore a very attractive therapeutic modality which due to the severity of the disease is already in clinical trials. On the other hand, pituitary tumours are usually benign, and in most cases, treatment is successful. Nevertheless, there are some instances, especially with the macroadenomas and some invasive tumours in which treatment fails. Gene therapy strategies for these adenomas therefore needs to progress substantially in terms of safety, adverse side effects and physiological impact on the normal pituitary gland before clinical implementation. In this paper, we will review gene delivery systems both viral and non-viral and several therapeutic strategies which could be implemented for the treatment of these diseases. These include cytotoxic approaches both conditional and direct, immune-stimulatory strategies, anti-angiogenic strategies and approaches which harness pro-apoptotic and tumour suppressor gene targets. We will also review the models which are currently available in which these gene therapy strategies can be tested experimentally. This new therapeutic modality holds enormous promise, but we still need substantial improvements both from the delivery, efficacy and safety stand points before it can become a clinical reality.

Adenoma↗
PubMed1996

Coamplification in tumors of KRAS2, type 2 inositol 1,4,5 triphosphate receptor gene, and a novel human gene, KRAG.

Analysis of a region of DNA, coamplified in tumors with KRAS2, resulted in the identification of the human homologue of the mouse KRAG gene. The gene was widely expressed in a range of cell lines, tumors, and normal tissue and demonstrated a high degree of alternate splicing. A human KRAG cDNA sequence, with a structure similar to that encoded by the amplified gene in mouse Y1 adrenal carcinoma cells, was isolated by RT-PCR. The predicted amino acid similarity between the two sequences was 91%, and hydrophobicity plots suggested a structure closely resembling that of transmembrane 4 superfamily members. Identification of a PCR-based restriction fragment length polymorphism confirmed biallelic expression of KRAG but suggested allele-specific splicing differences in tumors. Northern analysis of mRNA derived from a range of tissues suggested high level expression in muscle and confirmed alternate splicing. To facilitate the analysis of exon junctions, a YAC clone encoding the genomic sequence was identified. This allowed the localization of KRAG to human chromosome 12p11.2. Isolation of one end of this nonchimeric clone demonstrated a perfect match with a 247-bp sequence within the 3' untranslated region of the type 2 1,4, 5-inositol triphosphate receptor gene. Multiplex PCR confirmed the inclusion of both genes in the KRAS2 amplicon in human malignancy, suggesting that either may contribute to the malignant phenotype.

Alleles↗