Molecular and cellular investigations to optimise MIBG targeted radiotherapy for neuroblastoma

Información del proyecto

Identificador del acuerdo de subvención: BMH4983297

Proyecto cerrado

Fecha de inicio 1 Junio 1998

Fecha de finalización 31 Mayo 2001

Financiado con arreglo a

• Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

University of Glasgow
United Kingdom

Objetivo

Neuroblastoma is a cancer of childhood for which no improvement in cure rate has been achieved in recent years (Stiller, 1993). Significant advances have recently been made in identifying the genetic lesions, which characterise neuroblastoma and many of these are now routinely employed for diagnosis and as prognostic indicators. However, our improved understanding of the molecular peculiarities of neuroblastoma has not yet influenced therapy. The most promising new form of treatment of this malignancy is targeted radionuclide therapy using l3lI-conjugated metaiodobenzyl-guanidine (MIBG).

This radiopharmaceutical is selectively concentrated by tumour via ATPase-dependent process (variously known as noradrenaline transporter, NET, Uptake-1) which is responsible for the active accumulation of noradrenaline by sympathetic neurones and adrenal medullary cells. The recent description of the base sequence of the noradrenaline transporter gene (Pacholczyk et al, 1991) has facilitated the sensitive detection of its transcripts by reverse transcription-polymerase chain reaction (RT-PCR) (Montaldo et al, 1991). This has generated interest in the application of this molecular approach to the refinement of MIBG therapy (Mairs et al, 1994). We propose that the first direct clinical usage of this methodology should be for the rapid identification, via analysis of primary tumour biopsy specimens, of those neuroblastoma patients who are most likely to benefit from MIBG treatment. The evaluation of RT-PCR for patient selection will form part of a UKCCSG-coordinated study. However, an early indication of its usefulness can only be obtained through the cooperation of major European treatment centres, who would provide tumour samples for molecular examination. An important goal of research in the field of MIBG targeted radiotherapy is the development of strategies to enhance the uptake and retention of the radiopharmaceutical. Interferon-gamma has already been identified, using the above molecular technique, as a differentiation-inducing agent, which can increase neuroblastoma cellular concentration of MIBG in vitro via de novo synthesis of the specific transporter protein (Montaldo et al, 1992). Other maturation-inducing compounds will be sought and their mechanisms of potentiation of radiopharmaceutical uptake will be defined.

Although MIBG treatment for disseminated neuroblastoma is administered in conjunction with cytotoxic drug treatment, the potential ability of different chemotherapeutic regimes to influence radiopharmaceutical uptake by tumours is unknown. Since there are preliminary indications of up-regulation of tumour accumulation of MIBG by cytotoxic compounds in current clinical usage (Armour et al, 1996), we intend to undertake a detailed study of this phenomenon using the RT-PCR approach applied to cultured neuroblastoma cells to determine whether the modulation of genetic control is implicated. The most frequently encountered life-threatening side effect of MIBG treatment is thrombocytopenia. We will employ the RT-PCR methodology to establish whether or not the platelet precursors, megakaryocytes, act as MIBG accumulates by virtue of their expression of the noradrenaline transporter or other mono-amine carriers. This will lead to the development of means of circumventing thrombocyte depletion by selective transporter blockade. It is our objective to exploit the rapid molecular analysis afforded by the RT-PCR methodology to develop new clinical treatment approaches using MIBG targeting for neuroblastoma. This needs a concerted action between several European laboratories who have experience with the experimental models of this tumour. We believe that the proposed studies will allow us to devise the most rational use of MIBG in order to fulfil its therapeutic potential. 03

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias médicas y de la salud › medicina clínica › oncología

Programa(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Tema(s)

• 4.1.3 - Cell-selective targeting

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CON - Coordination of research actions

Coordinador

University of Glasgow

• Aportación de la UE: Sin datos
• Dirección: University Avenue ; G12 8QQ Glasgow ; Reino Unido
• Coste total: Sin datos