Pizer, Barry Leonard;
(1992)
The development of targeted radiotherapy for central nervous system leukaemia.
Doctoral thesis (Ph.D.), Institute of Cancer Research.
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Abstract
The use of antibodies to specifically deliver cytotoxic agents to tumour cells has been widely investigated as a means of increasing the therapeutic index of cancer therapy. Nowhere is this more likely to be of benefit than in the treatment of central nervous system (CNS) tumours, in which damage to vital structures by conventional therapies often results in significant sequelae. Many factors have, however, been identified which limit the clinical success of such targeted therapies. Some of these obstacles may be avoided by the administration of therapeutic agents into a tumour-bearing body compartment. This thesis examines the potential of antibody-targeted radionuclide therapy in the treatment of meningeal leukaemia. Three monoclonal antibodies (MoAbs) binding to leukaemic cells were fully characterised, and conditions established for antibody labelling with the beta-emitting radionuclide, iodine-131. The specificity of antibody-mediated hUj therapy against a single cell suspension of leukaemic cell lines was demonstrated using an in-vitro cell survival assay. Additional experiments have suggested a relationship between the degree of cell kill and the amount of radioisotope bound to the cell surface. These results were supported by a mathematical model. In recognition of the limitations of in-vitro models, a small animal model of CNS leukaemia was established. Prolonged survival of animals treated with intrathecally administered 151I-MoAbs was observed, as compared to untreated controls. A multicentre phase I/II clinical study was initiated, in which a transient response to a single intrathecal injection of 131I-MoAbs was noted in six of seven children with CNS relapse of acute lymphoblastic leukaemia. Toxicity was 2 acceptable. The biodistribution of radioconjugates was examined and models developed for the estimation of radiation dose to both cerebrospinal fluid and normal tissues. The results of these investigations, together with those from the in-vitro model, have suggested strategies by which the efficacy of therapy may be improved.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | The development of targeted radiotherapy for central nervous system leukaemia. |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by Proquest |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10107905 |
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