Current Pharmaceutical Design - Volume 6, Issue 14, 2000

After years of pre-clinical and clinical testing monoclonal antibodies (mAbs) finally offer new therapeutic choices for patients with haematological and solid malignancies both as unconjugated antibody and as vectors to target radionuclides in radioimmunotherapy (RIT). In recent years some of the most exciting clinical data have come from the use of RIT in the treatment of lymphoma and haematological malignancies and it would now appear highly likely that RIT will play a major role in the treatment strategies for these diseases. For the solid tumours there has also been considerable progress with RIT and mAbs have become a component of treatment protocols for breast cancer. This review highlights the important recent clinical progress that has been made with clinical RIT and provides some new insights into the important mechanisms of action of RIT in haematological malignancies.

For targeted radionuclide therapy to succeed as a single modality treatment, schemes must be devised which will enable the deposition in malignant cells of sterilising doses of radiation. Until such methods have been perfected, it is necessary to combine targeted radiotherapy in a rational manner with conventional anti-cancer treatments. Several means of delivery of therapeutic radionuclides are being evaluated but none of these yet appears to be as powerful as the simplest and most effective example, viz sodium ( 131 I)iodide treatment of disseminated thyroid carcinoma. The radiopharmaceutical ( 131 I)meta-iodobenzylguanidine ( 131 I MIBG) is an effective single agent for the treatment of neuroblastoma. However, uptake of the drug in malignant sites is heterogeneous, suggesting that this therapy alone is unlikely to cure disease. A growing body of experimental evidence indicates exciting possibilities for the integration of gene transfer with radionuclide targeting. This review covers aspects of the combination of gene manipulation and targeted radiotherapy, emphasising the potential of gene transfer to facilitate tumour targeting with low molecular weight radiopharmaceuticals.

Targeted radiotherapy or endoradiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor while sparing normal tissues. Radionuclides that decay by the emission of a-particles such as the heavy halogen astatine-211 ( 211 At) offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Herein, the radiobiological advantages of alpha-particle targeted radiotherapy will be reviewed, and the rationale for using 211 At for this purpose will be described. The chemistry of astatine is similar to that of iodine; however, there are important differences which make the synthesis and evaluation of 211 At-labeled compounds more challenging. Perhaps the most successful approach that has been developed involves the astatodemetallation of tin, silicon or mercury precursors. Astatine-211 labeled agents that have been investigated for targeted radiotherapy include ( 211 At)astatide, 211 At- labeled particulates, 211 At-labeled naphthoquinone derivatives, 211 At-labeled methylene blue, 211 At-labeled DNA precursors, meta-[211 At]astatobenzylguanidine, 211 At-labeled biotin conjugates, 211 At-labeled bisphosphonates, and 211 At-labeled antibodies and antibody fragments. The status of these 211 At-labeled compounds will be discussed in terms of their labeling chemistry, cytotoxicity in cell culture, as well as their tissue distribution and therapeutic efficacy in animal models of human cancers. Finally, an update on the status of the first clinical trial with an 211 At-labeled targeted therapeutic, 211 At-labeled chimeric anti-tenascin antibody 81C6, will be provided.

Targeted radiotherapy using Auger electron-emitting pharmaceuticals offers both advantages and challenges compared to alternative alpha - or beta -emitting agents. The low energy Auger electrons deposit their energy within the target cell thereby minimizing collateral damage. To achieve this effect, however, the radiopharmaceutical must incorporate the appropriate radionuclide, be efficiently synthesized, and once administered, be distributed selectively to its biological target. This review covers the synthesis of agents which have prepared over the past decade either as Auger electron-emitting radiopharmaceuticals or which have the potential as such. While not an exhaustive review, the major classes of agents, such as hormone receptor ligands, nucleoside analogs and intercalating agents are described.

Dosimetry in targeted radiotherapy (TR) uses different calculation methods, whose degree of refinement is closely conditioned by the particular objective sought.It is more generally performed to establish a correlation between the quantity of radiation delivered to a target and the biological damage observed or that can be reliably predicted.It can thus be used to optimise treatments and allow comparison of different therapeutic approaches, as well as to study the basic methods of irradiation of biological matter.Two broad types of investigations can be found in the literature: microdosimetric ones (stochastic approaches used to study energy deposits) and macrodosimetric ones (non-stochastic or deterministic approaches). The mathematical formalism is consistent between these two types, and the calculation methods currently used are often similar.This review presents different approaches to the dosimetry of radionuclides used in TR.The introduction defines the general problem, the role of dosimetry in TR and the specific problems raised by targeting (non-uniformity of source distributions).The first part considers the types of calculation methods found in TR in relation to the basic quantities used to represent stochastic energy deposit on a cellular scale. In particular, it compares the formalism and the methods used in microdosimetric or conventional macrodosimetric approches. Although microdosimetry, or even track structure calculations, can provide the basic elements for modelling the absorbed dose process, a simplified dosimetric approach may be adequate to describe the phenomena observed. The scheme proposed by the MIRD committee relates to such an approach and is presented together with other methods allowing the calculation of the mean dose delivered (analytic methods, dose point kernels, Monte-Carlo, etc. ).The second part shows the application range for the various methods, providing selected examples of dosimetric approaches in TR on different scales, from the organ (or tissues) to the cell or even DNA, and a brief presentation of bone marrow dosimetry.