Radionuclide-antibody conjugates for single-cell cytotoxicity.
BACKGROUND
Radioimmunotherapy has primarily utilized high-energy beta-particles, which are intended to kill macroscopic tumor masses. Such conjugates do not kill single cells or micrometastases efficiently. For killing single cells, it may be preferable to use radiation with a much shorter path length, such as alpha-particles or Auger or conversion electrons.


METHODS
This selective review focuses on the use of radiolabeled antibody (Ab) conjugates to achieve single-cell kill. The advantages and disadvantages of particular types of radionuclides, the significance of intracellular localization of the Ab, and the potential clinical application of this approach are discussed. Potentially useful radionuclides are listed.


RESULTS
Auger and conversion electrons can kill cells effectively, with at least 6 logs of cell kill. Abs on the cell surface are only slightly less potent than Abs internalized into the cytoplasm, and this is consistent with theoretical considerations. alpha-Particles kill single cells very effectively, but the short half-lives of the available alpha-particle emitters are probably a disadvantage. High-energy beta-particles can also kill single cells if they bind in sufficient amounts, but their disadvantage appears to be greater nonspecific toxicity.


CONCLUSIONS
Single-cell kill can be obtained with radionuclide-Ab conjugates. The selection of the optimal radionuclide may depend on the details of the clinical situation, such as the size and accessibility of the tumor burden, and the particular Ab to be used. Direct comparisons of various radionuclides are required in order to identify the optimal approach. However, for single-cell kill, as required for therapy of micrometastases, the use of Auger and conversion electron emitters appears to have substantial advantages. While current methods limit the applicability of this approach to Abs having a high level of binding, it may be applicable to lower-density antigens if higher specific activities or more potent radionuclides can be used. Tumor cure may require a mixture of radionuclides intended to kill both single cells and large tumor masses.
Mattes
M Jules
MJ
Garden State Cancer Center, Belleville, New Jersey 07109, USA. mjmattes@gscancer.org
D000512:Alpha Particles; D000818:Animals; D001610:Beta Particles; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004583:Electrons; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D011868:Radioisotopes / Q000494:pharmacology*; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured
D018796:Immunoconjugates; D011868:Radioisotopes