Single-agent
radioimmunotherapy (RIT) has proven efficacy as a treatment for
hematological malignancies, particularly
non-Hodgkin's lymphoma. Although promising, RIT has been less effective for solid
tumors, in part because they are less radiosensitive.
Bone marrow transplantation permits the administration of larger
radiopharmaceutical doses, but the results of
bone marrow transplantation-supported RIT for solid
tumors have been marginal. The purpose of this publication is to provide an overview of promising RIT strategies for solid
tumors. It is apparent that combination
therapy is required, but optimization of the
radiopharmaceutical should be the first step. Metallic
radionuclides provide higher
tumor radiation doses but not necessarily an improved therapeutic index, that is, the ratio of
tumor:normal tissue radiation doses. Biodegradable
peptide linkers between the chelated
metal and the antibody improve the therapeutic index. Further improvements depend on identification of synergistic
therapies which recognize that: (a) continuous, low-dose
radionuclide therapy acts through apoptosis; and (b) apoptosis is often blocked because most
tumors have ineffective p53 and increased Bcl-2.
Taxanes are particularly attractive as synergistic agents for RIT because they induce cell cycle arrest in the radiosensitive G2-M phase and p53-independent apoptosis. Optimal sequence and timing for combined modality RIT are critical to achieve synergy. Data from preclinical and clinical studies will be reviewed to illustrate the potential of these strategies.