Application of cytokine intervention for improved radio-antibody dose delivery

Abstract

The goal of our studies was to determine whether administration of IL-1/GM-CSF to mice could reduce radio-antibodyinduced myelosuppression and allow either dose escalation of radio-antibody using 131 The potential efficacy of radiolabeled antibodies as a cancer therapeutic is dependent on the maximal tolerated dose (MTD) that can be achieved and on the frequency at which doses can be administered. Two factors influencing both the MTD and the dose frequency are the radionuclide and the form of immunoglobulin used.A variety of radionuclides are under investigation for radioimmunotherapy (RAIT), and several advantages and disadvantages of each have been reviewed (Goldenberg, 1993). The availability of each radionuclide and the physical characteristics vary, each radionuclide decaying at a characteristic rate, with the release of distinct radio-active emissions and with differences in the distance that their particles travel in tissue. The b decay from 131 I travels a relatively short distance (,1 mm), and its maximum energy of decay is only 806 keV. Other b-emitting radionuclides, such as 90 Y and 188 Re, have a higher maximum energy (2,270 and 2,120 keV, respectively) and diffuse their radiation effect over a larger distance within tissues, having maximum path lengths of up to a few millimeters. The objective in selecting a radionuclide for a particular therapeutic application is to maximize the tumor radiation dose while sparing radiation-sensitive tissues from circulating radiolabeled antibody (Ab). The choice of nuclide, therefore, is in part dependent on (i) tumor size, which affects cross-fire and the energy-absorbed fraction, and (ii) binding heterogeneity (Humm, 1986;Howell et al., 1989). Shorter-range emitters are considered appropriate for smaller tumor masses since they maximize local energy deposition. For larger tumor burdens (diameter .1 cm), they would be unable to produce high enough dose levels in certain regions within the tumor that are antigen-negative or where the Ab is unable to penetrate.Selection of the form of immunoglobulin is another variable to be optimized for effective RAIT. Analysis of the pharmacokinetics of intact Ab and its fragments reveals a shorter plasma half-life (t 1/2 ) and less non-specific retention by non-tumor tissue of bivalent and monovalent fragments (Covell et al., 1986). As a result of the faster clearance rate of fragments, the radiation dose to blood is also much lower than that of the intact Ab. Therefore, a higher dose of radiolabeled fragment can be administered to a mouse (e.g., 1,200 µCi 131 I-F[ab8] 2 vs. 275 µCi 131 I-IgG).Unlike external beam irradiation, radiation energy in RAIT is imparted at a low dose rate over several days to weeks to tissues from internally distributed sources. The total radiation dose delivered and the rate of energy deposition in individual tissues are determined by the biodistribution of the administered radionuclide and the physical characteristics of the emitted particles. Among many influential variables, Ab biodistribution is...

Therapeutic efficacy and dose‐limiting toxicity of auger‐electron vs. beta emitters in radioimmunotherapy with internalizing antibodies: Evaluation of 125I‐ vs. 131I‐labeled CO17‐1A in a human colorectal cancer model

“…In good accord with earlier observations with 131 I-iodinated IgG (e.g., Behr et al, 1997e;Blumenthal et al, 1997), the blood-based maximum tolerated red marrow dose was found to be at approximately 17 Gy for 131 I-17-1A. Depending on the fraction of 125 I being internalized into the bone marrow cells and the extent of photon contribution, blood doses range between 10 and 24 Gy for 125 I-CO17-1A, which is well in the same range.…”

Anti-oxidant vitamins reduce normal tissue toxicity induced by radio-immunotherapy

“…Previous studies have shown that cytokines (IL‐1, GM‐CSF) can also be used for dose intensification of RAIT (Blumenthal et al 1997, Blumenthal et al 1999). The efficacy of this method of intervention is limited to alleviating hematopoietic damage but does not affect GI toxicity or any other normal tissue injury.…”

Bioeffects of moderate-intensity static magnetic fields on cell cultures

“…This could help to explain why substrate adhesion is influenced by SMFs. Once again, the use of different fields can give different results, as for example with the inhibition of fibroblast adhesion in the presence of 60 and 1000 Hz EMFs, and melanoma cell adhesion in the presence of an SMF using a 4.7-T superconducting magnetic resonance imaging (MRI) magnet (Blumenthal et al, 1997b;Short et al, 1992).…”