Use of multi‐cell spheroids of ovarian carcinoma as an intraperitoneal radio‐immunotherapy model: Uptake, retention kinetics and dosimetric evaluation

Abstract

The purpose of this study, using multi-cell spheroids as an in vitro model of micrometastases of ovarian carcinoma for i.p. radio-immunotherapy, was to measure the uptake and retention kinetics of 111In-labeled F(ab')2 fragments of OC125 monoclonal antibody (MAb) in spheroids of the NIH:OVCAR-3 cell line and to estimate absorbed doses with beta-emitting radionuclides (kinetics was assumed to be similar to that of indium-111). With 0.2-mm-diameter spheroids at different MAb concentrations the highest binding value was determined. Retention kinetics showed a biological half-life of 50 hr. These data were used to calculate absorbed doses by integration of Berger's latest-point kernels. Mean absorbed doses when spatial distribution was considered to be uniform at the surface (no penetration) or throughout the spheroid (total penetration) were, respectively, 247 and 417 Gy with 153Sm, and 90 and 135 Gy with 90Y. Thus, the use of a similar MAb concentration and specific activity in patients should lead to high absorbed doses in i.p. radio-immunotherapy of micrometastases.

The selection of antibodies for targeted therapy of small-cell lung cancer (SCLC) using a human tumour spheroid model to compare the uptake of cluster 1 and cluster w4 antibodies

“…A rapid phase of accumulation during the first 8 h was followed by only a small increase in uptake over the next 16 h. The decrease in uptake of radiolabelled antibody after 8 h was not due to exhaustion of the supply of antibody as only a small fraction of antibody in the incubation medium bound to spheroids. The results are similar to those reported in studies of human melanoma, colon and ovarian carcinoma spheroids (Kwok et al, 1988;Langmuir et al, 1990;Bardies et al, 1992) Distance (,jrm) NCAM, ERIC-1, which suggests that the different behaviour was due to interaction of the antibody with its antigen. It is possible that the 72a subclass of SWA 11 behaved differently from the y1 subclass of NY.3D 1.…”

“…However, when we used an IgG2a cluster 1 antibody we did not see any difference in penetration into the spheroid compared with the IgGl cluster I antibody (data not shown). Antibody uptake in tumour spheroid models can be improved by greatly increasing the concentration of the incubating antibody (Kwok et al, 1988;Langmuir et al, 1990;Bardies et al, 1992). Studies were performed with 1 gig ml-1 antibody, as this is a concentration that can be realistically maintained in the blood of patients for several hours.…”

“…The inability of antibodies to penetrate deeply into a tumour mass reduces the efficacy of radioimmunoconjugate therapy (Bardies et al, 1992). Much work has been devoted to studying factors that affect the uptake and penetration of anti-tumour antibodies in tumours, as they have an important bearing on the success of antibody-targeted therapy.…”

Incorporation of iododeoxyuridine in multicellular glioma spheroids: implications for DNA-targeted radiotherapy using Auger electron emitters

“…Multicellular tumour spheroids are a well-established model of prevascular microtumours that provide a means of studying the intratumour distribution of therapeutic agents and of determining the effect of alternative schedules of administration on cellular incorporation. They have previously been used extensively in targeted therapy research to investigate diffusion gradients of alternative targeting agents (Langmuir et al,199 1;Mairs et al,199 1), to assess efficacies of alternative modalities (Rotmensch et al, 1994) and modulating agents (Langmuir and Medonca, 1992), to evaluate microdosimetry (Bardies et al, 1992) and to provide experimental model systems for testing hypotheses (Gaze et al, 1992).…”

Cell-Level Dosimetry and Biologic Response Modeling of Heterogeneously Distributed Radionuclides: A Step Forward

“…The 10-fold-lower cell killing in 2D cultures is likely attributable to the lack of b-particle cross-fire (because there are no b-particle-emitting cells in planes above and below the cell monolayer) (13) and of a radiologic bystander effect (14), effects that are likely important in vivo. Although 3D spheroid cultures may recapitulate the radiobiologic response of avascular micrometastases more accurately than 2D cultures (15)(16)(17)(18)(19)(20), the response of more macroscopic structures (such as organs or bulk tumors) is likely not reliably modeled by spheroids. Spheroids are typically only 100-200 mm in diameter, considerably shorter than the range of most b-particles, and therefore a relatively large portion of a b-particle's energy is deposited outside the spheroid.…”