Cytotoxicity of α-particle-emitting astatine-211-labelled antibody in tumour spheroids: no effect of hyperthermia

Abstract

Summary The high linear energy transfer, a-particle-emitting radionuclide astatine-211 (21'At) is of interest for certain therapeutic applications; however, because of the 55-to 70-jim path length of its a-particles, achieving homogeneous tracer distribution is critical. Hyperthermia may enhance the therapeutic efficacy of a-particle endoradiotherapy if it can improve tracer distribution. In this study, we have investigated whether hyperthermia increased the cytotoxicity of an 21'At-labelled monoclonal antibody (MAb) in tumour spheroids with a radius (approximately 100 gm) greater than the range of 21'At a-particles. Hyperthermia for 1 h at 420C was used because this treatment itself resulted in no regrowth delay. Radiolabelled chimeric MAb 81C6 reactive with the extracellular matrix antigen tenascin was added to spheroids grown from the D-247 MG human glioma cell line at activity concentrations ranging from 0.125 to 250 kBq ml-'. A significant regrowth delay was observed at 125 and 250 kBq ml-' in both hyperthermia-treated and untreated spheroids. For groups receiving hyperthermia, no increase in cytotoxicity was seen compared with normothermic controls at any activity concentration. These results and those from autoradiographs indicate that hyperthermia at 420C for 1 h had no significant effect on the uptake or distribution of this antitenascin MAb in D-247 MG spheroids.Keywords: monoclonal antibody; hyperthermia; spheroid; astatine-21 1; a-emitterThe use of a-particle-emitting radionuclides for endoradiotherapy has several potential advantages compared with 1-emitters. The high linear energy transfer (LET) of a-particles makes them highly cytotoxic, rendering even hypoxic cells vulnerable. In addition, a-particles have relatively short effective path lengths in tissue, decreasing the radiation delivered to normal tissues located in close proximity to the tumour. For example, the mean path length of the a-particles emitted by 7.2-h half-life 21'At is 55-70 gm compared with 800 gm for the 5-particles emitted by '3'I (Gaze et al, 1992;. In contrast, the short a-particle range is potentially problematic because of the necessity for achieving homogeneous distribution of the radionuclide in the tumour for effective therapy. The limited range of a-particles has led investigators to focus therapeutic applications in which the tumour is present in thin sheets, such as neoplastic meningitis and peritoneal metastasis. The efficacy of 21'At-labelled monoclonal antibodies (MAbs) in a rat model of neoplastic meningitis has been encouraging .Micrometastatic disease could offer another potential application of a-emitters if sufficiently homogeneous tracer distribution could be achieved. The determination of the most appropriate radionuclide for the treatment of small volume disease has been the focus of both experimental and theoretical studies (Humm and Cobb, 1990;Langmuir et al, 1990; 1992a higher absorbed dose fraction within the tumour compared with long-range 3-emitters such as 90Y, particularly for lesions of less than...

Astatine-211-Labeled Radiotherapeutics An Emerging Approach to Targeted Alpha-Particle Radiotherapy

“…For example, the α-particles of 211 At have an LET mean of ~97 keV/µm compared with a value of 0.22 keV/µm for 90 Y, probably the highest energy β-emitter being used for targeted radiotherapy. This is an important difference from an endoradiotherapy perspective because the LET mean of 211 At occurs where the relative biological effectiveness of radiation is highest (Fig.…”

“…A subsequent study compared the therapeutic efficacy of the 211 At-tellurium colloid to 165 Dy ferric hydroxide macroaggregates, 90 Y citrate, and 32 P chromic phosphate [37], β-emitting radiocolloids that have been used in the past in clinical endoradiotherapy. With 211 At-tellurium colloid, animals were cured of their murine ovarian carcinoma with doses of only 25-50 µCi.…”

“…Fig. 1 compares the maximum range of 211 At α-particles [1]with 131 I and 90 Y β-particles [2] in the context of 20-µm tumor cells. Clearly, the fraction of the radiation dose which is deposited in the tumor declines for the β-emitters as the tumor size decreases.…”

“…The vast majority of endoradiotherapeutic investigations, particularly in patients, have involved radionuclides such as 131 I and 90 Y that decay by the emission of β-particles. Fig.…”

“…Clearly, the fraction of the radiation dose which is deposited in the tumor declines for the β-emitters as the tumor size decreases. Humm [3] has calculated that the 211 At: 90 Y fractional absorbed dose ratio would be 9 and 33 for 1000 µm-and 200 µm-diameter tumors, respectively. The advantage under single-cell conditions is even more striking; more than 1,000 times fewer cell-surface disintegrations of 211 At would be needed compared with 90 Y to achieve a similar degree of cell killing [4].…”