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Binding, internalization and excretion of TGF alpha-dextran associated radioactivity in cultured human glioma cells
A Lövqvist1, A Lindström, J Carlsson
1Department of Radiation Sciences, Uppsala University, Sweden.
Abstract:
Conjugates based on transforming growth factor alpha, TGF alpha, or epidermal growth factor, EGF, are candidates for targeted radiotherapy against EGF-receptor rich tumours such as gliomas or squamous carcinomas. In this study, binding, internalization and excretion of radiolabelled TGF alpha and TGF alpha-dextran conjugates was analysed in an EGF-receptor rich human glioma cell line. The binding of 125I-TGF alpha was EGF-receptor specific and the binding pattern was similar to that of 125I-EGF. The TGF alpha-dextran conjugate also bound specifically but gave maximum binding for a longer time during continuous incubation compared to when only TGF alpha was used. The excretion pattern of internalized radioactivity was somewhat slower for 125I-TGF alpha-dextran, with 125I-labelling on the TGF alpha part, as compared to 125I-TGF alpha although most of the radioactivity in both cases was excreted within 4 hours. The fate of the dextran part of the conjugate, as followed by means of 125I-labelling of the dextran, was different since all radioactivity in that case remained cell-associated for at least up to 22 hours. Furthermore, by comparison with previously published results, it was seen that the radioactivity delivered through the TGF alpha part of TGF alpha-dextran was retained for a shorter period of time by the cells than when delivered by EGF in EGF-dextran conjugates. However, when the radioactivity was delivered by the dextran part of the conjugates, the radioactivity seemed to be retained equally well or even better when TGF alpha-dextran was applied. It is concluded that TGF alpha-dextran, as well as EGF-dextran, have interesting properties for targeting against EGF-receptors and that the dextran part is well retained in the cells and therefore might be a suitable carrier for toxic agents such as radionuclides. It is of high interest to continue with toxicological and pharmacological in vivo studies of the conjugates.
Insights
Transforming growth factor alpha (TGF alpha)-dextran conjugates show promise for targeted cancer radiotherapy. The dextran component offers effective cell retention, making it a suitable carrier for radionuclides in EGF-receptor rich tumors.
Area of Science:
- Biochemistry
- Oncology
- Radiopharmaceuticals
Background:
- Transforming growth factor alpha (TGF alpha) and epidermal growth factor (EGF) conjugates are investigated for targeted radiotherapy.
- These conjugates target tumors rich in EGF receptors, such as gliomas and squamous carcinomas.
Purpose of the Study:
- To analyze the binding, internalization, and excretion of radiolabeled TGF alpha and TGF alpha-dextran conjugates.
- To evaluate their potential for targeted cancer therapy in an EGF-receptor rich human glioma cell line.
Main Methods:
- Radiolabeling of TGF alpha and TGF alpha-dextran conjugates with Iodine-125 (125I).
- Analysis of specific binding to EGF receptors in a human glioma cell line.
- Assessment of internalization and excretion patterns of the radiolabeled components.
Main Results:
- 125I-TGF alpha exhibited specific EGF-receptor binding, similar to 125I-EGF.
- TGF alpha-dextran showed specific binding with prolonged maximum binding time.
- Internalized radioactivity from the TGF alpha part was excreted within 4 hours, while the dextran part remained cell-associated for over 22 hours.
- Radioactivity from the dextran part of TGF alpha-dextran conjugates was retained as well as or better than EGF-dextran conjugates.
Conclusions:
- Both TGF alpha-dextran and EGF-dextran conjugates demonstrate potential for targeting EGF receptors.
- The dextran component exhibits excellent cell retention, making it a promising carrier for radionuclides.
- Further in vivo toxicological and pharmacological studies are warranted for these conjugates.