Enhancement of radiation dose to the nucleus due to vesicular internalization of I-125 labeled A33 monoclonal antibody
- Memorial Sloan-Kettering Cancer Center, New York, NY (United States); and others
Isotopes which emit low energy electrons deposit a decreasing gradient of local energy as a function of distance from the isotope. Therefore if antibodies internalize and transport such isotopes to close proximity of the nucleus, an additional therapeutic advantage will be realized. We studied the subcellular distribution of a internalizing antibody, A33, which detects a restricted determinant on colon cancer cells, using fluorescent microscopy of fluorescinated A33. We developed a physical model to assess the dose deposited in the nucleus by electrons emitted from radiolabeled A33 accumulated inside vesicles. This model is based on the energy range relationship of electrons in water. Also, we developed another model to calculate the radiation dose to the nucleus from electrons emitted from extracellular space. The percent A33 bound to membrane and internalized were determined in-vitro at various time points. Cytotoxicity experiments were performed with I-125 and I-131 labeled A33 at various concentrations and specific activities. A33 accumulates in cytoplasmic vesicles (40% of total bound) which transports the activity close to the nucleus, and increases the radiation dose to the cancer cell nucleus by a factor of three compared to the average dose calculated based on the assumption of a uniform distribution on the cell membrane. We also show that the cytoplasm of antigen negative normal cells shield the nucleus from the electrons emitted from extracellular I-125. This shielding is 30 times less for I-131. The cytotoxicity experiment showed 10% cell survival with 10 microCi/ml of I-125-A33, but 90% survival with 100 microCi/ml of I-125-A33 in the presence of a 100 fold excess of cold A33. Similar experiments with I-131 were cytotoxic in both cases. The results of the cytotoxicity experiment is in agreement with the physical model and suggest the basis for an improvement in the ratio of tumor to marrow radiation dose by clinical use of I-125-A33.
- OSTI ID:
- 441590
- Report Number(s):
- CONF-950603-; ISSN 0161-5505; TRN: 96:002093-0015
- Journal Information:
- Journal of Nuclear Medicine, Vol. 36, Issue Suppl.5; Conference: 42. annual meeting of the Society of Nuclear Medicine, Minneapolis, MN (United States), 12-15 Jun 1995; Other Information: PBD: May 1995
- Country of Publication:
- United States
- Language:
- English
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