Colon cancer is very difficult to treat once it has spread beyond the primary site. Because of the poor results with systemic chemotherapy, it is essential to find other forms of therapy. Radioimmunotherapy (RIT) is an active field of research. The availability of several antibodies (Abs) to colon cancer-associated antigens makes this tumor a potential candidate for RIT. Little is known about the pattern of Ab penetration into tumors and the resulting heterogeneous dose distributions and their biological effectiveness.
The Specific Aims of this project are: 1. To evaluate the kinetics of Ab delivery, penetration and uptake into tumors. 2. To elucidate the dosimetry of RIT at the cellular level and to create models to allow dose prediction, 3. To investigate the effect of different Abs and isotopes in defined experimental models. Four human colon cancer cell lines will be used in this project, grown as multicellular spheroids and as xenografts in nude mice. The spheroid model comprises a heterogeneous population of cells representative of micrometastases and tumor micro- environments in vivo. Results in spheroids can then guide in vivo experiments. Several monoclonal Abs to carcino-embryonic antigen (CEA) and their fragments will be used.
Specific Aim 1 will be addressed by incubating spheroids for varying times with I-125- labelled Ab. Penetration will be assessed by autoradiography and immunofluorescence. Similar experiments will be performed in nude mice.
Specific Aim 2 is being addressed by the construction of two mathematical dosimetry models, one for micrometastases, the second for vascularized tumors. The effect of overlapping dose distributions from multiple areas of isotope deposition and the effects of varying concentrations of isotope in the tumor will be analyzed with these models. The model will be evaluated for several beta- emitters of potential use in RIT. Miniature thermoluminescent dosimeters will be used to determine actual absorbed dose in both spheroids and xenografts. Correlations will be made with Ab distribution as determined by autoradiography and comparisons will be made with the predicted dose from the models.
For Specific Aim 3. RIT experiments will be performed in spheroids and xenografts using isotopes and Abs (intact vs. fragments) that are predicted to be useful by earlier studies. Growth delay and clonogenic survival assays will be used as end points. At the completion of this project, planned directions will be: 1. the evaluation of tumors other than colon cancer, 2. research on combined modality therapy and 3. the development of clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA052285-02
Application #
3459885
Study Section
Radiation Study Section (RAD)
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Sri International
Department
Type
DUNS #
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
Langmuir, V K (1996) The use of radioimmunotherapy in combination with bioreductive agents. Recent Results Cancer Res 141:137-43
Langmuir, V K; Rooker, J A; Osen, M et al. (1994) Synergistic interaction between tirapazamine and cyclophosphamide in human breast cancer xenografts. Cancer Res 54:2845-7
Langmuir, V K; Fowler, J F; Knox, S J et al. (1993) Radiobiology of radiolabeled antibody therapy as applied to tumor dosimetry. Med Phys 20:601-10
Langmuir, V K; Wessels, B W; Mendonca, H et al. (1992) Comparisons of sectioned micro-TLD dose measurements with predicted dose from 131I-labeled antibody. Med Phys 19:1213-6
Langmuir, V K; Mendonca, H L (1992) The combined use of 131I-labeled antibody and the hypoxic cytotoxin SR 4233 in vitro and in vivo. Radiat Res 132:351-8
Langmuir, V K; Mendonca, H L; Vanderheyden, J L et al. (1992) Comparisons of the efficacy of 186Re- and 131I-labeled antibody in multicell spheroids. Int J Radiat Oncol Biol Phys 24:127-32
Langmuir, V K; Mendonca, H L; Woo, D V (1992) Comparisons between two monoclonal antibodies that bind to the same antigen but have differing affinities: uptake kinetics and 125I-antibody therapy efficacy in multicell spheroids. Cancer Res 52:4728-34