Most currently existing methods used to determine doses during radioimmunotherapy (RIT) often rely on the false assumption of a spatially homogeneous radio-innumoconjugate (RIC) distribution throughout the tumor. Such methods often are based on the MIRD formalism which is inadequate to describe the pattern of energy deposition at the level of resolution of individual cells. New calculation models are essential for the development of rational strategies in RIT. We propose to develop an integrated approach to high resolution alpha and beta particle RIC dosimetry which will define the 3-D pattern of energy deposition at the cell nuclear level. Dosimetry will be performed on tissue samples taken from congenic mice inoculated with the Thy 1.2+ murine tumor cell line EL-4 and subsequently treated with anti-Thy1.2 antibodies labeled with Y- 90 (for beta particle therapy) or Bi-212 (for alpha particle therapy) via a number of injection routes. Two complementary dosimetric approaches will be used: (1). Methodologies will be developed for a 3-D reconstruction of the radiolabel coordinates in relation to the tumor cell nuclei targets based on data obtained by computer-assisted image analysis performed on serial tumor tissue sections and autoradiographs. A Monte-Carlo method will be used to evaluate the energy deposition to the individual tumor cell nuclei from all surrounding radiolabels so that a 3-D distribution of dose to each individual target nucleus is defined. (2). A new type of real-time miniature solid state radiation probe (outer diameter approx. 0.5 mm) will be developed for insertion into tumor and normal tissue structures. This probe will be based on field effect transistor technology and works on the model of electron traps as in thermoluminescent dosimetry (TLD). Unlike TLD technology, these probes can provide continuous readings of total dose and dose-rates achieved within the tissue during RIT. By performing parallel clonogenic cell-survival assays on cells taken from RIC-treated animals, we will confirm experimentally the radiobiologic predictions obtained using these new approaches to RIC dosimetry. The overall goal of this proposal is to allow rigorous determinations of energy deposition patterns after alpha and beta particle RIT in mice and to use parallel radiobiologic cell-survival assays to interpret these data. The dosimetric tools developed here will be appropriate for later application to clinical radio-immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA050886-01
Application #
3195498
Study Section
(SRC)
Project Start
1989-08-01
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Gladstone, D J; Chin, L M (1995) Real-time, in vivo measurement of radiation dose during radioimmunotherapy in mice using a miniature MOSFET dosimeter probe. Radiat Res 141:330-5
Humm, J L; Macklis, R M; Lu, X Q et al. (1995) The spatial accuracy of cellular dose estimates obtained from 3D reconstructed serial tissue autoradiographs. Phys Med Biol 40:163-80
Humm, J L; Macklis, R M; Yang, Y et al. (1994) Image analysis for the study of radionuclide distribution in tissue sections. J Nucl Med 35:1217-25
Gladstone, D J; Lu, X Q; Humm, J L et al. (1994) A miniature MOSFET radiation dosimeter probe. Med Phys 21:1721-8
Palayoor, S T; Humm, J L; Atcher, R W et al. (1993) G2M arrest and apoptosis in murine T lymphoma cells following exposure to 212Bi alpha particle irradiation. Nucl Med Biol 20:795-805
Lu, X Q; Chin, L M (1993) Sampling techniques for the evaluation of treatment plans. Med Phys 20:151-61
Humm, J L; Chin, L M (1993) A model of cell inactivation by alpha-particle internal emitters. Radiat Res 134:143-50
Macklis, R M; Beresford, B A; Palayoor, S et al. (1993) Cell cycle alterations, apoptosis, and response to low-dose-rate radioimmunotherapy in lymphoma cells. Int J Radiat Oncol Biol Phys 27:643-50
Humm, J L; Roeske, J C; Fisher, D R et al. (1993) Microdosimetric concepts in radioimmunotherapy. Med Phys 20:535-41
Humm, J L; Macklis, R M; Bump, K et al. (1993) Internal dosimetry using data derived from autoradiographs. J Nucl Med 34:1811-7

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