Our objective is to demonstrate and utilize the ability of nuclear magnetic resonance (NMR) to monitor the efficacy of radioimmunotherapy (RIT) on cancer. While the research proposed herein specifies the use of human tumors implanted in nude mice, the long-term objective is to develop protocols that will have application to human cancer patients. Specifically, this project proposes the use of 31P surface coil NMR to study sequentially the metabolic events manifested through alterations in high energy phosphate metabolites that occur during RIT of human tumors implanted in nude mice. Our group has demonstrated that syngeneic melanomas in mice could be cured using I-131-labeled monoclonal antibodies (MAbs) developed against this melanoma with survival of the animal. We have developed methods for producing, purifying and radiolabeling antibodies and fragments, and have examined the pharmacokinetic behavior in animals and patients of several MAbs against human melanoma, breast cancer, prostate cancer and lymphoma. We conclude that Lym-1 antibody against human B-cell lymphoma is the most attractive candidate for RIT in patients. In a pilot study human lymphoma implanted in nude mice was cured with I-131-Lym-1 MAb. We had dramatic success treating a moribund patient with lymphoma using I-131-Lym-1. Two doses of radiolabeled MAb reduced massive tumor by 80%; a third treatment is planned. We propose to use I-131-Lym-1 to irradiate human B-cell lymphoma implanted in nude mice and to observe subsequent changes in high energy phosphate metabolites using 31P surface coil NMR. Observations during our preliminary work suggest that the pattern of NMR spectral changes that accompany therapy may be predictive of success full RIT. We seek to substantiate our previous work on determining 31P NMR spectral changes that accompany both normal tumor growth as well as alterations following administration of radiolabeled antibody or fragments, and to expand the previous work to establish the effects of subcurative and fractionated dose schedules. In order to improve the characterization of the tumor status, NMR rotating frame experiments currently under development at UC Davis for delineation of tissue regions will be utilized to obtain spectra from discrete regions of the tumor. The significance of the research is its potential to further define the metabolic changes that occur in tumors during successful RIT, and to monitor these changes noninvasively to assist in determining the optimal frequency, spacing, and amounts of fractionated RIT for effective therapy. With the advent of whole body NMR spectrometers, the research may have direct clinical potential. The scope of this research is not intended to encompass the comprehensive radiobiological aspects of RIT, but specifically to delineate the changes in high energy phosphate metabolism that occur during successful RIT of specific tumors.
| DeNardo, G L; DeNardo, S J; O'Grady, L F et al. (1990) Radiation treatment of B cell malignancies with immunoconjugate. Front Radiat Ther Oncol 24:194-201;discussion 202-3 |
