The overall objective of the proposed research is to develop new strategies in radiation oncology using the Auger effect of iodine-125 and the alpha emissions of astatine-211. We will also synthesize and evaluate the cytotoxicity of radiolabeled steroids and peptide hormones. We will expand our understanding of receptor-mediated cytotoxicity using iodinated steroid hormones and their analogues. We will apply the strategies developed for breast cancer to other steroid receptor containing tumors (viz., endometrium and prostate). Both approaches offer the potential of specifically localizing lethal amounts of ionizing radiation within target tumors while sparing the surrounding normal tissue. We will synthesize position specific, carrier-free 125-I-labeled estrogens and progestins with high receptor affinity, prolonged nuclear retention time and low non-specific binding. The goals can be accomplished using flourine substituted estrogen, 11b-methoxy substitutions and mesylate/chloromethyl derivatives. We will synthesize several progesterones including fluorinated derivatives, iodo- megesterol, an agent with enhanced PgR affinity, and iodomibolerone which binds to both progesterone and androgen receptors. We will synthesize 211-At-labeled steroids and peptide hormones (viz., prolactin and oxytocin) which, on the basis of 125-I studies, show high receptor affinity for breast cancer cells. We will also determine the cytotoxicity of these compounds in breast cancer cell lines. We will study the in vivo distribution and therapeutic activity of 125-I and 211-At labeled steroid and peptide ligands in experimental tumor models - MCF-7 cells in athymic mice, DMBA mammary tumors, LNCaP prostatic carcinoma and MTW9 mammary adenocarcinoma. This proposal aims to answer general quantitative questions about the potential use of Auger and alpha emitters for radiation therapy. The research has significance at two levels - in the field of oncology, the emphasis is on the possibility of using the radiotoxicity of Auger and alpha emitters for cancer treatment; in the field of cellular and molecular radiation biology, the emphasis is on the mechanism of action of alpha particles and the Auger effect.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA037553-04A2
Application #
3175341
Study Section
Radiation Study Section (RAD)
Project Start
1984-04-01
Project End
1992-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Overall Medical
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Epperly, M W; Damodaran, K M; McLaughlin, W H et al. (1991) Radiotoxicity of 17 alpha-[125I]iodovinyl-11 beta-methoxyestradiol in MCF-7 human breast cancer cells. J Steroid Biochem Mol Biol 39:729-34
McLaughlin, W H; Pillai, K M; Edasery, J P et al. (1989) [125I]iodotamoxifen cytotoxicity in cultured human (MCF-7) breast cancer cells. J Steroid Biochem 33:515-9
McLaughlin, W H; Milius, R A; Pillai, K M et al. (1989) Cytotoxicity of receptor-mediated 16 alpha-[125I]iodoestradiol in cultured MCF-7 human breast cancer cells. J Natl Cancer Inst 81:437-40
McLaughlin, W H; Thramann Jr, W M; Lambrecht, R M et al. (1988) Preliminary observations of malignant melanoma therapy using radiolabeled alpha-methyltyrosine. J Surg Oncol 37:192-7
Blumenthal, R D; McLaughlin, W H; Jordan, J J et al. (1988) Mouse ovarian tumor cells: an experimental model for progestin-mediated radiotherapy. J Surg Oncol 39:96-100
Blumenthal, R; McLaughlin, W; Jordan, J et al. (1987) Secretion of a growth inhibitory factor by ZR-75-1 human breast cancer cells. Biochem Biophys Res Commun 149:642-8
Milius, R A; McLaughlin, W H; Lambrecht, R M et al. (1986) Organoastatine chemistry. Astatination via electrophilic destannylation. Int J Rad Appl Instrum A 37:799-802