iodotamoxifen and Breast-Neoplasms

Tamoxifen binds to estrogen receptors (ERs) and prevents breast cancer cell proliferation. This study is aimed at developing a ligand for imaging ER (+) breast tumors by positron emission tomography (PET) or single photon emission computed tomography (SPECT). [18F]-Labeled tamoxifen analogue ([18F]FTX) was prepared in 30-40% yield and [131I]-labeled tamoxifen analogue ([131I]ITX) was prepared in 20-25% yield. In mammary tumor-bearing rats, the biodistribution of [18F]FTX at 2 h showed a tumor uptake value (% injected dose/gram tissue) of 0.41 +/- 0.07; when rats were pretreated with diethylstilbestrol (DES), the value changed to 0.24 +/- 0.017. [131I]ITX at 6 h showed a tumor uptake value of 0.26 +/- 0.166; when rats were pretreated with DES, the value changed to 0.22 +/- 0.044. Priming tumor-bearing rats with estradiol, a tumor uptake value for [131I]ITX was increased to 0.48 +/- 0.107 at 6 h. In the [3H]estradiol receptor assay, tumors had a mean estrogen receptor density of 7.5 fmol/mg of protein. In gamma scintigraphic imaging studies with [131I]ITX, the rabbit uterus uptake can be blocked by pretreatment with DES. Both iodo-tamoxifen and tamoxifen reduced ER(+) breast tumor growth at the dose of 50 micrograms in tumor-bearing mice. The findings indicate that tamoxifen analogue uptake in tumors occurs via an ER-mediated process. Both analogues should have potential for diagnosing functioning ER(+) breast cancer.

Topics: Animals; Autoradiography; Breast Neoplasms; Female; Fluorine Radioisotopes; Humans; Iodine Radioisotopes; Mammary Neoplasms, Experimental; Middle Aged; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors, Estrogen; Tamoxifen; Tissue Distribution; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Tumor Cells, Cultured

We evaluated the uptake and radiotoxicity of [125I]iodotamoxifen (125ITAM) in MCF-7 human breast cancer cells in the presence or absence of excess non-radioactive estradiol (E2) or iodotamoxifen (ITAM). Studies in cells under wash-out conditions and in nuclei isolated from previously exposed cells showed that 125ITAM binds estrogen receptor (ER) and antiestrogen binding sites (AEBS) and has the capacity for considerable non-specific binding. The radiotoxicity of 125ITAM was a complex function related to ER content and/or function as well as interactions with ER, AEBS and non-specific binding. Addition of E2 or ITAM abolished ER mediated cell killing. ITAM but not E2 abolished AEBS mediated cytotoxicity. Non-specific binding accounted for considerable cytotoxicity. Although these studies confirm the radiotoxicity of nuclear bound 125I, multiple nuclear binding sites, variability in ER content and function and non-specific binding will all adversely influence ultimate clinical efficacy.

Topics: Breast Neoplasms; Humans; Iodine Radioisotopes; Receptors, Estrogen; Tamoxifen; Tumor Cells, Cultured

Auger effects from 125I decay are singularly damaging if localized in DNA as the thymidine analogue 125I-iododeoxyuridine (125IUdR). Recent experience with steroid sex hormones extends these observations by demonstrating cytotoxicity in sites other than the DNA backbone. We have compared the cytotoxicity in human MCF-7 breast cancer cells of 125IUdR, 125I-iodotamoxifen, a nonsteroidal antiestrogen that is translocated from the cytoplasm to the nucleus of receptor containing cells, and 125I-iodoantipyrine, a biological indicator of the body water space. Cytotoxicity is critically dependent upon subcellular localization.

Topics: Antipyrine; Breast Neoplasms; Cell Line; Cell Survival; Humans; Idoxuridine; Iodine Radioisotopes; Receptors, Estrogen; Tamoxifen