Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an inorganic compound
Reexamination Certificate
1998-09-02
2001-05-29
Jones, Dameron (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an inorganic compound
C424S001650, C424S001850
Reexamination Certificate
active
06238644
ABSTRACT:
BACKGROUND OF THE INVENTION
It has long been known that iodide appears in the milk of mammals. The levels of iodide in the milk of a variety of mammals including humans are 20-30 fold higher than that present in the maternal plasma. Since about 50% of the iodide in milk is incorporated into milk proteins, the mechanisms that drive the accumulation of iodide in milk could include the functioning of an iodide transporter and/or enzymes involved in iodide incorporation into proteins. Early experiments showed a decreased
131
I accumulation in milk when lactating rats were injected with perchlorate (an inhibitor of the iodide transporter) or methimazole (an inhibitor of peroxidase). Perchlorate was more potent in inhibiting total
131
I uptake, whereas methimazole, primarily inhibited
131
I binding to milk proteins. These in vivo studies suggest that both an iodide transporter and a peroxidase enzyme are present in mammary cells, and are involved in the accumulation of iodide in milk during lactation.
Studies in the literature focusing on the hormonal regulation of iodide transport in the mammary gland are limited. It has been reported that thyroid stimulating hormone (TSH) or thyroxin injected into lactating rats had no effect on
131
I secretion into milk. In addition, prolactin (PRL), growth hormone (GH), insulin or cortisol had no effect on iodide uptake into cultured mammary tissues taken from lactating rats.
Studies in the literature concerning iodide uptake in neoplastic mammary cells reported that radioactive iodide concentration in biopsied human breast tissue with carcinoma or dysplasia is higher than in histologically normal tissues from the same patients.
SUMMARY OF THE INVENTION
The instant invention involves a method for treating a breast cancer of a patient. The method includes the administration of a radioisotope of iodine to the breast cancer of the patient in a dosage of between 5 and 50 milliCuries over the course of one day. Additional doses of iodine radioisotopes may be administered in dosage of between 1 milliCurie and 50 milliCurie as clinically warranted.
The instant invention utilizes a composition for mammary tissue uptake. This composition includes an inorganic radioactive iodide salt and a parenterally injectable carrier therefor. The radioactive iodide salt includes alkali metal iodides, alkali earth iodides, transition metal iodides, iodine pentoxide and iodine tribromide. Adjuvants are optionally added to this composition in order to increase iodine uptake by mammary tissue, and/or inhibit iodine uptake by the thyroid gland. The compositions of the instant invention find utility as breast cancer therapeutics and as radioimaging dyes.
DETAILED DESCRIPTION OF THE INVENTION
The treatment of breast cancer currently is limited to malignant growths large enough to be targeted surgically or by external radiation sources. In contrast, the instant invention delivers radioisotopes of iodine to mammary cells as an ion. Due to the selective uptake of iodide by mammary cells, malignant cell clusters too small to be otherwise treated receive a radiation dose. The treatment of breast cancer as described in the instant invention is effective in lessening the likelihood of metastasis and in inhibiting or killing cancerous cells.
The instant invention harnesses the natural ability of mammary cells to concentrate iodide internally. While the mechanisms of iodide uptake are not fally understood, a radioisotope of iodine is administered in vivo and generates therapeutic dosimetries of radioactive decay products in those tissues in which the cells concentrate iodide. A therapeutic administration ranges from between 1 milliCurie (mCi) and 50 milliCuries.
In order to further localize radioactive iodine uptake within mammary cells, substances are optionally administered which function to: 1) stimulate mammary cell uptake, such as prolactin or dopamine antagonists; or 2) inhibit uptake by other body tissues, such as thyroid hormones.
Substances are administered to further localize iodine uptake in mammary cells at times prior to, in concert with, or after the administration of the radioactive iodine, depending on the factors including pharmokinetics of the specific substance, the radiation dosimetry and the radioisotope half life.
The instant invention also finds application in the radioimaging of mammary tissues. Radiation flux variations which relate to cellular condition are detectable by conventional radioimaging techniques, owing to the increased metabolism of malignant cells relative to normal cells.
Based on the above observations, a method for treating breast cancer is described in the instant invention. While all radioisotopes of iodide are operative in the instant invention, it is preferred that
125
I and/or
131
I be administered to treat breast cancer, owing to the decay mode, decay energy, isotope half life and other properties. More preferably,
125
I is administered to treat breast cancer.
The radioisotope of iodine is administered as an iodide salt that is soluble in a carrier solution compatible with physiological pH and molality. The radioisotope of iodine is administered in the form of an alkali metal, alkali earth or transition metal iodide, iodine pentoxide, or iodine tribromide compounds. Preferably, the radioisotope of iodine is administered as sodium iodide or potassium iodide.
The instant invention functions in part because an iodide transporter is present in neoplastic mammary cells. It is observed that radioactive iodide is concentrated by more than 80-fold in MCF-7 cells cultured for 10 minutes with
125
I. MCF-7 cells are a neoplastic mammary cell line of human origin. These studies support the existence of an iodide transporter in at least certain neoplastic mammary cells.
The radioisotope of iodine is administered parenterally with a suitable carrier, for example in saline or buffered vehicles with or without various adjuvants. The adjuvants optionally include hormones to further increase the iodide transport in mammary cells and decrease the uptake of other cell types containing iodide transporters.
In a single bolus method of the instant invention, between 5 and 50 mCi of radioactive iodine is administered. Preferably, the iodine is administered as the sodium salt of
125
I or
131
I.
In a multiple bolus method of the instant invention between 1 and 50 mCi of radioactive iodine is administered per dosage. Between 2 and 20 such dosages are administered over a period of three days to four weeks. The individual dosages may be of equivalent dosimetry, or the dosimetry may vary between the doses. Preferably, the iodine is administered as the sodium salt of
125
I or
131
I.
In an infusion method of the instant invention, the radioisotope of iodine is administered intravenously by means of an infusion pump for from 1 day to 30 days. The daily dosimetry being between 1 and 50 mCi per day. Preferably the iodine is administered as the sodium salt of
125
I or
131
I.
Optionally, steps are taken to elevate prolactin levels, in order to stimulate the iodide uptake process in neoplastic mammary cells. In such instances, prolactin is administered for from three to sixty days prior to the administration of the radioisotope of iodide therapy. Prolactin, for such purposes is administered in doses ranging from 0.01 to 5 milligrams per kilogram body weight per day. Alternatively, clinically significant doses of a dopamine antagonist are administered for three to sixty days prior to the radioisotope therapy. The dopamine antagonist thereby serves to elevate endogenous prolactin levels.
The inventor has discovered that PRL doubles the rate of iodide accumulation in cultured mammary tissues taken from 12-14 day pregnant mice. In time course studies of the instant invention, it is observed that there is an initial effect of PRL after 4 hr, whereas a maximum two- to threefold increase in iodide accumulation occurs after 24 hr. In dose-response studies, 1 ng/ml PRL elicited a significant response, whereas PRL concentrations >5 ng/ml stimulated maximum response
Gifford, Krass, Groh Sprinkle, Anderson & Citkowski, P.C.
Jones Dameron
Wayne State University
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