Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-06-26
2003-05-20
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S170000
Reexamination Certificate
active
06566353
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
BACKGROUND OF THE INVENTION
This invention relates generally to a method of treating malignancy-associated hypercalcemia (MAH), and in particular, to the use of active forms of vitamin D to reduce hypercalcemia associated with inhibit the hyperproliferative diseases.
Extensive research during the past two decades has established important biologic roles for vitamin D apart from its classic role in bone and mineral metabolism. Specific nuclear receptors for 1&agr;,25-dihydroxyvitamin D
3
, the hormonally active form of vitamin D, are present in cells from diverse organs not involved in calcium homeostasis. For example, specific, biologically active vitamin D receptors have been demonstrated in the human prostatic carcinoma cell line, LNCaP, (Miller et al., 52
Cancer Res.
(1992) 515-520); Vitamin D receptors have also been described for many other neoplastic cells, e.g., carcinomas of the breast and carcinomas of the colon.
It has been reported that certain vitamin D compounds and analogues are potent inhibitors of malignant cell proliferation and are inducers/stimulators of cell differentiation. For example, U.S. Pat. No. 4,391,802 issued to Suda et al. discloses that 1&agr;-hydroxyvitamin D compounds, specifically 1&agr;,25-dihydroxyvitamin D
3
and 1&agr;-hydroxyvitamin D
3
, possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia. Antiproliferative and differentiating actions of 1&agr;,25-dihydroxyvitamin D
3
and other vitamin D
3
analogues have been reported with respect to cancer cell lines. More recently, an association between vitamin D receptor gene polymorphism and cancer risk has been reported, suggesting that vitamin D receptors may have a role in the development, and possible treatment, of cancer.
These previous studies have focused exclusively on vitamin D
3
compounds. Even though these compounds may indeed be highly effective in promoting differentiation in malignant cells in culture, their practical use in differentiation therapy as anticancer agents is severely limited because of their equally high potency as agents affecting calcium metabolism. At the levels required in vivo for effective use as, for example, antileukemic agents, these same compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of 1&agr;,25-dihydroxyvitamin D
3
and other vitamin D
3
analogues as anticancer agents is precluded, or severely limited, by the risk of hypercalcemia.
Hyperalcemia is frequently associated with malignancy (MAH), and is often a major contributor to morbidity and complicates clinical management of the malignancy. Parathyroid hormone related protein (PTHrP) is closely related to parathyroid hormone (PTH) and binds to the same receptor as PTH as well as other receptors. PTHrP is one of the main causative substances of such hypercalcemia, and is overproduced by malignant cells. 1,25-dihydroxyvitamin D
3
has been found to repress the transcription of the PTHrP gene in cells, however, the 1,25-dihydroxyvitamin D
3
compounds themselves increase serum calcium levels. Therefore a need exists for compounds with greater specific activity and selectivity of action, i.e., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a method of treating malignancy-associated hypercalcemia (MAH) such as that associated with hyperproliferative cell growth and/or abnormal cell differentiation. The method includes use of active vitamin D compounds to treat hypercalcemia and reduce serum parathyroid hormone related protein (PTHrP) levels.
The foregoing, and other advantages of the present invention, are realized in one aspect thereof in a method of treating malignancy-associated hypercalcemia from the hyperproliferative activity of human neoplastic or hyperplastic cells, comprising treating the cells with an effective amount of a hypocalcemic hydroxyvitamin D compound having a hydrocarbon moiety substituted at the C-24 position on the sidechain of the molecule. The treating step includes inhibiting proliferation of, and inducing and enhancing differentiation in such cells.
A hydroxyvitamin D compound in accordance with the present invention is an active vitamin D and is suitably represented by the formula (I) described hereafter. Suitable compounds of formula (I) are 1&agr;,24-dihydroxyvitamin D
2
, 1&agr;,24-dihydroxyvitamin D
4
, 1&agr;,25-dihydroxyvitamin D
4
, 1&agr;,25-dihydroxyvitamin D
2
, 1&agr;-hydroxyvitamin D
2
and 1&agr;-hydroxyvitamin D
4
.
The effective or therapeutic amount of the hypocalcemic hydroxyvitamin D compounds administrable in accordance with the present invention to patients in need on a daily basis per kilogram of body weight ranges from 0.01 &mgr;g/kg/day to 2.0 &mgr;g/kg/day.
In another aspect of the invention, lowering serum parathyroid hormone related protein (PTHrP) levels in patients suffering from hypercalcemia is accomplished by a method comprising, administering to these patients an effective amount of a hypocalcemic vitamin D compound, to lower the serum parathyroid hormone related protein (PTHrP) level.
The hypocalcemic vitamin D compounds are also valuable for the treatment of breast, prostate and colon cancer, as well as other neoplasms such as pancreatic cancer, endometrial cancer, testicular cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, retinoblastoma, and sarcomas of the soft tissue and bone, i.e. neoplasms that express a vitamin D receptor.
In accordance with the present invention, when effective amounts of the hypocalcemic vitamin D compounds are administered to patients with MAH, significantly redeuced hypercalcemia is observed than is observed after the same amount of an activated vitamin D
3
(e.g., 1&agr;-OH D
3
, 1&agr;,25-(OH)
2
D
3
) is administered in previously known formulations. Thus, the compound in accordance with the present invention has an improved therapeutic index relative to active forms of vitamin D
3
analogues.
Accordingly, another aspect of the invention is a method of treating malignancy associated hyercalcemia comprising administering to a subject who is suffering therefrom an effective amount of active vitamin D compound which has, or attains through metabolism in vivo, a vitamin D receptor (VDR) binding affinity substantially equivalent to the binding affinity of 1&agr;,25-dihydroxyvitamin D
3
and has a hypercalcemia risk substantially lower that that of 1&agr;,25-dihydroxyvitamin D
3
, to normalize or reduce serum calcium levels.
For treatment for malignancy-associated hypercalcemia and the underlying malignant condition in accordance with the present invention, the active vitamin D is suitably administered alone as an active ingredient in a pharmaceutical composition, or is co-administered with an anticancer agent.
Further, included within the scope of the present invention is the co-administration of a hypocalcemic vitamin D compound with a cytotoxic or anticancer agent. Such agents suitably include antimetabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vincristine, vinblastine, taxanes such as paclitaxel, docetaxel), an alkylating agent (e.g., cyclophasphamide, melphalan, biochoroethylnitrosurea, hydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin, JM-216, CI-973), anthracyclines (e.g., doxrubicin, daunorubicin), antibiolitics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitiors (e.g., etoposide, camptothecins) or any othe
Bishop Charles W.
Mazess Richard B.
Bone Care International, Inc.
Criares Theodore J.
Peterson Jeffrey D.
Welch Teresa J.
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