Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-06-26
2003-01-07
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S168000
Reexamination Certificate
active
06503893
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
BACKGROUND OF THE INVENTION
This invention relates generally to a method of treating hyperproliferative diseases, and in particular, to the use of active forms of hypocalcemic vitamin D to inhibit the hyperproliferative cellular activity of these diseases and to promote differentiation of the cells.
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 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. This indicates a need 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 hyperproliferative disease conditions such as those characterized by hyperproliferative cell growth and/or abnormal cell differentiation. The method includes use of active vitamin D compounds to inhibit abnormal cell growth and promote cell differentiation.
The foregoing, and other advantages of the present invention, are realized in one aspect thereof in a method of inhibiting the hyperproliferative activity of neoplastic or hyperplastic cells, comprising treating the cells with an effective amount of a hypocalcemic vitamin D compound. The treating step includes inhibiting proliferation of, and inducing and enhancing differentiation in such cells.
The hypocalcemic vitamin D compounds of the present invention include vitamin D compounds having a hydrocarbon moiety substituted at the C-24 position on the sidechain of the molecule and a hydroxy group substituted in at least one of the C
1
, C
24
or C
25
positions.
The vitamin D compound of the present invention is an active vitamin D and is suitably represented by the formula (I) described hereafter. The compounds of formula (I) suitably include 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
.
Hypocalcemic vitamin D compounds are valuable for the treatment of breast and colon cancer, as well as other neoplasms such as pancreatic cancer, endometrial cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell cancer of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, melanoma, retinoblastoma, and sarcomas of the soft tissue and bone.
In accordance with the present invention, when effective amounts of hypocalcemic vitamin D compounds are administered to patients with cancer or neoplasms, the proliferative activity of the abnormal neoplastic cells is inhibited, reduced, or stabilized, and cell differentiation is induced, promoted or enhanced, with significantly less hypercalcemia and hypercalciuria 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 human cancer comprising administering to a subject who has cancer an effective amount of hypocalcemic 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 a hypercalcemia risk substantially lower that that of 1&agr;,25-dihydroxyvitamin D
3
, to inhibit, decrease or stabilize the cellular abnormal proliferative activity of the cancer.
For treatment for malignant conditions in accordance with the present invention, the hypocalcemic vitamin D compounds can be suitably administered alone as an active ingredient, as an antiproliferative agent in a pharmaceutical composition, or co-administered with an anticancer agent.
Further, included within the scope of the present invention is the co-administration of the vitamin D of formula (I) 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 other antineoplastic agents. (estramustine phosphate, prednimustine).
It is anticipated that the hypocalcemic vitamin D compounds used in combination with various anticancer drugs can give rise to a significantly enhanced cytotoxic effect on cancerous cells, thus providing an increased therapeutic effect. Specifically, as a significantly increased growth-inhibitory effect is obtained with the above disclosed combinations utilizing lower concentrations of the anticancer drugs compared to the treatment regimes in which the drugs are used alone, there is the potential to provide therapy wherein adverse side effects associated with the anticancer drugs are considerably reduced than normally observed with the anticancer drugs used alone in larger doses. Possible dose ranges of these co-administered anticancer agents are about 0.1 to 20 mg/kg/day.
Also included within the scope of the present invention is the co-administration of effective dosages of the analogue of formula (I) in conjunction with admi
Bishop Charles W.
Mazess Richard B.
Bone Care International, Inc.
Michael & Best & Friedrich LLP
Peterson Jeffrey D.
Reamer James H
Welch Teresa J.
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