Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-06-26
2003-06-03
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S167000
Reexamination Certificate
active
06573256
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
BACKGROUND OF THE INVENTION
This invention relates generally to a method of inhibiting angiogenesis associated with the hyperproliferation of malignant cells, and in particular, to the use of active forms of vitamin D to inhibit angiogenesis of malignant 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.
Cancerous cells derive from a single cell that has mutated in a way that permits it to escape from the biochemical controls that limit the multiplication of normal cells. Once that cell fails to respond normally to growth inhibitors, it starts to proliferate. When the growing tumor reaches a certain diameter, however, simple diffusion in and out of the tumor tissue no longer suffices to supply oxygen and nutrients and remove waste. Further growth depends on angiogenesis (i.e., the formation of new blood vessels from the existing vascular bed), and the small tumor must produce factors that stimulate the growth of blood vessels. Therefore, the inhibition of angiogenesis, in turn leads to the decrease of proliferation of malignant and neoplastic cells.
Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis. This growth factor stimulates the endothelial cell proliferation, sprouting, migration and morphogenesis. A recent study has found that 1&agr;,25-dihydroxyvitamin D
3
significantly inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation. (See “1&agr;,25-Dihydroxyvitamin D
3
Ihibits Angiogenesis In Vitro and In Vivo”, Mantell, D. J., Owens, P. E., Bundred, N. J., Mawer, E. B., Canfield, A. E., Circulation Research, Aug. 4, 2000, pp. 214-220. Incorporated herein by reference). It was also demonstrated that 1&agr;,25-dihydroxyvitamin D
3
induced the regression of sprouting elongated endothelial cells, where the regression was due to the induction of apoptosis within the cell population. As mentioned earlier however, use of such vitamin D
3
analogs as anticancer agents is limited due to the inherent calcemic activity of the compounds. Therefore a need exists for compounds with the ability to inhibit angiogenesis of malignant cells but which have less calcemic activity.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a method of inhibiting angiogenesis associated with malignant cells. The method includes use of hypocalcemic active vitamin D compounds to inhibit angiogenesis. The present invention also provides a method of inducing the apoptosis of cancer cells by the use of active vitamin D compounds, and includes a method for treating cancer by regressing tumor cells by the use of active vitamin D compounds.
The foregoing, and other advantages of the present invention, are realized in one aspect thereof in a method of inhibiting angiogenesis associated with malignant cells, comprising treating the cells with an effective amount of a hypocalcemic vitamin D compound. The hypocalcemic vitamin D compound of the present invention include hypocalcemic vitamin D compounds having a hydrocarbon moiety substituted at the C-24 position on the sidechain of the molecule and having a hydroxyl group substituted in at least one of the C
1
, C
24
or C
25
positions.
The hypocalcemic vitamin D compound 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 1&agr;-hydroxyvitamin D compound 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, the apoptosis of cancer cells is accomplished by a method comprising, administering to patients an effective amount of a hypocalcemic vitamin D compound to induce the apoptosis of cancer cells.
In yet another aspect of the invention, a method for treating cancer by regressing tumor cells is disclosed, comprising administering to patients an effective amount of a hypocalcemic vitamin D compound to induce the regression of cancer cells.
In accordance with the present invention, when effective amounts of the hypocalcemic vitamin D compounds are administered to patients with cancer or neoplasms, the proliferative activity of the abnormal neoplastic cells is inhibited or maintained, 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. Furthermore, the compounds of the present invention can be administered in doses significantly higher than that of active vitamin D
3
analogs due to their lower calcemic effect.
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 active vitamin D compound which has, attained 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 decrease or stabilize the cellular abnormal proliferative activity of the cancer.
For treatment for malignant conditions in accordance with t
Bishop Charles W.
Mazess Richard B.
Bone Care International, Inc.
Criares Theodore J.
Michael & Best & Friedrich LLP
Peterson Jeffrey D.
Welch Teresa J.
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