Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-09-21
2003-02-18
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S168000
Reexamination Certificate
active
06521608
ABSTRACT:
FIELD OF THE INVENTION
This invention concerns the use of Vitamin D and its analogs in the treatment of tumors and hyperproliferative disorders.
BACKGROUND OF THE INVENTION
Vitamin D is a generic term for a family of secosteroids that have affinity for the Vitamin D receptor, and are involved in the physiologic regulation of calcium and phosphate metabolism. Exposure to the sun and dietary intake are common sources of Vitamin D, but deficiencies of this vitamin can cause rickets and osteomalacia. Supplementation of dairy and other food products has reduced the incidence of Vitamin D deficiency conditions in modern society, and medical research concerning this vitamin has turned to its therapeutic effects in a variety of pathological conditions.
Vitamin D
3
is synthesized in human skin from 7-dehydrocholesterol and ultraviolet light. Vitamin D
3
, or its analog Vitamin D
2
, can be ingested from the diet, for example in fortified milk products. Vitamin D
2
and D
3
undergo hydroxylation first in the liver to 25-hydroxyvitamin D, then in the kidney to 1&agr;,25-dihydroxycholecalciferol (also known as 1,25-dihydroxyvitamin D or calcitriol), which is the principal biologically active form of Vitamin D. The biological production of this active form of the vitamin is tightly physiologically regulated.
Vitamin D exerts its calcium regulating activity through both genomic and nongenomic pathways. Although the nongenomic pathways remain poorly characterized, the genomic responses are mediated through binding to the nuclear Vitamin D receptor (VDR). The VDR is a ligand-activated transcription factor, which binds the Vitamin D
3
response element contained within the promoter/enhancer region of target genes. Vitamin D maintains calcium levels in the normal range by stimulating intestinal calcium absorption. When intestinal absorption is unable to maintain calcium homeostasis, Vitamin D stimulates monocytic cells to become mature osteoclasts, which in turn mobilize calcium from bones.
Appreciation for Vitamin D's non calcium-related biological activities began in 1979, with Stumpf's discovery that radioactive Vitamin D localizes to many tissues not associated with calcium metabolism (
Science
206:1188-1190, 1979). In 1981, Abe et al. reported that mouse myeloid leukemia cells possessed VDR, and that their exposure to Vitamin D led to terminal differentiation (
PNAS USA
78:4990-4994, 1981). Since then VDR has been described in carcinomas of the prostate, breast, colon, lung, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinoma, renal cell carcinoma, myeloid and lymphocytic leukemia, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma, and sarcomas of the soft tissues and bone.
In vitro assays using 1,25 dihydroxyvitamin D or its analogues demonstrated antiproliferative effects in cell lines derived from many malignancies including adenocarcinomas of the prostate (
Molec. and Cell. Endocrinology
126:83-90, 1997
; Proc. Amer. Assoc. Cancer Res
. 38:456, 1997
; J. Ster. Biochem. and Molec. Biol
. 58:277-288, 1996
; Endocrinology
137:1551561, 1996
; Endocrinology
136:20-26, 1995
; Cancer Research
54:805-810, 1994
; Endocrinology
132:1952-1960, 1993; and
Anticancer Research
14:1077-1081, 1994), breast (
Proc. Amer. Assoc. Cancer Res
. 38-456, 1997
; Biochemical Pharmacology
44:693-702, 1992); colon (
Biochemical and Biophysical Research Communications
179:57-62, 1991
; Archives of Pharmacology
347:105-110, 1993); pancreas (
British Journal of Cancer
73:1341-1346, 1996); and endometrium (
Journal of Obstetrics and Gynaecology Research
22:529-539, 1996); lung (
Anticancer Research
16:2953-2659, 1996); myeloid leukemia (
PNAS USA
78:4990-4994, 1981); melanoma (
Endocrinology
108:1083-1086, 1981); and sarcomas of the soft tissues (
Annals of Surgical Oncology
3:144-149, 1996) and bone (
Journal of the Japanese Orthopaedic
Association 69:181-190, 1995).
Studies in animals have shown antiproliferative activity of Vitamin D or its analogues in prostate cancer (
Urology
46:365-369, 1994); breast cancer (
J. NCl
89:212-218, 1997
; Lancet
1:188-191, 1989); squamous cell carcinoma (
Molecular and Cellular Differentiation
3:31-50, 1995); myeloid leukemia (Blood 74:82-93, 1989 and
PNAS USA
80:201-204, 1983) and retinoblastoma (
Archives of Opthalmology
106:541-543, 1988
; Archives of Opthalmology
106:536-540, 1988). The mechanism of Vitamin D's antiproliferative effects remains unknown, although it has been proposed that Vitamin D increases synthesis of TGF-&bgr;1 and TGF-&bgr;2, decreases the expression of epidermal growth factor receptors, leads to dephosphorylation of the retinoblastoma protein, induces cell cycle arrest in G1, perhaps by induction of the cyclin dependent kinase inhibitors p21(waf1) and p27(kip1), and induces the production of insulin-like growth factor binding protein.
The patent literature is replete with attempts to treat tumors with Vitamin D compounds. U.S. Pat. No. 4,391,802 disclosed treating leukemioid diseases with 1&agr;-hydroxy Vitamin D derivatives. The use of 1&agr;-hydroxy derivatives with a 17 side chain greater in length than the cholesterol or ergosterol side chains was disclosed in U.S. Pat. No. 4,717,721. Additional Vitamin D analogs are described in U.S. Pat. No. 4,851,401 (cyclopentano-Vitamin D analogs), U.S. Pat. No. 4,866,048, U.S. Pat. No. 5,145,846 (Vitamin D
3
analogs with alkynyl, alkenyl, and alkanyl side chains), U.S. Pat. No. 5,120,722 (trihydroxycalciferol), U.S. Pat. No. 5,547,947 (fluoro-cholecalciferol compounds), U.S. Pat. No. 5,446,035 (methyl substituted Vitamin D), U.S. Pat. No. 5,411,949 (23-oxa-derivatives), U.S. Pat. No. 5,237,110 (19-Nor-Vitamin D compounds), U.S. Pat. No. 4,857,518 (hydroxylated 24-homo-Vitamin D derivatives). Additional Vitamin D analogs are shown in U.S. Pat. Nos. 4,804,502; 5,374,629; 5,403,940; 5,446,034; and 5,447,924.
Few attempts have been made to test Vitamin D's antiproliferative effects in humans with cancer. Koeffler et al.,
Cancer Treatment Reports
69:1399-1407, 1985, gave 2 mcg of 1,25-dihydroxyvitamin D daily for 8 weeks or longer to 18 patients with myelodysplastic syndrome. Eight of 18 patients had minor and transient improvements in the peripheral blood counts, but by the end of the 12 week study no patient showed significant improvement and 4 patients experienced symptomatic hypercalcemia. Bower et al.,
Lancet
337:701-702, 1991, treated 19 patients with locally advanced or cutaneous metastatic breast cancer with topical calcipotriol, a Vitamin D analogue. Three of the 14 patients who completed 6 weeks of treatment showed a 50% reduction in the bidirectional diameter of the treated lesions and one other patient showed minimal response, however hypercalcemia was a complication of the treatment. Palmieri-Sevier et al.,
Am. J. Medical Sciences
306:309-312, 1993, reported a case of long term remission of parathyroid carcinoma which appeared to be induced and maintained by Vitamin D therapy. Rustin et al.,
Brit. J. Can
. 74:1479-1481, 1996, performed a clinical trial with a continuous dose of calcitriol in patients with ovarian cancer, and again encountered hypercalcemia.
A phase II trial of oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory prostate cancer was reported by Osborn et al.,
Urol. Oncol
., 1:195-198, 1995. Fourteen patients were given a daily oral dose of 0.5-1.5 mcg calcitriol, but no significant response was demonstrated, and clinical deterioration was documented in most of the patients. Thirteen of the patients experienced hypercalcemia, which is the most common side effect of treatment with Vitamin D and its analogs. Concern that hypercalcemic effects of Vitamin D would preclude the achievement of therapeutic, anti-neoplastic serum levels has inhibited the study of the use of this vitamin in humans with cancer. It is an object of this invention to provide a method of treatment with Vitamin D drugs (such as calcitriol) that avoids such hypercalcemia, while permitting the use of this class o
Beer Tomasz M.
Henner William D.
Criares Theodore J.
Kim Jennifer
Klarquist & Sparkman, LLP
Oregon Health & Science University
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