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Compositions and Methods for Cancer Treatment

a technology of calcidiol and cancer, applied in the field of cancer chemotherapy, can solve the problems of severely limited clinical use of calcitriol and hampered treatment efficacy of systemically applied calcitriol analogs for cancer treatment, and achieve the effect of inhibiting apoptosis

Inactive Publication Date: 2010-06-10
WOMEN & INFANTS HOSPITAL OF RHODE ISLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention is about a new compound called B3CD that can inhibit the growth of cancer cells and promote their death. B3CD is a modified version of a compound called calcidiol, which is a non-calcemic precursor to calcitriol, a more powerful anti-angiogenic compound. B3CD has been found to be effective in inhibiting the growth of breast, prostate, and neuroblastoma cells in animal models. Unlike other calcitriol analogs, B3CD does not cause lethal hypercalcemia at high doses. The patent text also describes the process of synthesizing B3CD and its potential use as a chemotherapeutic drug."

Problems solved by technology

Unfortunately, the clinical use of calcitriol was severely limited by its hypercalcemic side effects.
However, the therapeutic efficacy of systemically applied calcitriol analogs for treating cancer remains hampered by lethal hypercalcemia at the supraphysiological doses needed to reach clinical improvement.

Method used

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  • Compositions and Methods for Cancer Treatment
  • Compositions and Methods for Cancer Treatment
  • Compositions and Methods for Cancer Treatment

Examples

Experimental program
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Effect test

example 1

Analogs of B3CD

[0136]Derivatization of the A-ring hydroxyl group of calcidiol with bromoacetic acid imparted remarkable anticancer activity to B3CD. A library of compounds based on the B3CD scaffold will be designed and developed to improve the B3CD structure-activity profile by stepwise structural changes. A series of A-ring analogs of B3CD derivatized at the 3-OH position will be prepared (FIG. 2A). The basic A-ring synthon for these derivatives has been previously reported and readily incorporate electrophiles at C-3 position of A-ring (Frosch, J V, Lythogoe, B and Sakense, A K. Calciferal and its Derivatives. XVII. Ring A Components for synthetic work on vitamin D3 and on model compounds, J. Chem. Soc.: OrganieBioOrganic Chem 1974, 17:2005-2009). The important features of new derivatives will include replacement of —Br functionality with —F, —Cl, —Br, —I, —N3, —N2, —NH2, —CN, —S—CH3, and —N═C═S functionalities. The chain length between the A-ring and the functionality will be va...

example 2

Anticancer Activity

[0140]A panel of cancer cells is used to evaluate the antiproliferative and cytotoxic activities of B3CD and related analogs. The cells include colon (Colo), breast (MCF-7 and MDA-MB-231), lung (A549), prostate PC3 and LNCaP), melanoma (SK-MEL-31), renal (Caki-1), ovarian (OVCAR-3), bladder (T24), pancreatic (BxPC-3), hepatocarcinoma (Hep3B), neuroblastoma (SH-SY5Y), glioblastoma (SNB-19), medulloblastoma (D283 Med), skin (LS123), squamous cell carcinoma (Sec-15), acute promyelocytic leukemia (APL), myeloblastic (HL-60) and myelomonocytic (U937).

[0141]The anticancer activity testing will be carried out by high throughput screening. The cancer cells will be cultured in 96 well plates and treated with the library. B3CD has been tested in this system and was effective at a 200 nM dose. For general screening, 2-200 nM doses will be used. Cells will be treated with the compounds for 12, 24, 48 and 72 hours. A 96 well plate format allows testing a large number of compou...

example 3

In Vitro Treatment of Neuroblastoma Cells

[0143]Materials and methods. Proliferation was measured by MTS and BrdU incorporation assays. Apoptosis was assessed by DNA fragmentation, Cell Death Detection ELISA and caspase-3-assays. Effect of B3CD on TrkB signaling by BDNF was assessed by Western Blot analysis of AKT and ERK phosphorylation. The effect on angiogenesis was determined by chick chorioallantoic membrane (CAM) assay and aortic ring assay.

[0144]B3CD was tested on the panel of cell described above. B3CD showed potent antiproliferative and cytotoxic effects on neuroblastic, ovarian, endothelial cells and prostate cancer cells, but did not show an effect on proliferation of skin, smooth muscle, breast, pancreatic, osteosarcoma and macrophage cells (FIG. 3). Such cell-type specificity is not uncommon. In addition, B3CD induced apoptosis; distinct DNA laddering characteristic of apoptosis was observed in neuroblastic, ovarian and prostate cancer cells. However, keratinocytes were ...

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Abstract

Bromoacetoxycalcidiol (B3CD), which is structurally related to calcidiol, exhibits cytotoxic and apoptotic activity toward cancer cells, including highly aggressive neuroblastoma cells. A series of small molecules designed around the structure of B3CD is expected to have growth inhibitory and apoptogenic activities toward a wide range of malignancies. B3CD shows no apparent toxicity in vivo, indicating potential value as a chemotherapeutic agent which will be particularly useful in treating highly aggressive tumors.

Description

RELATED APPLICATIONS[0001]This application claims priority to: U.S. provisional application Ser. No. 60 / 658,627, filed Mar. 4, 2005. The aformentioned application is incorporated herein in its entirety by this reference.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The invention relates generally to the field' of cancer chemotherapy and particularly to biologically active calcidiol derivatives for cancer cell inhibition.[0004]2. Description of Background Art[0005]Cancer is the second most common disease and also one of the most feared. Cancer occurs when cells continue to divide and fail to die at the appropriate time. Under normal circumstances, cells grow and divide to produce more cells as needed in order to maintain a healthy body. Tumors may form when this orderly process is disrupted by changes in regulatory processes that control normal cell growth and death, resulting in uncontrolled cell growth. Cancer may be induced by genetic changes, external factors su...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/695C12N5/09A61K31/047A61K31/215A61K31/4188C07C69/533C07C69/608C07C211/25C07C43/18C07C323/15C07F7/08A61P35/00
CPCA61K31/59A61P35/00A61P35/02
Inventor SWAMY, NARASIMHASUNDARESHA, HEMA MALINI K.
Owner WOMEN & INFANTS HOSPITAL OF RHODE ISLAND
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