Therapeutic and diagnostic applications of prostatic acid phosphatase in prostate cancer

a prostate cancer and prostatic acid phosphatase technology, applied in the field of prostate cancer diagnosis and treatment, can solve the problems of uncureable disease relapse, hormone therapy, unrehabilitative, etc., and achieve the effects of reducing the growth rate of cancer cells, prolonging and/or restoring the effect and increasing the efficacy of androgen deprivation therapy

Inactive Publication Date: 2006-12-28
BOARD OF RGT UNIV OF NEBRASKA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] The present invention provides novel methods of using human cellular PAcP in prostate cancer diagnosis and therapy. The inventor has discovered that induced expression of cellular PAcP can increase the efficacy of androgen deprivation therapy by prolonging and / or restoring its effect. Furthermore, cellular PAcP itself is useful as a therapeutic because its expression concurs with a diminished growth rate of cancer cells. The cellular level of PAcP exhibits a consistent negative correlation with the growth of several human prostate cancer cell lines. The data indicate that cellular PAcP down-regulates prostate cell growth, apparently by dephosphorylating c-ErbB-2 / neu. Thus, reduced cellular PAcP expression in cancer cells can lead to prostate tumor progression and, conversely, by increasing the cellular PAcP concentration, tumor progression should be impeded or prevented.

Problems solved by technology

Hormone therapy, however, is not curative, and disease relapse will inevitably occur, usually within 24 months (Gittes, 1991, N. Eng. J. Med. 324:236-245).
The molecular mechanism(s) underlying this transition from androgen-responsive to androgen-unresponsive prostate cancer is not understood, slowing the development of effective treatments.
Nevertheless, controversial results exist (Yam et al., 1982, Ann.

Method used

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  • Therapeutic and diagnostic applications of prostatic acid phosphatase in prostate cancer
  • Therapeutic and diagnostic applications of prostatic acid phosphatase in prostate cancer
  • Therapeutic and diagnostic applications of prostatic acid phosphatase in prostate cancer

Examples

Experimental program
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Effect test

example i

Human Prostatic Acid Phosphatase is a Marker for Androgen-Responsive Prostate Cancer Cell Lines

Experimental Procedures

[0090] Materials. FBS and RPMI 1640 medium were purchased from Life Technologies, Inc. The heat-inactivated dialyzed FBS that was a certified grade FBS containing less than 74 pM testosterone, was prepared as described previously (Lin et al., 1993, Arch. Biochem. Biophys. 300:384-390). The steroid-reduced medium consisted of RPMI 1640 medium supplemented with 2 or 5% (v / v) heat-inactivated dialyzed FBS. Thus, the final concentration of testosterone was less than 4 pM (Lin et al., 1993, Arch. Biochem. Biophys. 300:384-390). Hepes, bovine serum albumin, Tris, p-nitrophenyl phosphate, DHT, L-(+)-tartaric acid, citric acid, formaldehyde, and EtBr were all purchased from Sigma. [[α]-32P]dCTP was from NEN Life Science Products. All other reagents were obtained as described in previous publications (Lin and Clinton, 1987, Adv. Prot. Phosphatases 4:199-228; Lin et al., 19...

example ii

Xenograft Animal Model System Mimics Clinical Human Prostate Cancers

Materials and Methods

[0126] Cell cultures. Different LNCaP cells including clone-33 (i.e., passages 20-30), -51 (passages 45-60), and -81 (passages 85-120) were described previously (Lin et al., 1998, J. Biol. Chem. 273:5939-5947). Clone-33 LNCaP cells represented the LNCaP parental cells, and expressed a high level of endogenous PAcP (Lin et al., 1998, J. Biol. Chem. 273:5939-5947). The expression of PAcP was decreased in clone-51 cells, and further diminished in clone-81 cells. LNCaP-23, -28, -34, and -40 cells were subcloned cells from clone-81 LNCaP cells that transfected with a full length human PAcP cDNA driven by a pCMV-neo expression vector followed by G418 selection (Lin et al., 1998, J. Biol. Chem. 273:5939-5947). These PAcP cDNA transfected LNCaP cells expressed a low level of endogenous cellular PAcP as well as an exogenous cellular PAcP (Lin et al., 1998, J. Biol. Chem. 273:5939-5947). LNCaP-CMV cell...

example iii

Analysis of the Promoter of the Human Prostatic Acid Phoasphatase Gene

Materials and Methods

[0143] Materials. Cell culture medium, fetal bovine serum (FBS), gentamicin and Lipofectin reagent were obtained from Life Technologies, Inc. The MasterAmp PCR Optimization kit was from Epicentre Technologies Corp. Zero Blunt PCR cloning kit, and pCR-Blunt vector were obtained from Invitrogen Corp. pCATBasic, pCATEnchancer, pCATPromoter, pSV-, 6-galactosidase vectors and CAT assay kit were purchased from Promega Corp. DNA manipulations of plasmids were performed by conventional molecular biology techniques (Sambrook et al., 1989 Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).

[0144] Cells culture. LNCaP cells were routinely maintained in RPMI1640 medium supplemented with 5% FBS, 1% glutamine, and 0.5% gentamicin. To examine androgen effect on PAcP expression, cells were maintained in a steroid-reduced medium, i.e., phenol red-free RPMI...

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Abstract

Presented is a therapeutic method to treat prostate carcinomas in mammals comprising the administration of cellular PAcP protein. Also presented is a method to diagnose androgen-insensitive prostate carcinomas by determining the expression level of cellular PAcP in the prostate carcinomas, a decrease in expression being indicative of androgen-insensitivity. A promoter region that is specifically expressed in prostate tissue is presented, as is a xenograft animal model that mimics human prostate carcinomas in the expression of cellular PAcP.

Description

[0001] This application claims priority to U.S. 60 / 116,551, filed 21, Jan. 1999, the entirety of which is incorporated by reference herein.[0002] Pursuant to 35 U.S.C. §202(c), it is acknowledged that the U.S. Government has certain rights in the invention described herein, which was made in part with funds from NIH grants CA52112 and CA72274.FIELD OF THE INVENTION [0003] This invention relates to the fields of prostate cancer diagnosis and treatment. BACKGROUND OF THE INVENTION [0004] Various scientific and scholarly articles are referred to in brackets throughout the specification. These articles are incorporated by reference herein to describe the state of the art to which this invention pertains. [0005] Prostate cancer has the highest incidence of male cancers in the U.S. However, the molecular mechanisms underlying prostate carcinogenesis that may lead to new therapeutic treatments remain enigmatic. Tyrosine phosphorylation signaling in prostate cell proliferation is mediated b...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A01K67/027C12Q1/68C07H21/04C12P21/06C07K14/82A61K48/00
CPCC12Q1/6886G01N33/57434C12Q2600/112C12Q2600/106
Inventor LIN, MING-FONG
Owner BOARD OF RGT UNIV OF NEBRASKA
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