Anti-Tumor Efficacy of a Novel Antisense Anti-MDM2 Mixed-Backbone Oligonucleotide in Human Colon Cancer Models: p53-Dependent and p53-Independent Mechanisms View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2002-04-01

AUTHORS

Hui Wang, Li Nan, Dong Yu, J. Russell Lindsey, Sudhir Agrawal, Ruiwen Zhang

ABSTRACT

BackgroundThe MDM2 oncogene is amplified or overexpressed in many human cancers and MDM2 levels are associated with poor prognosis. MDM2 not only serves as a negative regulator of p53 but also has p53-independent activities. This study investigates the functions of the MDM2 oncogene in colon cancer growth and the potential value of MDM2 as a drug target for cancer therapy, by inhibiting MDM2 expression with an antisense antihuman-MDM2 oligonucleotide.Materials and MethodsThe selected antisense mixed-backbone oligonucleotide was evaluated for its in vitro and in vivo antitumor activity in human colon cancer models: LS174T cell line containing wild-type p53 and DLD-1 cell line containing mutant p53. The levels of MDM2, p53 and p21 proteins were quantified by Western blot analysis.ResultsIn vitro antitumor activity was found in both cell lines, resulting from specific inhibition of MDM2 expression. In vivo antitumor activity of the oligonucleotide occurred in a dose-dependent manner in both models and synergistically or additive therapeutic effects of MDM2 inhibition and the cancer chemotherapeutic agents 10-hydroxycamptothecin and 5-fluorouracil were also observed.ConclusionsThese results suggest that MDM2 have a role in tumor growth through both p53-dependent and p53-independent mechanisms. We speculate that MDM2 inhibitors have a broad spectrum of antitumor activities in human cancers regardless of p53 status. This study should provide a basis for future development of anti-MDM2 antisense oligonucleotides as cancer therapeutic agents used alone or in combination with conventional chemotherapeutics. More... »

PAGES

185-199

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/bf03402011

DOI

http://dx.doi.org/10.1007/bf03402011

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1075096121

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/12149568


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43 schema:description BackgroundThe MDM2 oncogene is amplified or overexpressed in many human cancers and MDM2 levels are associated with poor prognosis. MDM2 not only serves as a negative regulator of p53 but also has p53-independent activities. This study investigates the functions of the MDM2 oncogene in colon cancer growth and the potential value of MDM2 as a drug target for cancer therapy, by inhibiting MDM2 expression with an antisense antihuman-MDM2 oligonucleotide.Materials and MethodsThe selected antisense mixed-backbone oligonucleotide was evaluated for its in vitro and in vivo antitumor activity in human colon cancer models: LS174T cell line containing wild-type p53 and DLD-1 cell line containing mutant p53. The levels of MDM2, p53 and p21 proteins were quantified by Western blot analysis.ResultsIn vitro antitumor activity was found in both cell lines, resulting from specific inhibition of MDM2 expression. In vivo antitumor activity of the oligonucleotide occurred in a dose-dependent manner in both models and synergistically or additive therapeutic effects of MDM2 inhibition and the cancer chemotherapeutic agents 10-hydroxycamptothecin and 5-fluorouracil were also observed.ConclusionsThese results suggest that MDM2 have a role in tumor growth through both p53-dependent and p53-independent mechanisms. We speculate that MDM2 inhibitors have a broad spectrum of antitumor activities in human cancers regardless of p53 status. This study should provide a basis for future development of anti-MDM2 antisense oligonucleotides as cancer therapeutic agents used alone or in combination with conventional chemotherapeutics.
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50 DLD-1 cell line
51 LS174T cell line
52 MDM2
53 MDM2 expression
54 MDM2 inhibition
55 MDM2 inhibitors
56 MDM2 levels
57 MDM2 oncogene
58 MethodsThe
59 Mixed
60 T cell lines
61 Vitro Antitumor Activity
62 Western blot analysis
63 activity
64 additive therapeutic effect
65 agents
66 analysis
67 anti-MDM2 antisense
68 anti-tumor efficacy
69 antisense
70 antitumor activity
71 basis
72 blot analysis
73 broad spectrum
74 cancer
75 cancer chemotherapeutic agents
76 cancer growth
77 cancer model
78 cancer therapeutic agents
79 cancer therapy
80 cell lines
81 chemotherapeutic agents
82 chemotherapeutics
83 colon cancer growth
84 colon cancer model
85 combination
86 conventional chemotherapeutics
87 development
88 dose-dependent manner
89 drug targets
90 effect
91 efficacy
92 expression
93 function
94 future development
95 growth
96 human cancers
97 human colon cancer models
98 inhibition
99 inhibitors
100 levels
101 levels of MDM2
102 lines
103 manner
104 materials
105 mechanism
106 mixed-backbone oligonucleotide
107 model
108 mutant p53
109 negative regulator
110 oligonucleotide
111 oncogene
112 p21 protein
113 p53
114 p53 status
115 p53-independent activities
116 p53-independent mechanism
117 poor prognosis
118 potential value
119 prognosis
120 protein
121 regulator
122 results
123 role
124 specific inhibition
125 spectra
126 status
127 study
128 target
129 therapeutic agents
130 therapeutic effect
131 therapy
132 tumor growth
133 values
134 vivo antitumor activity
135 wild-type p53
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