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Growth inhibition of human tumor cell lines by antisense oligonucleotides designed to inhibit p120 expression
L Perlaky1, Y Saijo, R K Busch
1Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Abstract:
The human nucleolar antigen p120 was detected with an anti-p120 monoclonal antibody (MAbp120) in most human malignant tumors (Freeman et al., Cancer Research, 48, 1244-1251, 1988). Stable transfection of the sense p120 cDNA caused malignant transformation of NIH/3T3 cells in vitro, and the antisense p120 constructs markedly delayed the growth of these transformed cells (Perlaky et al., Cancer Research, 52, 428-436, 1992). Several p120 antisense phosphorothioate oligonucleotides designed to hybridize with different regions of the p120 sequence were screened on human tumor cell lines in vitro. Marked growth inhibition of HeLa, LOX and HRCC cell lines was found, particularly with antisense p120 oligonucleotide ISIS 3466 in combination with N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA); oligonucleotide ISIS 3466 is complementary to a non-translated region at the 3' end of the molecule. Preliminary in vivo studies on human LOX ascites tumor in nude mice showed marked inhibitory effects on tumor growth by the antisense oligonucleotide ISIS 3466 in the presence of DOTMA when treated on alternate days.
Insights
Antisense p120 oligonucleotides, particularly ISIS 3466 with DOTMA, significantly inhibit human tumor cell growth in vitro and in vivo. This suggests p120 is a potential therapeutic target for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Antisense Therapeutics
Background:
- The human nucleolar antigen p120 is frequently detected in malignant tumors.
- p120 gene transfection can induce cellular transformation, and its inhibition can delay tumor cell growth.
Purpose of the Study:
- To evaluate the efficacy of p120 antisense phosphorothioate oligonucleotides in inhibiting human tumor cell growth.
- To identify specific antisense sequences and delivery agents effective against various cancer cell lines.
Main Methods:
- Screening of multiple p120 antisense oligonucleotides against human tumor cell lines (HeLa, LOX, HRCC) in vitro.
- Assessment of growth inhibition using antisense oligonucleotide ISIS 3466 in combination with DOTMA.
- Preliminary in vivo studies using LOX ascites tumor in nude mice.
Main Results:
- Antisense p120 oligonucleotide ISIS 3466 demonstrated marked growth inhibition of HeLa, LOX, and HRCC cell lines.
- The combination of ISIS 3466 and DOTMA showed significant inhibitory effects on tumor growth in vivo.
- ISIS 3466 is complementary to a 3' non-translated region of the p120 molecule.
Conclusions:
- p120 antisense oligonucleotides, especially ISIS 3466 with DOTMA, represent a promising therapeutic strategy for inhibiting cancer cell proliferation.
- Targeting the p120 nucleolar antigen offers a potential avenue for novel anti-cancer drug development.
