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Efficacy of p120 antisense-mediated therapy for pancreatic cancer
J W Freeman1, W E Strodel, P C McGrath
1University of Kentucky Medical Center, Division of General Surgery, Lexington, Kentucky 40536-0084, USA.
Abstract:
p120 antisense oligodeoxynucleotides were used to determine whether they inhibited cell growth of MIA PaCa-2, a highly tumorigenic human pancreatic carcinoma cell line. Growth inhibition assays were determined in vitro by the ability of these oligomers to inhibit DNA synthesis and cell growth. For in vivo studies, nude mice were injected with cells and palpable tumors were found in 16 of 20 animals by day 14. Sixteen animals (8 in each group) were then treated daily (25 mg/kg intraperitoneally) for up to 40 days with nonsense control oligomers or p120 antisense oligomers. p120 Antisense oligomers inhibited the in vitro proliferation of MIA PaCa-2 cells in a dose-dependent manner, and optimal growth inhibition of greater than 90% was achieved at an antisense oligomer concentration of 100 micromol/L. The tumor volume was calculated for antisense- and nonsense-treated animals. Fifteen days after the beginning of treatment, control animals had a significantly greater (P=0.0035) tumor volume (425=244 mm3 above baseline) as compared to p120 antisense-treated animals (166+/-116 mm3). Seven of the eight control animals formed tumors that had a volume greater than 1200 mm3 45 days after treatment was begun, whereas only three of eight p120 antisense-treated animals had tumors that were this large. Two of the latter three animals had relatively large, palpable tumors (>150 mm3) prior to treatment. Twenty days after treatment was stopped (day 60), all animals had tumors larger than 1200 mm3. p120 Antisense oligomers were effective for inhibiting in vitro growth of the pancreatic cancer cell line MIA PaCa-2. In preliminary studies, p120 antisense oligomers appeared to inhibit the rate of growth in nude mice; however, no cures were achieved. The most effective response was seen in animals with initial low tumor burden.
Insights
p120 antisense oligodeoxynucleotides effectively inhibited MIA PaCa-2 pancreatic cancer cell growth in vitro. In vivo studies showed a reduced tumor growth rate in mice treated with p120 antisense oligomers, particularly in those with lower initial tumor burdens.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Pancreatic carcinoma, particularly the MIA PaCa-2 cell line, exhibits high tumorigenicity.
- Targeting specific genes like p120 is a strategy for cancer therapy.
Purpose of the Study:
- To investigate the efficacy of p120 antisense oligodeoxynucleotides in inhibiting the growth of MIA PaCa-2 pancreatic cancer cells.
- To evaluate the in vitro and in vivo effects of p120 antisense oligomers on tumor growth.
Main Methods:
- In vitro growth inhibition assays measuring DNA synthesis and cell proliferation.
- In vivo studies using nude mice xenograft models treated with p120 antisense oligomers or control oligomers.
- Tumor volume measurements and statistical analysis to compare treatment groups.
Main Results:
- p120 antisense oligomers demonstrated dose-dependent inhibition of MIA PaCa-2 cell proliferation in vitro, achieving over 90% inhibition at 100 micromol/L.
- In vivo, p120 antisense oligomer treatment resulted in significantly smaller tumor volumes compared to controls (166+/-116 mm3 vs. 425+/-244 mm3 at 15 days).
- While effective in slowing tumor growth, p120 antisense oligomers did not achieve complete tumor eradication, with tumors regrowing after treatment cessation.
Conclusions:
- p120 antisense oligodeoxynucleotides are effective in inhibiting the in vitro growth of the MIA PaCa-2 pancreatic cancer cell line.
- Preliminary in vivo studies suggest p120 antisense oligomers can inhibit tumor growth rate in mice, with better outcomes in animals with lower initial tumor burden.
- Further research is warranted to explore the therapeutic potential and optimize delivery of p120 antisense oligomers for pancreatic cancer treatment.