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Angiogenesis inhibitor TNP-470 reduces human pancreatic cancer growth
1Department of Surgery, UCLA School of Medicine, Los Angeles, Calif 90095-6904, USA.
Abstract:
In this study we investigated the effects of the angiogenesis inhibitor TNP-470 on human pancreatic cancer cells in vitro and in vivo. The action of TNP-470 on vascular endothelial growth factor (VEGF) was also assessed. In vitro human pancreatic cancer cells (MIAPaCa-2, AsPC-1, and Capan-1), and human umbilical vein endothelial cells (HUVEC) were exposed to increasing concentrations (1 pg/ml to 100 microg/ml) of TNP-470. Cell proliferation was assessed after 3 days by cell count and MTT assay. In vivo, 5 x 10(6) pancreatic cancer cells were injected subcutaneously into nude mice. Four weeks later, 1 mm3 fragments of the resulting tumors were implanted into the pancreas of other mice. Animals received either TNP-470 (30 mg/kg every other day) or vehicle subcutaneously for 14 weeks. The volume of the primary tumor and metastatic spread were determined at autopsy. Concentrations of VEGF were determined in serum (VEGF(S)) and ascites (VEGF(A)) by enzyme-linked immunosorbent assay. Microvessel density was analyzed by immunohistochemistry in CD31-stained tumor sections. In vitro, proliferation and viability of the human pancreatic cancer cell lines were significantly inhibited at high concentrations of TNP-470 (> 1 microg/ml). In contrast, TNP-470 effectively decreased the growth of HUVEC at 100 pg/ml. In vivo, tumor volume and dissemination scores were significantly lower in all three pancreatic cancer cell lines. VEGF(S) and VEGF(A) were not different between treated groups. Treatment with TNP-470 significantly reduced neoangiogenesis in tumors of all three human pancreatic cancer cell lines: MIAPaCa-2 = 74.8 +/- 7.8/0.74 mm2 vs. 24.8 +/- 3.7/0.74 mm2; AsPC-1 = 65.3 +/- 5.0/0.74 mm2 vs. 26.0 +/- 3.4/0.74 mm2; and Capan-1 = 82.2 +/- 5.8/0.74 mm2 vs. 26.9 +/- 2.5/0.74 mm2 (P < 0.001). However, survival was not statistically different between groups. TNP-470 reduced tumor growth and metastatic spread of pancreatic cancer in vivo. This was probably due to the antiproliferative effect of the agent on endothelial cells rather than to the direct inhibition of pancreatic cancer cell growth. TNP-470 activity was not associated with alteration of VEGF secretion.
Insights
The angiogenesis inhibitor TNP-470 reduced pancreatic cancer growth and metastasis in vivo by inhibiting endothelial cell proliferation, not directly impacting cancer cells or vascular endothelial growth factor (VEGF) secretion.
Area of Science:
- Oncology
- Cancer Biology
- Angiogenesis Research
Background:
- Pancreatic cancer is a leading cause of cancer-related mortality.
- Tumor growth and metastasis are critically dependent on angiogenesis.
- TNP-470 is an angiogenesis inhibitor with potential anti-cancer activity.
Purpose of the Study:
- To investigate the efficacy of TNP-470 against human pancreatic cancer.
- To assess the effects of TNP-470 on cancer cell proliferation and angiogenesis.
- To evaluate the impact of TNP-470 on vascular endothelial growth factor (VEGF) levels.
Main Methods:
- In vitro studies using human pancreatic cancer cell lines (MIAPaCa-2, AsPC-1, Capan-1) and human umbilical vein endothelial cells (HUVEC).
- In vivo studies in nude mice with human pancreatic tumors, assessing tumor volume, metastatic spread, and microvessel density.
- Enzyme-linked immunosorbent assay (ELISA) for serum and ascites VEGF levels.
- Immunohistochemistry for CD31-stained tumor sections to analyze microvessel density.
Main Results:
- TNP-470 inhibited pancreatic cancer cell and HUVEC proliferation in vitro at high concentrations.
- In vivo, TNP-470 significantly reduced primary tumor volume and metastatic spread across all tested pancreatic cancer cell lines.
- Microvessel density was significantly reduced in tumors treated with TNP-470.
- No significant differences in serum or ascites VEGF levels were observed between treated and control groups.
- Survival rates were not statistically different between TNP-470 treated and vehicle groups.
Conclusions:
- TNP-470 demonstrates anti-tumor and anti-metastatic effects in pancreatic cancer models.
- The primary mechanism appears to be the inhibition of endothelial cell proliferation, leading to reduced angiogenesis.
- TNP-470's efficacy is not linked to direct inhibition of pancreatic cancer cell growth or alteration of VEGF secretion.
