Antiangiogenic therapy for human pancreatic carcinoma xenografts in nude mice
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Published on: June 20, 2015
Lin Jia1, Mei-Hua Zhang, Shi-Zhen Yuan
1Department of Digestive Diseases, First People's Municipal Hospital of Guangzhou, Guangzhou Medical College, Guangzhou 510180, Guangdong Province, China. gzjialin@hotmail.com
Aim:
To investigate the anti-tumor effects of antiangiogenic therapy (a combination of TNP-470, an antiangiogenic compound, with gemcitabine, an antimetabolite) on human pancreatic carcinoma xenografts and its mechanism.
Methods:
A surgical orthotopic implantation (SOI) model was established by suturing small pieces of SW1990 pancreatic carcinoma into the tail of pancreas in nude male mice. Mice then received either single therapy (n = 24) or combined therapy (n = 32). Mice receiving single therapy were randomly divided into control group, G100 group receiving 100 mg/kg gemcitabine IP on d 0, 3, 6 and 9 after transplantation, and T30 group receiving 30 mg/kg TNP-470 s.c on alternate days for 8 wk. Mice receiving combined therapy were randomly divided into control group, T15 group, G50 group and combination group (TNP-470 30 mg/kg and gemcitabine 50 mg/kg). Animals were killed 8 wk after transplantation. Transplanted tumors, liver, lymph node and peritoneum were removed. Weight of transplanted tumors, the T/C rate (the rate of mean treated tumor weight to mean control tumor weight), change of body weight, metastasis rate, and 9-wk survival rate were investigated. Tumor samples were taken from the control group, T30 group, G100 group and combination group. PCNA index (PI) and microvessel density (MVD) were investigated by immunohistochemical staining for PCNA and factor VIII, respectively.
Results:
There was a significant inhibitory effect on primary tumor growth of pancreatic carcinoma in G100 group, compared to T30 group, whereas tumor metastasis was significantly inhibited in T30 group compared to G100 group. There was no significant improvement in survival rate in these two groups. No significant inhibitory effect on tumor growth and metastasis in T15 group and G50 group. However, significant anti-tumor and anti-metastatic effects were observed in the combination group with a significant improvement in survival rate. The inhibitory effect on tumor growth in combination group enhanced 2 times in comparison with G50 group and 5 times in comparison with T15 group. Moreover, 25% of the animals bearing tumors were cured by the combination therapy. The levels of MVD and PI were 14.50+/-5.93 and 0.41+/-0.02, 12.38+/-1.60 and 0.30+/-0.07, 7.13+/-2.99 and 0.37+/-0.03, and 5.21+/-1.23 and 0.23+/-0.02 respectively in the control group, G100 group, T30 group and combination group. A significant inhibitory effect on PI level and MVD level was observed in G100 group and T30 group respectively whereas both MVD and PI levels were significantly inhibited in the combination group (P<0.05).
Conclusion:
Antiangiogenic therapy shows significant anti-tumor and anti-metastatic effects, and is helpful to reduce the dosage of cytotoxic drugs and the side effects. These effects are related to the antiangiogenic effect of TNP-470 and cytotoxic effect of gemcitabine.
Insights
This study shows that combining TNP-470 (antiangiogenic therapy) with gemcitabine (cytotoxic drug) significantly inhibits pancreatic cancer growth and metastasis in mice. This combination therapy also improved survival rates and reduced drug dosage requirements.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Pancreatic carcinoma is a challenging malignancy with limited treatment options.
- Antiangiogenic therapy and chemotherapy are established cancer treatment modalities.
- Investigating combination therapies can reveal synergistic effects for improved outcomes.
Purpose of the Study:
- To evaluate the anti-tumor and anti-metastatic effects of combined TNP-470 and gemcitabine therapy.
- To elucidate the underlying mechanisms of this combination therapy in pancreatic cancer xenografts.
- To assess the impact on survival rates and potential for reduced drug dosage.
Main Methods:
- A surgical orthotopic implantation (SOI) model using human pancreatic carcinoma SW1990 xenografts in nude mice.
- Administration of single-agent therapies (TNP-470 or gemcitabine) and combination therapy.
- Assessment of primary tumor growth, metastasis, body weight changes, and survival rates.
- Immunohistochemical analysis of Proliferating Cell Nuclear Antigen (PCNA) index and Microvessel Density (MVD).
Main Results:
- Combination therapy significantly inhibited both primary tumor growth and metastasis compared to single-agent therapies.
- The combination therapy led to a significant improvement in survival rates, with 25% of animals cured.
- Combined treatment significantly reduced both MVD and PCNA index, indicating antiangiogenic and anti-proliferative effects.
- Single-agent therapies showed partial effects on tumor growth or metastasis but not survival.
Conclusions:
- Combined antiangiogenic therapy (TNP-470) and chemotherapy (gemcitabine) demonstrate significant anti-tumor and anti-metastatic efficacy in pancreatic cancer.
- This combination therapy offers a promising strategy for improving survival outcomes and potentially reducing the dosage of cytotoxic agents.
- The observed effects are attributed to the synergistic action of TNP-470's antiangiogenic properties and gemcitabine's cytotoxic effects.
