Antiangiogenic therapy for human pancreatic carcinoma xenografts in nude mice.
OBJECTIVE
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).


CONCLUSIONS
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.
Jia
Lin
L
Department of Digestive Diseases, First People's Municipal Hospital of Guangzhou, Guangzhou Medical College, Guangzhou 510180, Guangdong Province, China. gzjialin@hotmail.com
Zhang
Mei-Hua
MH
Yuan
Shi-Zhen
SZ
Huang
Wen-Ge
WG
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002277:Carcinoma / Q000473:pathology*; D003510:Cyclohexanes; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010190:Pancreatic Neoplasms / Q000473:pathology*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D000093542:Gemcitabine
D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D003841:Deoxycytidine; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D000093542:Gemcitabine