[Anti-tumor efficacy of interventional chemotherapy with liposomal doxorubicin for hepatic metastasis of pancreatic cancer in nude mouse model].

OBJECTIVE: To investigate the anti-tumor effect of interventional chemotherapy with liposome doxorubicin for hepatic metastasis of pancreatic tumor in nude mice. METHODS: After the establishment of hepatic metastatic model of pancreatic tumor, the nude mice received various formulations via a spleen injection to imitate the interventional chemotherapy. In each of two following experiments, 42 nude mice were randomly divided into 6 groups. They received liposomal doxorubicin (including high, intermittent and low-dose), free doxorubicin, gemcitabine plus cisplatin and control respectively. In the first experiment, the doses were 6, 3, 1.5, 3, 3 mg/kg and 100 µl 10% glucose for each group respectively. And in the second experiment, 9, 6, 3, 6, 6 mg/kg, and 100 µl 10% glucose respectively. The efficacies of interventional injection of liposomal doxorubicin with different doses were examined in terms of tumor growth retardation for the hepatic metastatic foci of pancreatic tumor. RESULTS: In the first experiment, the difference of median hepatic tumor volume was significant among the three groups of mice receiving liposomal doxorubicin with incremental doses in a dose-dependent manner [high dose: (3 ± 1) mm(3), middle dose: (55 ± 18) mm(3), low dose: (90 ± 23) mm(3), P < 0.05]. The liposomal doxorubicin led to a substantial delay of tumor growth as compared to the free drug or gemcitabine plus cisplatin at the same dose (both P < 0.05). In addition, all animals were well-tolerated with no obvious acute toxicity. In the second experiment, significant difference was obtained for the mice injected with different doses of liposomal doxorubicin [(11 ± 4) mm(3), (13 ± 4) mm(3), (50 ± 18) mm(3), P < 0.05]. It was correlated with tumor growth delay. The mice administered with either 9 mg/kg or 6 mg/kg were more efficacious to retard tumor growth than those given 3 mg/kg (P < 0.05). Despite its enhanced effectiveness as compared to mice in gemcitabine plus cisplatin group (P < 0.05), the liposomal doxorubicin at a dose of 6 mg/kg resulted in a marginally delayed tumor growth compared to those of free doxorubicin at the same dose (P > 0.05). No evident acute toxic response was observed for each group of mice receiving liposomal doxorubicin. In contrast, approximately half of the animals receiving either free doxorubicin or gemcitabine plus cisplatin died of toxic responses. CONCLUSION: Liposomal doxorubicin may be a potential interventional chemotherapeutic agent for hepatic metastasis of pancreatic tumor because of improved anti-tumor efficacy and reduced toxicity in comparison to free doxorubicin and gemcitabine plus cisplatin.

[Anti-tumor effect of pcDNA3. 1-Egr. 1p-p16 gene combined with radiotherapy in tumor-bearing nude mice].

OBJECTIVE: To investigate the optimal doses of X-ray irradiation and plasmid injection in the anti-tumor effect of the pcDNA3. 1-Egr. 1p-p16 gene combined with radiotherapy in vivo. METHODS: We observed the anti-tumor effect of the pcDNA3. 1-Egr. 1p-p16 gene combined with radiotherapy with different doses of X-ray irradiation (2, 10, 20 Gy) and plasmid injection (10, 20, 30 microg) in nude mice with JF-305 pancreatic carcinoma, and detected the expression of p16 in tumor by RT-PCR. RESULTS: The tumor growth rate of the nude mice irradiated locally with 20 Gy X-rays after the plasmid injection was significantly lower (P < 0.05 ) than that of the nude mice irradiated locally with 2 Gy or 10 Gy X-ray 3 days after the irradiation. The tumor growth rate of the nude mice injected locally with 20 microg or 30 microg plasmid was significantly lower (P <0.05 ) than that of the nude mice injected locally with 10 microg plasmid. Both pcDNA3. 1-Egr. 1p-p16 group and pcDNA3. 1-Egr. 1p-p16 +20 Gy group had p16 mRNA expression, but the mRNA level of pcDNA3. 1-Egr. 1p-p16 +20 Gy group was higher than that of pcD- NA3. 1-Egr. 1p-p16 group. CONCLUSION: In the pcDNA3. 1-Egr. 1p-p16 gene combined with radiotherapy in vivo the optimal dose of X-ray irradiation was 20 Gy and the optimal dose of plasmid injection was 20 microg. The anti-tumor effect of pcDNA3. 1-Egr. 1p-p16 combined with radiotherapy is better than that of radiotherapy or gene therapy alone, which may be related with the enhanced p16 expression in tumor after the irradiation.

[Effects of sorafenib and liposome doxorubicin on human poorly differentiated thyroid carcinoma xenografts in nude mice].

OBJECTIVE: To evaluate the therapeutic effects of sorafenib and liposome doxorubicin on poorly differentiated thyroid carcinoma (PDTC) xenografts in nude mice. METHODS: Sorafenib and liposome doxorubicin were applied to PDTC xenografts in nude mice. The mice were randomized into seven groups: blank control (A), vehicle control (B), single liposome doxorubicin (C), single sorafenib group (D), liposome doxorubicin combined with low dose sorafenib group (E), combined group with medium dosage of sorafenib (F), combined group with high-dose of sorafenib(G). The volume, weight and growth inhibition rate of tumours were measured to evaluate the therapeutic effects of drugs. RESULTS: Sorafenib and liposome doxorubicin showed significant antitumor activity in the PDTC xenografts. The mean tumor volumes of seven groups were (1274.13 ± 393.76) mm(3), (1060.00 ± 469.05) mm(3), (726.76 ± 488.22) mm(3), (451.54 ± 97.75) mm(3), (518.37 ± 164.44) mm(3), (310.51 ± 210.53) mm(3), and (228.44 ± 129.21) mm(3), respectively. The mean tumor weights of the seven groups were (1.13 ± 0.42)g, (0.91 ± 0.39)g, (0.78 ± 0.45)g, (0.55 ± 0.17) g, (0.52 ± 0.19) g, (0.34 ± 0.21) g, and (0.19 ± 0.09) g separately. The tumor inhibition rates of group C to G were 30.8%, 40.8%, 42.3%, 62.9%, 72.6% separately. CONCLUSIONS: Sorafenib and liposome doxorubicin, no matter for single agent or in combination, showed significant antitumor activity in the PDTC PDTC xenografts in vivo. The tumour-inhibited effect of single sorafenib is better than that of single liposome doxorubicin. Liposome doxorubicin combined with medium dosage of sorafenib had a better therapeutic effect and less side effects.

[Effect of irradiation-induced pcDNA3.1-Egr.1p-p16 on cell apoptosis and cell cycle of JF305 cells].

OBJECTIVE: To observe the effect of pcDNA3.1-Egr.1p-p16 plasmid on apoptosis and cell cycle of pancreatic carcinoma JF305 cell line. METHODS: JF305 cells were cultured and transfected with pcDNA3.1-Egr.1p-p16 plasmid via Lipofectamine(TM) 2000, followed by irradiation by 6MV-X at 4 Gy (dose rate 2.50 Gy/min). The cell cycle and cell apoptosis changes were analyzed by flow cytometry. RESULTS: In cells infected with pcDNA3.1-Egr.1p-p16 plasmid and those with pcDNA3.1-Egr.1p-p16 plasmid infection before 4 Gy irradiation, the percentages of viable apoptotic cells were 6.4% and 10.4%, and those of advanced stage apoptotic or dead cells were 16.8% and 33.8%, significantly higher than those in the control group (P<0.05). JF305 cell apoptosis in 4 Gy irradiation group was obviously increased in comparison with non-irradiated plasmid-infected cells (P<0.05). Irradiation resulted in a predominant G(2) arrest of the plasmid-infected JF305 cells. Both pcDNA3.1-p16 plasmid and pcDNA3.1-Egr.1p-p16 plasmid infections could induce G1 arrest of JF-305 cells, and irradiation did not produce significant changes in G(1)-arrested cells in the two plasmid infection groups, but cells arresting at G(2) phase increased. CONCLUSION: pcDNA3.1-Egr.1p-p16 can induce JF-305 cells apoptosis, which is enhanced by irradiation. pcDNA3.1-Egr.1p-p16 tranfection may result in G(1) arrest of the cells, and when combined with irradiation, the cells arrested at G(2) phase can increase.