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Antitumor activity of the angiogenesis inhibitor TNP-470 in rabbits with VX2 carcinoma of the tongue
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023-C1Tumor biology
0 2 3 - C 1 Tumor b i o l o g y
1. Antitumor Activity of the Angiogenesis Inhibitor TNP470 in,Rabbits with VX2 Carcinoma of the Tongue
Ninomiya, Y., Matsumoto, K., Wakae, H., Tomioka, T. Fukuoka Dental College, Fukuoka, Japan It is well established that tumor angiogenesis plays an important role in tumor progression. A semisynthetic analogue of fumagillin, TNP-470, has been shown to be a potent angiogenesis inhibitor that prevents tumor growth. In this study, we studied the activity of TNP-470 upon intra-tumor (i.t.) injection versus i.v. injection using rabbits with VX2 carcinoma of the tongue. The i.v. injection of TNP-470 showed an inhibitory effect on tumor growth with 37% inhibition at a concentration of 20 mg/kg and 66% at 40 mg/kg. The i.t. injection of TNP-470 markedly inhibited the growth of the tongue tumor with 71% inhibition at a concentration of 5 mg/kg and 93% at 10 mg/kg, indicating that the activity of low dose TNP-470 upon i.t. injection was even stronger than that,of the i.v. injection. The expression of proliferating cell nuclear antigen (PCNA) of the tumor cells was analyzed by the CAS 200 computer system. The ratio of PCNA expressing cells was significantly decreased by i.t. injection of TNP-470 at 10 mg/kg, confirming the strong inhibitory effect of i.t. treatment on tumor growth. Microvessels in the tumor tissue were immunohistologically identified using anti-CD31 antibody. The number of microvessels was reduced to 20% of that in the control by the i.t. injection of TNP-470 (10 mg/kg). These data suggest that i.t. injection of the low dose angiogenesis inhibitor has a strong inhibitory activity against tumor angiogenesis and growth in rabbits with carcinoma of the tongue.
2. Effect of Bisphosphonate on an Experimental Jaw Metastasis Model in Nude Mice
Nishiyama, A., Sasaki, A., Lim, D. D. J., Alcalde, R. E., Etoh, Y, Suzuki, A., Matsumara, T. Department of OMS II, Okayama University Dental School, Okayama, Japan The incidence of metastatic cancer to the oral region is approximately 1% of all oral malignant tumors. It is well known that the most frequent metastatic sites are the jaws, in which metastasis is presented as osteoclast mediated osteolysis. Metastatic tumors in the jaws often cause significant morbidity such as intractable neuralgic pain and difficulty in oral feeding, consequently, declining the quality of patients, lives. Despite the clinical importance, there is scarce information about the mechanism of this metastasis and its treatment. Therefore, we examined the effects of third generation bisphosphonate (YM175), a very potent inhibitor of osteoclastic bone resorption, in an experimental jaw metastasis model in nude mice using breast cancer cells. The in-
tracardiac injection of human breast cancer cell line MDA231 significantly leads to osteolytic metastases at the mandibular angle and molar regions of the mandible with a pattern of distribution that closely mimicks the pattern of jaw metastasis in humans. Starting with the inoculation of MDA231 cells into the left heart ventricle, YM175 (6 gg/ mouse/day) or PBS(control) was subcutaneously administrated daily for 4 weeks. After this period, the metastatic MDA231 cells preferentially and aggressively developed in the medullary cavity of the premolar-molar and angle regions of the untreated mandible. Numerous osteoclasts were present along the trabecular bone surfaces with aggressive bone resorption. YM175, however, significantly inhibited the development of osteolytic bone metastases in the jaw, as assessed by radiography and histological sections. These results suggested that an inhibitor of osteoclastic bone resorption, bisphosphonate, may be a useful new adjuvant therapy for the treatment of cancers that have colonized bone in the jaw.
3. Synergistic Induction of the Expression of Cell Adhesion Molecules by Cisplatin and 5-fluorouracil in a Human Cancer Cell Line
Takizawa, K., Kamijo, R., lto, D., Nagumo, M. Second Department of Oral and Maxillofacial Surgery, Schod of Dentistry, Showa University, Tokyo, Japan For the treatment of squamons cell carcinoma, chemotherapy, as well as other treatments such as surgical operation, is widely accepted to be effective. Cisplatin (CDDP) and 5-fluorouracil (5-FU) are common antitumor agents used effectively for the treatment of patients with head and neck cancer. In this study we examined whether CDDP and 5-FU, alone or in combination, could modulate the expression of cell adhesion molecules, which are involved in recognition of cancer cells by T lymphocytes, on a squamous cell carcinoma cell line, NA. When N A cells were exposed to CDDP and 5-FU for 18 hours, the expression of intercellular adhesion molecule-1 (ICAM-1) was synergistically induced, whereas C D D P or 5F U alone could not induce the expression ICAM-1 as determined by flow cytometry. Expression of other cell adhesion molecules such as VCAM-1 and E-selectin on N A cells was also synergistically upregulated by simultaneous treatment with CDDP and 5-FU. In contrast, the expression of Ecadherin on N A cells was not upregulated by the treatment with CDDP and/or 5-FU. RT-PCR analysis revealed that the induction of these cell adhesion molecules on N A cells might be due to transcriptional induction of m R N A s encoding these cell adhesion molecules. The expression of lymphocyte function associated antigen-1 (LFA-1), a counter-receptor of ICAM-1 on T lymphocytes, was not up-regulated by the treatment with CDDP and/or 5-FU. Our results suggest that the combined treatment with CDDP and 5-FU may be beneficial in generating optimal antigen presentation of cancer cells to T lymphocytes.
023-C1Tumor biology
0 2 3 - C 1 Tumor b i o l o g y
1. Antitumor Activity of the Angiogenesis Inhibitor TNP470 in,Rabbits with VX2 Carcinoma of the Tongue
Ninomiya, Y., Matsumoto, K., Wakae, H., Tomioka, T. Fukuoka Dental College, Fukuoka, Japan It is well established that tumor angiogenesis plays an important role in tumor progression. A semisynthetic analogue of fumagillin, TNP-470, has been shown to be a potent angiogenesis inhibitor that prevents tumor growth. In this study, we studied the activity of TNP-470 upon intra-tumor (i.t.) injection versus i.v. injection using rabbits with VX2 carcinoma of the tongue. The i.v. injection of TNP-470 showed an inhibitory effect on tumor growth with 37% inhibition at a concentration of 20 mg/kg and 66% at 40 mg/kg. The i.t. injection of TNP-470 markedly inhibited the growth of the tongue tumor with 71% inhibition at a concentration of 5 mg/kg and 93% at 10 mg/kg, indicating that the activity of low dose TNP-470 upon i.t. injection was even stronger than that,of the i.v. injection. The expression of proliferating cell nuclear antigen (PCNA) of the tumor cells was analyzed by the CAS 200 computer system. The ratio of PCNA expressing cells was significantly decreased by i.t. injection of TNP-470 at 10 mg/kg, confirming the strong inhibitory effect of i.t. treatment on tumor growth. Microvessels in the tumor tissue were immunohistologically identified using anti-CD31 antibody. The number of microvessels was reduced to 20% of that in the control by the i.t. injection of TNP-470 (10 mg/kg). These data suggest that i.t. injection of the low dose angiogenesis inhibitor has a strong inhibitory activity against tumor angiogenesis and growth in rabbits with carcinoma of the tongue.
2. Effect of Bisphosphonate on an Experimental Jaw Metastasis Model in Nude Mice
Nishiyama, A., Sasaki, A., Lim, D. D. J., Alcalde, R. E., Etoh, Y, Suzuki, A., Matsumara, T. Department of OMS II, Okayama University Dental School, Okayama, Japan The incidence of metastatic cancer to the oral region is approximately 1% of all oral malignant tumors. It is well known that the most frequent metastatic sites are the jaws, in which metastasis is presented as osteoclast mediated osteolysis. Metastatic tumors in the jaws often cause significant morbidity such as intractable neuralgic pain and difficulty in oral feeding, consequently, declining the quality of patients, lives. Despite the clinical importance, there is scarce information about the mechanism of this metastasis and its treatment. Therefore, we examined the effects of third generation bisphosphonate (YM175), a very potent inhibitor of osteoclastic bone resorption, in an experimental jaw metastasis model in nude mice using breast cancer cells. The in-
tracardiac injection of human breast cancer cell line MDA231 significantly leads to osteolytic metastases at the mandibular angle and molar regions of the mandible with a pattern of distribution that closely mimicks the pattern of jaw metastasis in humans. Starting with the inoculation of MDA231 cells into the left heart ventricle, YM175 (6 gg/ mouse/day) or PBS(control) was subcutaneously administrated daily for 4 weeks. After this period, the metastatic MDA231 cells preferentially and aggressively developed in the medullary cavity of the premolar-molar and angle regions of the untreated mandible. Numerous osteoclasts were present along the trabecular bone surfaces with aggressive bone resorption. YM175, however, significantly inhibited the development of osteolytic bone metastases in the jaw, as assessed by radiography and histological sections. These results suggested that an inhibitor of osteoclastic bone resorption, bisphosphonate, may be a useful new adjuvant therapy for the treatment of cancers that have colonized bone in the jaw.
3. Synergistic Induction of the Expression of Cell Adhesion Molecules by Cisplatin and 5-fluorouracil in a Human Cancer Cell Line
Takizawa, K., Kamijo, R., lto, D., Nagumo, M. Second Department of Oral and Maxillofacial Surgery, Schod of Dentistry, Showa University, Tokyo, Japan For the treatment of squamons cell carcinoma, chemotherapy, as well as other treatments such as surgical operation, is widely accepted to be effective. Cisplatin (CDDP) and 5-fluorouracil (5-FU) are common antitumor agents used effectively for the treatment of patients with head and neck cancer. In this study we examined whether CDDP and 5-FU, alone or in combination, could modulate the expression of cell adhesion molecules, which are involved in recognition of cancer cells by T lymphocytes, on a squamous cell carcinoma cell line, NA. When N A cells were exposed to CDDP and 5-FU for 18 hours, the expression of intercellular adhesion molecule-1 (ICAM-1) was synergistically induced, whereas C D D P or 5F U alone could not induce the expression ICAM-1 as determined by flow cytometry. Expression of other cell adhesion molecules such as VCAM-1 and E-selectin on N A cells was also synergistically upregulated by simultaneous treatment with CDDP and 5-FU. In contrast, the expression of Ecadherin on N A cells was not upregulated by the treatment with CDDP and/or 5-FU. RT-PCR analysis revealed that the induction of these cell adhesion molecules on N A cells might be due to transcriptional induction of m R N A s encoding these cell adhesion molecules. The expression of lymphocyte function associated antigen-1 (LFA-1), a counter-receptor of ICAM-1 on T lymphocytes, was not up-regulated by the treatment with CDDP and/or 5-FU. Our results suggest that the combined treatment with CDDP and 5-FU may be beneficial in generating optimal antigen presentation of cancer cells to T lymphocytes.