Suppression effects of human recombinant tissue inhibitor of metalloproteinases-1(TIMP-1) on tumor proliferation using in vivo treatment model of well-differentiated colon cancer cell line, HT29.
To investigate the suppressive effect of human recombinant TIMP-1 (rh-TIMP-1) on tumor proliferation using an in vivo xenograft system, HT29 was suspended in 0.1 ml phosphate buffered saline (PBS) and then subcutaneously injected in the back of female mice (BALB/C nu/nu). The mice were divided into 2 groups an and the tumor diameter was measured after rh-TIMP-1 (2 mg/kg) (rh-TIMP-1 group) or PBS (control group) was administered injections according to the following schedules. Schedule 1 : Beginning 2 weeks after the subcutaneous injection of HT29, an intraperitoneal injection of rh-TIMP-1 or PBS were performed twice a day (every 12 h) for 14 consecutive days. Schedule 2 : Beginning 1 week after the subcutaneous injection of HT29, an intraperitoneal injection was performed twice a day for 14 consecutive days. Schedule 3 : Intraperitoneal injections were started simultaneously with the subcutaneous injection of HT29, and then performed twice a day for 21 consecutive days. The mice were sacrificed and the tumors extirpated for immunohistochemical investigation. In addition, gelatin zymography and a cell proliferation assay were performed. With Schedule 1, the changes in the tumor diameter in the rh-TIMP-1 group followed the same course as those in the control group, and no suppressive effect on tumor proliferation was observed. However, with Schedule 3, a remarkable suppressive effect was observed throughout the treatment period. In immunostaining, more cases negative for MMP-9 were observed in the rh-TIMP-1 group than in the control group. Cases negative for CD34 were significantly more observed in the rh-TIMP-1 group than in the control group with Schedule 3. All of the results were obtained through the suppressive effect of rh-TIMP-1 on angiogenesis.
Ohtani
Yuu
Y
Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan. ccw02410@hkg.odn.ne.jp
Aoe
Motoi
M
Hara
Fumikata
F
Tao
Hiroyuki
H
Koshimune
Ryuichiro
R
Hirami
Yuuji
Y
Hanabata
Tetsuro
T
Shimizu
Nobuyoshi
N
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology*
D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D045726:Metalloproteases