Preoperative treatment with tegafur suppositories enhances apoptosis and reduces the intratumoral microvessel density of human colorectal carcinoma.
BACKGROUND
This study examined the effect of tegafur, a depot of 5-fluorouracil, in human colorectal carcinomas in terms of apoptosis, cell proliferation, and expression of p53 gene and angiogenesis-related molecules.


METHODS
A total of 32 patients with colorectal carcinoma were divided into 2 groups; 20 patients received tegafur suppositories (TS) at 1 g/day for 14 days before surgery, and 12 patients did not receive any chemotherapy. Surgically removed specimens were examined immunohistochemically for Ki-67, CD34, p53, p21, Bax, vascular endothelial growth factor (VEGF), and thymidine phosphorylase (dThdPase). Apoptotic tumor cells were visualized by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick-end labeling (TUNEL) procedure.


RESULTS
The mean percentage of apoptotic index (AI) was 6.9 +/- 1.2 in the 20 TS-treated tumors and 4.4 +/- 1.0 in the 12 nontreated tumors (P < 0.001). In contrast, the mean percentage of Ki-67 labeling index (KI) became significantly lower in the former group (P < 0.05). The frequency of p21 expression was significantly higher in the TS-treated group than in the nontreated group (P < 0.05), whereas no difference was detected in p53 and Bax expression between the two groups. The mean intratumoral microvessel density was 47.8 +/- 19.8 in the TS-treated tumors and 66.8 +/- 16.5 in the nontreated tumors (P < 0.01). The frequency of dThdPase expression, but not of VEGF expression, became significantly lower with the TS treatment. p53 expression did not correlate with AI, KI, IMV density, or the expression of VEGF, p21, or Bax, except for dThdPase, which was significantly higher in the 18 p53 positive tumors (P < 0.05).


CONCLUSIONS
Preoperative TS treatment enhances apoptosis and suppresses angiogenesis of colorectal carcinomas in a p53-independent manner.
Matsuura
T
T
First Department of Pathology, Tottori University, Yonago, Japan.
Fukuda
Y
Y
Fujitaka
T
T
Nishisaka
T
T
Sakatani
T
T
Ito
H
H
D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000032:analysis; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000737:chemistry / Q000473:pathology / Q000601:surgery*; D016228:Endothelial Growth Factors / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000032:analysis; D008222:Lymphokines / Q000032:analysis; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D011300:Preoperative Care; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2; D013488:Suppositories; D005641:Tegafur / Q000008:administration & dosage*; D013939:Thymidine Phosphorylase / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051028:bcl-2-Associated X Protein
D018952:Antigens, CD34; D000964:Antimetabolites, Antineoplastic; C494826:BAX protein, human; D016228:Endothelial Growth Factors; D019394:Ki-67 Antigen; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013488:Suppositories; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051028:bcl-2-Associated X Protein; D005641:Tegafur; D013939:Thymidine Phosphorylase