Takao Inada

Effect of preoperative 5-fluorouracil on apoptosis of advanced gastric cancer

Several studies have reported on apoptosis and the effect of anticancer chemotherapy.

Severe 5-fluorouracil-related toxicity in a Japanese patient with dihydropyrimidine dehydrogenase deficiency

Abstract Dihydropyrimidine dehydrogenase (DPD) is the major enzyme involved in the catabolism of pyrimidines and fluoropyrimidines. Severe 5-fluorouracil (5-FU) toxicity has been reported in patients with DPD deficiency in Western countries. We now report a case of 5-FU-related severe toxicity in a Japanese patient with DPD deficiency. A-44 year-old woman with gastric cancer associated with peritoneal dissemination underwent palliative gastrectomy at the Tochigi Cancer Center. After surgery, she was treated with a combination of mitomycin C (12.5 mg/m2, bolus iv) and 5-FU (312.5 mg/m2 per day, continuous infusion). Eight days after commencement, the chemotherapy was discontinued because of severe gastrointestinal toxicity.On day 12 the patient developed a high fever with granulocytopenia (617.4 granulocytes/μl). DPD-activity in peripheral blood mononuclear cells (PBMC) was extremely low (up to 8.9 pmol/mg protein per min) and serum and urine uracil concentrations were high, at 225.2 ng/ml and 2334.2 ng/mg creatinine, respectively. To our knowledge, this appears to be the first case of 5-FU-related severe toxicity due to DPD deficiency reported in a Japanese patient.

Interferon alpha-2a shows antitumor activity in combination with 5-fluorouracil against human colon carcinoma xenografts : a study in reference to thymidylate synthetase activity inhibition

To clarify the mode of antitumor activity shown by a combination of recombinant human interferon alpha-2a (IFN) and 5-fluorouracil (5-FU), experimental therapy was performed on human colon carcinoma (Co-4) xenografts serially transplanted into nude mice, using IFN and 5-FU, either alone or in combination. IFN alone showed dose-dependent antitumor activity and 5-FU also revealed a moderate antitumor effect. Although IFN, given as 600,000 units/mouse daily sc×14, and 5-FU, given as 60 mg/kg q4d×3 ip, showed additive antitumor activity against Co-4, the thymidylate synthetase (TS) inhibition rate was unchanged in the tumors treated with the IFN/5-FU combination in comparison with those treated with 5-FU alone. This suggests that the antitumor activity of IFN and 5-FU in combination does not involve augmentation of the TS inhibition by 5-FU.

Long-term postoperative survival of a gastric cancer patient with numerous para-aortic lymph node metastases

A56-year-old man with advanced gastric cancer was referred to our hospital. Preoperative abdominal computed tomography revealed numerous enlarged lymph nodes, including the lymph nodes of the paraaortic region. The patient underwent total gastralectomy, splenectomy, left-adrenalectomy and resection of the body and tail of the pancreas by Applebys method, along with paraaortic lymph node dissection. Microscopic examination revealed that the tumor was a solid type, poorly differentiated adenocarcinoma, which displayed invasion of the serosal surface. There were apparently many lymph node metastases. We identified 31 cancer-positive paraaortic nodes, while the total number of lymph node metastases was 81. It was not possible to administer sufficient postoperative adjuvant chemotherapy, as the patient experienced postoperative complications, including pancreatic fistula and watery diarrhea. Despite the lack of sufficient chemotherapy, the patient has subsequently remained disease-free for 9 years and 3 months, and continues to visit our hospital as an outpatient. In conclusion, we wish to emphasize the need for a critical application of paraaortic lymph node dissection as one modality of multidisciplinary treatment in patients with advanced gastric cancer in whom paraaortic lymph node metastasis is strongly suspected preoperatively.

A pharmacodynamic and pharmacokinetic study of fluoropyrimidines in a nude mouse system and in postoperative patients with gastric cancer

To evaluate the effect of the oral fluoropyrimidines, tegafur and uracil (UFT) and 5-fluorouracil (5-FU), a pharmacodynamic analysis was conducted using a nude mouse system and patients. In the nude mouse system, UFT and 5-FU showed similar marginal effects against the human tumor xenograft Co-4, and the concentration of 5-FU in serum 1 h after the last administration being 0.04 μg/ml, which was assumed to be the minimum effective concentration. (MEC). Postoperative patients were subdivided into three groups, being: those who underwent subtotal gastrectomy and received UFT; those who underwent subtotal gastrectomy and received 5-FU; and those who underwent total gastrectomy and received UFT. In the UFT groups, the concentration of 5-FU in the portal and peripheral blood showed similar elimination in terms of the peak concentration (Cmax) and the area under the curve (AUC). In the 5-FU groups, the AUC and Cmax were significantly higher in portal blood than peripheral blood. The concentrations in the portal blood of the 5-FU group and in the portal and peripheral blood of the UFT group were significantly higher than the MEC (0.04 μg/ml). From these pharmacodymamic data, it was concluded that postoperative chemotherapy with oral fluoropyrimidines can achieve the MEC in portal and peripheral blood.

Evaluation of the Pylorusfunction after Pylorus-Preserving Distal Gastrectomy by the Gastrointestinal and Biliary Scintigraphy.

幽門保存胃切除例(pylorus preserving distal gastrectomy: 以下, PPDG と略記)8例を対象として, 消化管・胆道シンチグラフィーによる術後機能評価を行い, 早期胃癌術前症例および通常の幽門側切除, Billroth-1法吻合症例(以下, B-1と略記)との比較を行った. 胆道シンチグラフィーによる胆汁排泄開始時間はPPDG群, 術前群, B-1群において有意な差異は認められなかった. また胆汁の残胃内逆流は, B-1では40%以上に認められるのに対し, PPDG群では術後6か月, 1年ともに, 術前群と同様に認められなかった. 消化管シンチグラフィーによる食物の胃からの排出は, PPDG群では術後6か月において, 術前群, B-1群と比べて有意な停滞が認められるものの, 術後1年の比較では, B-1群と差が認められず, 幽門機能の経時的な回復が示唆された.

THE MODULATING EFFECT OF INTERFERON ALPHA-2A ON THE ANTITUMOR ACTIVITY OF UFT AGAINST A HUMAN GASTRIC CARCINOMA XENOGRAFT, SC-1-NU, IN NUDE MICE

The modulating effect of recombinant human interferon alpha-2a (IFN) on the antitumor activity of UFT, a mixed compound of tegafur and uracil at a molar ratio of 1:4, was investigated against SC-1-NU, a human gastric cancer xenograft serially transplanted in nude mice. IFN was administered subcutaneously at a dose of 60,000 IU/mouse daily for 14 days, and UFT was given at a dose of 15 mg/kg as tegafur daily, except on Sundays, for 3 weeks. The agents were administered either alone or simultaneously. Synergistic antitumor activity on SC-1-NU was produced by the combination of IFN and UFT without any increment of side effects, and the combination therapy also increased intratumoral thymidylate synthetase (TS) inhibition and the amount of 5-fluorouracil (5-FU) in the intratumoral RNA. Thus, IFN seems to modulate the antitumor activity of UFT against SC-1-NU through an inhibition of DNA synthesis and RNA distortion, and therefore this combination could be useful for clinical application.

Apoptosis and Proliferative Activity of Advanced Gastric Cancer.

術前未治療進行胃癌切除例101例を対象として, 組織学的進行度と腫瘍細胞のS期分画 (S-phase fraction), apoptosis, bcl-2蛋白 (Bcl-2) 発現を検討し, 進行胃癌における増殖活性とapoptosisの関与を検討した.腫瘍細胞のS-phase fraction, apoptosisはflow cytometryによるapoptosis-DNA二重染色により, Bcl-2発現は免疫組織染色にて検討した.S-phase fractionはstage IV症例において高かったが, 他の因子と進行度との関連は見られなかった.apoptosis分画はBcl-2陽性例では陰性例に比べ有意に低く, また組織分化度より見るとBcl-2の発現は未分化型において高率であった.未分化型のS-phase fractionは分化型に比べ高く, S-phase fractionとapoptosis分画の間に逆相関の傾向が認められた.したがってapoptosisそのものは癌進行度との直接関係は認められないが, Bcl-2陽性例では低いことから, 腫瘍増殖を規定する一因である可能性が示唆された.

A Case of Esophageal Carcinoma, which Responded to Radiochemotherapy, Covering the Surface of Esophageal Leiomyoma.

症例は54歳男性.1990年6月集団検診にて食道の異常を指摘され当院を受診.食道造影で胸部上部食道に20×16×10mm大の隆起性病変を認め, 内視鏡で表面にびらんを伴う表在隆起型食道癌と診断した.腫瘤表面よりの生検では扁平上皮癌が得られた.治療は放射線照射50Gyと5-Fu 1,000mg/m2/dayおよびシスプラチン25mg/m2/dayをともに5日間持続静注による化学療法2コース施行した.治癌効果判定で腫瘍の縮小が認められなかったため1991年3月7日手術を施行した.病理組織学的には隆起性病変は正常食道粘膜に覆われており, 腫瘍は粘膜筋板より発生した平滑筋腫であった.腫瘍の表面上皮には生検材料で見られた癌細胞は認められなかった.平滑筋腫を覆う上皮に一致して癌が併存していたが, 放射線化学療法により癌は消失し, 平滑筋腫のみ残存したものと考える.