Combined treatment with TNP-470 and 5-fluorouracil effectively inhibits growth of murine colon cancer cells in vitro and liver metastasis in vivo.

The combined effects of TNP-470 (TNP), a semisynthetic analogue of fumagillin, and 5-fluorouracil (5FU), a representative chemotherapeutic agent for colorectal cancer, were investigated using murine colon 26 adenocarcinoma (CT 26) cells. In a cell-proliferation study in vitro, 50% inhibitory concentrations (IC50) were determined to be 5.2 microg/ml and 240 ng/ml for TNP and 5FU, respectively. When CT 26 cells were treated with TNP and 5FU in combination, a remarkable cytotoxic effect was obtained. Isobologram analysis revealed synergism of these two agents in inhibition of the cell growth. In vivo, using a dorsal air sac assay, we found that TNP significantly inhibited the CT 26-induced angiogenesis. In addition, the combination of TNP and 5FU exerted a synergistic anti-tumor effect in a model of hepatic metastasis by portal injection of CT 26 cells. Since TNP is known to exert inhibitory effects on tumor cell growth through suppression of cell cycle progress from the G1 to S phases as well as neovascularization, it is speculated that the treatment with TNP enhanced the anti-tumor effect of 5FU through suppression of the cell cycle and tumor-derived angiogenesis. Taken together, these results suggest that combined treatment with TNP and 5FU is potentially useful for inhibition of tumor cell growth and liver metastasis of colorectal cancer.

TNP-470 antiangiogenic therapy for advanced murine neuroblastoma.

The finding that angiogenesis plays an important role in the progression and metastasis of malignant tumors has led to the development of several antiangiogenic drugs. The authors report here an examination of the effect of the antiangiogenic agent TNP-470 on the growth, metastases, and survival of two differing murine neuroblastoma cell lines, TBJ and C1300. We found that TNP-470 significantly reduced primary tumor volumes in mice injected with either cell line. In addition, antiangiogenic therapy significantly reduced the size of axillary lymph node metastases in both groups as well as decreased the size of liver metastases in mice receiving TBJ neuroblastoma. TNP-470 treatment also improved animal survival. These data suggest that antiangiogenic therapy retards the growth of primary and metastatic murine neuroblastoma. We speculate that antiangiogenic therapy may be a useful therapeutic modality in the treatment of advanced neuroblastoma once side effects and appropriate dosage requirements are determined.

[Two hepatocellular carcinoma patients with biloma after transarterial embolization with lipiodol (Lip-TAE) leading to occlusion of portal vein].

We presented two patients with post-Lip-TAE biloma resulting in portal occlusion, and reviewed 20 previous studies including our cases to investigate their clinical characteristics. Case 1. A 31-year-old woman suffered from an HCC located at the S8 segment, and had a superselective embolization of feeding arteries using 3 ml of Lip, 300 mg of CBDCA, and 40 mg of Epi-Adriamycin (Epi-ADM). Eleven weeks later, CT showed multiple cystic lesions, and the percutaneous transhepatic drainages of the lesions were established. At 21 weeks after Lip-TAE, we found occlusion of the right branch of portal vein on CT, but she recovered from this condition, and was discharged 1 year later. Case 2. A 62-year-old man was diagnosed as HCC located at S7-6 segments, and was infused with 3 ml of Lip, 150 mg of CBDCA, and 30 mg of Epi-ADM through a right hepatic artery. Ten weeks later, CT showed a cystic lesion in the S7-8 segments, occlusion of the right anterior segmental branch of the portal vein, and the same drainage was also established. Unfortunately, he died of liver failure 18 weeks later. In the literature, biloma after Lip-TAE occurred at 71.2 mean days, ranging from 7 to 180 days, a with remarkable increase in biliary tree-associated enzymes. Seven (35%) of 20 patients died of liver failure or sepsis during 3 weeks and 1 year, and 3 (60%) of 5 patients accompanied by occlusion of a certain portal branch frequently died. We consider that these patients need intensive care and should be under long follow-up.

Effect of cadmium in the zinc deficient rat.

Three-w-old male Sprague-Dawley rats were given a zinc (Zn)-deficient (0 ppm Zn) or a Zn-adequate diet (30 ppm Zn) supplemented with 0, 0.5 or 100 ppm cadmium (Cd) for up to 5 mo. The proximal convoluted tubules of the kidneys had degenerative changes in the rats fed the Zn-deficient diet containing 100 ppm Cd [Zn 0, Cd 100], but there were no lesions in other groups. Electron microscopy showed cytoplasmic vacuolation of the proximal tubules, mitochondrial swelling and coagulative necrosis in Zn 0:Cd 100 rats. The present study revealed diminished bone growth and cortical thinning of the femur, but there was no osteomalacia seen in Itai-Itai disease patients. The results indicate that Zn deficiency may enhance the renal toxicity of Cd, but that dietary Cd did not cause osteomalacia even under severe Zn-deficient conditions.

[A case of metastatic breast cancer successfully treated with weekly low-dose epirubicin (EPI), cyclophosphamide (CPA), 5-fluorouracil (5-FU) and medroxyprogesterone (MPA)].

We reported a case of successful treatment of disseminated breast cancer with epirubicin (EPI), 5-fluorouracil (5-FU), and medroxyprogesterone (MPA). The patient was a 49-year-old female with bone and liver metastasis developed 5 years after surgery. The primary tumor was ER-positive, and she had been treated previously with adjuvant therapy using UFT and tamoxifen. The treatment consisted of 3 cycles of thrice-weekly EPI (40mg), 5-FU (500mg) and CPA (500mg). The patient was then treated with a weekly schedule of EPI (10mg), 5-FU (50mg/day), CPA (50mg/day) and MPA (400mg/day). After 2 years, her bone and liver metastasis showed remarkable remission (PR). No side effects of this chemotherapy were observed. In the search for palliative treatments which have a minimal impact on normal lifestyle, low toxicity is important. PR was continued for 2 years, and the patient enjoyed a favorable quality of life. This low dose-weekly approach was very well tolerated, yet was effective.

[Efficacy of transarterial embolization combined with percutaneous ethanol injection therapy for recurrent hepatocellular carcinoma].

One hundred and eighty-nine patients with hepatocellular carcinoma (HCC) underwent hepatectomy since 1987 to 1992 in our institute. Recurrences were detected on residual liver in 84 patients up to December 1993. Sixty-seven of 84 patients were treated with re-resection (group-O, n = 11), transarterial embolization (TAE) combined with percutaneous ethanol injection therapy (PEIT) (group-TP, n = 13), TAE alone (group-T, n = 34) and intraarterial chemotherapy (group-IA, n = 9). Among these 67 cases, the efficacy of treatment for recurrences was investigated. There was no significant difference in age, positive ratio of hepatitis B virus, ICG R15 and percentage of underlying liver cirrhosis among the 4 groups. However, the frequency of patients with 2 nodules or less, was significantly higher in group-O than in other groups. Cumulative 1-, 2- and 3-year survival rates (%) were 88.9, 64.8 and 51.9 in group-O, 92.1, 55.4 and 55.4 in group-TP, 70.9, 49.6 and 31.0 in group-T, and 16.9, 0 and 0 in group-IA, respectively. The survival rate after recurrences in group-TP was higher than in group-IA and group-T, and almost equivalent to that of group-O. Either re-resection or TAE combined with PEIT might assure- a favorable prognosis in patients with recurrent HCC.

[Progress in targeting therapy for hepatic cancer].

Targeting therapy for hepatic cancer is divided into a method using Lipiodol as drug carrier and a method employing immunological responses of monoclonal antibodies to the tumor antigens. For the latter method, immuno-conjugates of antibodies and cytotoxic agents have been studied. Because of the lower response rates of conventional chemotherapy. Lipiodol as drug carrier provides the most effective targeting therapy on hepatic cancer at the present time. Immunotherapy using cytotoxic cells, however, did not result in sufficient clinical efficacy on the liver cancer. The system for accumulation of the effective and sufficient number of cytotoxic cells or immunoconjugates in the targeting tumor tissues are expected to be investigated.

[A case of double cancer of gastric and hepatocellular carcinoma associated with cirrhosis treated by hepatic resection after intra-hepatic arterial infusion chemotherapy].

A case of double cancer, early gastric cancer and hepatocellular carcinoma, was reported. The patient was diabetic and had liver cirrhosis. After gastrectomy for gastric cancer which was hemorrhagic, he was treated by intra-hepatic arterial infusion chemotherapy followed by hepatic resection. Histopathologically, about half of the main tumor showed necrosis, but very viable new cancer cell nests were seen around the main nodule. The patient is in good condition without recurrence of hepatic lesion 1 year after resection. The usefulness of arterial infusion chemotherapy was demonstrated in the case of double cancer, in which it is difficult to resect both cancers simultaneously.