p53 inhibits vascular endothelial growth factor expression in solid tumor.

BACKGROUND: The p53 tumor-suppressor gene is one of the most frequently mutated genes in cancers, and its mutations affect various biological actions, such as tumor growth, apoptosis, and so on. During hypoxia, p53 is stabilized by interaction with hypoxia-inducible factor-1 (HIF-1). This interaction raised the possibility for regulating HIF-1 activity by p53, which is still to be elucidated. METHODS: First, we introduced various types of the p53 mutant gene into Hep3B and evaluated the role of p53 in hypoxic responses, including vascular endothelial growth factor (VEGF) production and HIF-1 activation. Second, Hep3B-vector cells and Hep3B-p53 cells were subcutaneously injected into BALB/c (nu/nu) mice, and tumor progression and the hypoxic responses were analyzed. Finally, we investigated the role of the p53 mutant genes in the level of vascularity in human pancreatic neoplasia. RESULTS: Here, we showed that expression of wild-type p53, but not null or mutated p53, significantly suppressed HIF-1 activity and production of VEGF, which mostly depends on the HIF-1ß protein level. In a tumor xenograft model, we consistently found that loss of p53 promotes VEGF production, neovascularization, and tumor progression via accumulation of HIF-1ß protein. Furthermore, in clinical pancreatic neoplasia, tumors with mutated p53 have significantly higher levels of vascularity than those with wild-type p53. CONCLUSION: These results indicate that loss of p53 contributes to neovascularization through regulation of HIF-1.

Spontaneous esophageal rupture treated with staged operations.

Spontaneous esophageal rupture is a life-threatening entity. Here, a 64-year-old male who presented with sudden onset of severe back pain was diagnosed as having an esophageal rupture to the right pleural cavity. Emergency operation was carried out 16 hours after the onset. The rupture was as large as 7 cm and the surrounding tissue was fragile and necrotic. We performed an esophagectomy as a primary salvage procedure. An esophageal reconstruction was carried out successfully 6 months after the initial operation. Staged operative strategy including esophagectomy is still an important option to treat this kind of high risk patient.

[A case of gastric cancer with multiple liver metastases responding to TS-1].

We report the case of a 58-year-old male with Stage IV gastric cancer accompanied by multiple liver metastases, which responded to chemotherapy using TS-1. The patient was treated with daily oral administration of 120 mg TS-1 for 4 weeks followed by 2 weeks rest as 1 cycle. After 4 cycles, most of the liver metastases had disappeared and serum CEA level was reduced from 140 to 53.9. The patient received chemotherapy at our outpatient clinic for 9 months during which time there was no regrowth after the first treatment. The current case suggests that TS-1 may have a potent therapeutic efficacy in cases of advanced gastric cancer.

[A case report of both CAF and docetaxel-resistant breast cancer responding to paclitaxel weekly therapy].

A 58-year-old woman underwent CAF and docetaxel therapy for lung, liver and bone metastases from breast cancer operated on 14 years ago. Because of progressive disease due to secondary resistance to CAF and docetaxel, the patient was given three courses of paclitaxel therapy (60 mg/m2, day 1, 8, 15, repeated every 4 weeks). The paclitaxel weekly therapy brought about no adverse effects and remarkable effects against lung and liver metastases (PR). Although the duration of the response to the paclitaxel therapy was limited to about two months due to the progression of skull bone metastasis, paclitaxel weekly therapy may be effective against both CAF and docetaxel-resistant breast cancer.

[Clinical study of weekly administration of paclitaxel for advanced and metastatic gastric cancer].

Ten cases of advanced and metastatic gastric cancer treated by weekly administration of paclitaxel were studied. The patients were 50-72 years of age, including 9 men and 1 woman. In this study, paclitaxel was administered by 1 hour intravenous infusion at a dose of 50-80 mg/m2 every week. Administration was continued for 3 weeks with 1 week rest. One to four cycles were performed at minimum. Paclitaxel was administered in 5 cases as 1st line treatment, 4 cases as 2nd line treatment and 1 case as 3rd line treatment. There were 2 partial responders and no complete responders, and the overall response rate was 20%. The response rate was 100% in liver, 100% in lung, 16% in lymphnodes, and 0% in peritonial dissemination. The clinical symptoms of pain and jaundice abated in one case, the size of the tumor decreased in one case, and a temporary decrease of ascites due to peritonial dissemination was seen in two cases. The level of tumor marker was decreased in 3 out of 10 cases. Side effects included grade 3/4 leukopenia in 10% of patients, and alopecia in 50%, but peripheral neuropathy was not observed. Weekly administration of paclitaxel appears to be well-tolerated and effective against advanced and metastatic gastric cancer.

[Clinical study of weekly paclitaxel administration for metastatic breast cancer based on time to progression (TTP) and survival].

We studied 13 women aged 29-62 years for response to weekly administration of paclitaxel for metastatic breast cancer. Paclitaxel was administered by 1-hour intravenous infusion at a dose of 60-80 mg/m2 once a week. Administration was continued for 3 weeks with a 1-week rest for at least 3 cycles. This was first-line treatment in 1 patient, second-line treatment in 7, and third-line treatment in 5. The overall response rate was 68% among 13 partial responders and there were no complete responders. By recurrence site, the response rate was 71% in the liver, 75% in the lung, 18% in bone, and 67% at local sites. Pain was ameliorated in 4 of 8 patients and local recurrence of tumors decreased in 6 of 8 cases. Tumor markers decreased in 6 of 12 cases. Time to progression reached beyond 6 months in 6 of 13 cases, and was limited to within only 3 months in 6 cases. In terms of survival, 4 of 13 patients who were treated by paclitaxel as a 3rd line treatment for liver or lung metastasis died within 3 months after administration. Weekly administration of paclitaxel appears to be effective against metastatic breast cancer. However, the selection of cases based on the timing of administration is considered to be important to prolong the time to progression and improve survival.

[A case of peritoneal metastasis of gastric cancer responding to TS-1, administered for four consecutive weeks with two-week rests].

We treated a patient with gastric cancer considered to be unresectable due to peritoneal metastasis, who responded remarkably to treatment with TS-1. The patient was a 62-year-old male. His diagnosis was gastric cancer, for which he underwent surgery on February 22, 2001. Laparotomy disclosed many nodules measuring 2-3 mm in diameter in the abdominal cavity, so rapid pathological tests were conducted during the operation. The test results indicated peritoneal metastasis from gastric cancer. Therefore, simple laparotomy was employed as the best option. On day 13 after surgery, oral administration of TS-1, bid., at a daily dose of 120 mg was commenced. In our outpatient clinic, he was given 3 courses, each comprising 4 weeks' medication and 2 weeks' discontinuation. Subsequently, upper digestive tract endoscopy was performed but only scars in the gastric vestibular area were observed. Biopsy could not detect any malignant findings. Medication was discontinued due to the patient's preference and he died of gastric cancer 10 months after operation.