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We examined the anti-metastatic effect of a newly developed inhibitor of synthetic matrix metalloproteinase (MMP), ONO-4817, on experimental pulmonary metastasis of murine renal cell carcinoma (Renca) cells and on tumor cell invasion, through reconstituted basement membrane (Matrigel) in vitro using the same cells. Oral administration of ONO-4817 (50-200 mg/kg/day) to Renca-bearing mice resulted in a dose-dependent inhibition of lung metastasis without a loss of body weight. ONO-4817 at the high dose of 200 mg/kg showed a tendency to prolong the survival of the mice. We also found that oral administration of ONO-4817 significantly inhibited the angiogenic response (number of vessels oriented towards the tumor mass) and the growth of tumors inoculated i.d. in syngeneic mice. In addition, ONO-4817, at non-cytotoxic concentrations of less than 10 microM, caused a marked inhibition of the invasion of Renca cells as compared to the vehicle control. Gelatin zymography revealed that ONO-4817 inhibited the enzymatic activity of MMP-2 produced by Renca cells in a concentration-dependent manner. In conclusion, ONO-4817 effectively inhibited lung metastasis of Renca cells through its anti-invasive and anti-angiogenic properties. These results suggest that use of the MMP inhibitor (MMPI) ONO-481 7 may provide a therapeutic basis for preventing lung recurrence and metastasis of renal cell carcinoma.

Several studies have shown that the Kampo medicine Juzen-taiho-to (Si-Quan-Da-Bu-Tang in Chinese) has various biological activities, including anti-tumor effects when combined with surgical excision or with chemotherapeutic drugs. Here we investigated the effect of combined therapy with interferon (IFN)-alpha A/D and Juzen-taiho-to on experimental lung metastasis of murine renal cell carcinoma (Renca) cells. Five consecutive administrations of IFN-alpha A/D to Renca-bearing mice resulted in dose-dependent inhibition of lung metastasis. IFN-alpha A/D at the dose of 100,000 IU/mouse significantly inhibited the metastasis, but a marked loss of body weight was observed during and after the administration. In contrast, oral administration of Juzen-taiho-to (50 mg/mouse) alone tended to inhibit the metastasis, but the effect was not statistically significant. The combination treatment of suboptimal doses of IFN-alpha A/D and Juzen-taiho-to markedly augmented the antimetastatic effect without causing any loss of body weight, as compared with either treatment alone. Similar results were also obtained by treatment with IFN-gamma in combination with Juzen-taiho-to. Clinically, immunotherapy with IFNs has been primarily approved for the treatment of patients with metastatic renal cell carcinoma, but sufficient efficacy has not yet been obtained. Therefore, the combination of IFNs with Juzen-taiho-to may provide a means to increase the therapeutic potential of IFNs and to decrease their toxicity for the treatment of metastatic renal cell carcinoma.

Thirty five patients with renal pelvic and ureteral tumors were treated at our hospital between 1979 and December 1992. Thirty patients were male and five were female. They ranged in age from 44 to 80 years old (average 67.4 years). The most frequent symptoms were hematuria that was found in 31 cases (24 gross hematuria and 7 microscopic hematuria). Histopathologically, there were 30 transitional cell carcinomas (TCC), 1 squamous cell carcinoma (SCC), 2 TCC > SCC and 1 papillary adenocarcinoma. As to staging, 1 was pTis, 5pTa, 11pT1, 3pT2, 11pT3 and 4pT4. As to grading, 9 were G1, 16 G2 and 9 G3. The incidence of cancerous vessel invasion was noted in 8 of the 29 patients. The 5-year survival rate (Kaplan-Meier's method) was 44.9% for all of the patients. The 5-year survival rate according to staging and according to grading were as follows: 76.7% for low stage (pTis, pTa, pT1, pT2), 24.9% for high stage (pT3, pT4), and 83.3% for G1, 59.9% for G2 and 0% for G3. The 5-year survival rate was 20.8% and 68.7% in the patients with and without vessel invasion, respectively. Grade, stage and cancerous vessel invasion was suggested to be associated with the prognosis in renal pelvic and ureteral tumors.