bropirimine and Kidney-Neoplasms

Urological cancers have a variety of biological characteristics. Thus, anti-cancer agents in this field are often developed focusing on the biological characteristics. For example, LH-RH agonist and anti-androgens have been developed for androgen-sensitive prostate cancer, interferons and IL-2 for renal cell cancer, and BCG for superficial bladder cancer. In this manuscript, new agents which are thought to be promising in the urological field, bropirimine for bladder cancer and liarozole for prostate cancer, are briefly introduced.

Topics: Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Carcinoma, Renal Cell; Cytosine; Humans; Imidazoles; Kidney Neoplasms; Male; Prostatic Neoplasms

Bropirimine [2-amino-5-bromo-6-phenyl-4-(3H)-pyrimidinone] is a low-molecular-weight compound that acts as an inducer of interferon in several animal species. Experiments were designed to explore the possibility of using this drug for the treatment of renal-cell carcinoma (RCC). Euthymic BALB/c mice were inoculated with murine RCC (Renca) cells and given graded doses of Bropirimine p.o. for 5 consecutive days beginning on day 1 following tumor inoculation. These mice were killed and tumors were excised on day 21. Bropirimine significantly (P < 0.01) inhibited the tumor growth at a daily dose of 1,000 or 2,000 mg/kg. No adverse effect or toxicity was noted at 1,000 mg/kg, and at 2,000 mg/kg there was only a marginal body-weight reduction without any other appreciable side effect. In addition to the inhibition of tumor growth, there was a small yet significant (P < 0.05) increase in the duration of survival (in days) in the Bropirimine-treated animals. When the treatment was delayed to begin on day 6 following tumor inoculation, Bropirimine did not suppress tumor growth in euthymic mice, pointing to the importance of the timing of the treatment. In athymic nude BALB/c mice lacking T-cells or T-cell function, Bropirimine also inhibited tumor growth (P < 0.01). The antitumor effect of this drug was abolished by pretreatment with anti-asialo GM1 serum, which eliminated natural killer (NK) activity in euthymic mice. In vivo treatment with Bropirimine augmented the cytotoxicity of lymphocytes isolated from the spleens or lungs of the tumor-bearing mice, which were active against Renca and YAC-1 cells in vitro. This activity was NK-cell-dependent as judged on the basis of the results of the in vitro complement-dependent cytotoxicity assay. Since Bropirimine induced interferon (IFN)-alpha/beta production, significantly (P < 0.05) elevating its serum concentration, and since this drug mimics the effects of IFN-alpha/beta, it seemed likely that the Bropirimine-induced NK cell augmentation we found was mediated by IFN-alpha/beta. These results suggest that Bropirimine, a booster of NK activity, may have potential as an adjunct to other therapeutic modalities in the treatment of human RCC.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cytosine; Cytotoxicity Tests, Immunologic; Female; Interferon Inducers; Interferons; Kidney Neoplasms; Killer Cells, Natural; Mice; Mice, Inbred BALB C

Aryl pyrimidinones, including bropirimine, exert anti-tumor activity through the induction of interferon (IFN)-alpha. Herein, the direct anti-tumor effect of bropirimine on 17 renal cell carcinoma (RCC) surgically obtained was examined using an organ culture system closely resembling the in vivo state, and also using the heterotransplanted nude mouse system. The findings obtained using the organ culture system showed that bropirimine inhibited 3H-thymidine uptake significantly in 15 of the 17 RCC (88.2%) compared with the control. Furthermore, the 3H-thymidine uptake was dose-dependently inhibited in 3 of the 17 tumors (17.6%). The oral administration of bropirimine against RCC heterotransplanted in nude mice (JRC 901: an erythropoietin-producing strain) tended to inhibit tumor growth dose-dependently, but not significantly (mean tumor weight ratio: T/C ratio: over 43%, degeneration degree of tumor: incomplete). However, the production of erythropoietin from the JRC 901 was significantly inhibited. These findings suggest that bropirimine has a direct anti-tumor activity, without the mediation of IFN-alpha induction, against human renal cell carcinoma.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cytosine; Drug Screening Assays, Antitumor; Humans; Interferon Inducers; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Organ Culture Techniques