Thymidylate synthase activity after preoperative administration of 5-FU in patients with gastric or colorectal cancer

Continuous intravenous injection of 5-FU was given at 300 mg/m2 to patients with gastric or colorectal cancer for consecutive 3 days preoperatively, and the relationships between the time until collection of samples (from final administration of 5-FU to excision of tissue samples) and total thymidylate synthase (TS total) activity, free thymidylate synthase (TS free) activity, thymidylate synthase inhibition rate (TSIR), thimidine kinase (TK) activity, and tissue 5-FU and FdUMP concentrations investigated. TS total was shown to gradually reduce with time, but the relationship between time and the other assay items could not be identified due to large variability in the data. TS total and TK also proved to be affected also by the sites at which the samples were collected, and exhibited significantly higher enzyme activity in tumor tissue than that in normal tissue.     

Arsenic trioxide and the growth of human T-cell leukemia virus type I infected T-cell lines

A novel therapeutic potential for acute promyelocytic leukemia using arsenic trioxide (As(2) O(3) ) has been reported. Recent in vitro studies demonstrated that As(2) O(3) effectively inhibits the growth of some cell lines derived from patients with malignant lymphoma, chronic lymphocytic leukemia and multiple myeloma. Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T-cell origin caused by human T-cell leukemia virus type-I (HTLV-I) the prognosis of which still remains very poor. A possible role of As(2) O(3) for the treatment of ATL is demonstrated from evidence that As(2) O(3) significantly inhibits the growth of HTLV-I infected T-cell lines and induces apoptosis in fresh ATL cells at clinically achievable concentration of the agent. The growth inhibition of As(2) O(3) treated HTLV-I infected T-cell lines was induced by both apoptosis and G(1) phase accumulation. Cleaved bcl-2 protein and an enhanced expression of bak protein in the cells were coincidentally observed during As(2) O(3) treatment. A broad spectrum caspase inhibitor, z-Val-Ala-DL-Asp-fluoromethylketone inhibited the apoptosis induced by As(2) O(3). Increased expression of p53, Cip1/p21 and Kip1/p27, and dephosphorylation of retinoblastoma protein (pRb) were detected in the As(2) O(3) treated cells. In conclusion, As(2) O(3) might become a new therapeutic tool in the treatment of ATL as As(2) O(3) induces apoptosis by destruction of the bcl-2 protein and enhancement of the bak protein production proceeding to activate caspases, and also induces G(1) phase accumulation by enhancement of p53, Cip1/p21, Kip1/p27 and dephosphorylation of pRb to HTLV-I infected T-cell lines.     

Renal dysfunction in children with vesicoureteral reflux

It is well recognized that reflux nephropathy is one of the commonest causes of end-stage renal failure (ESRF) in children. We made a retrospective study of 28 children with vesicoureteral reflux (VUR) who showed impaired renal function, as defined by either the serum creatinine of more than 1.0 mg/dl or BUN of more than 20 mg/dl. There were 20 boys and 8 girls, and the incidence of both sexes was 4.8% and 1.9% respectively. Of patients, proteinuria was detected in 22, and hypertension in 7. Five patients progressed to ESRF during his or her clinical course. About half of the patients in this series presented proteinuria or growth retardation which had led to urological check-up. Bilateral reflux was demonstrated in 24 patients, and all of the remaining 4 with unilateral reflux had hypoplastic or dysplastic contralateral kidney. Micturition cystourethrography revealed moderate or severe reflux in 86% of the ureters either at the first examination or during the follow-up periods. Urographic findings which suggested renal dysfunction included bilateral small kidney, unilateral small kidney with contralateral renal scarring, and bilateral generalized renal scarring. According to the pattern of the progression of renal dysfunction, patients were subdivided into 3 groups. Group I; patients showed bilateral renal hypoplasia on urography, and renal dysfunction progressed to ESRF before the age of 10 years despite surgical treatment. In patients of group II, gradual decrease of renal function led to ESRF at the age of puberty, although SCr was around 1.2-1.5 mg/dl when they were about 10 years old. In group III, renal function was stable at about 1.0 mg/dl of SCr during childhood. Temporary improvement of renal function was observed in only 3 of 21 children who were followed for more than 1 year after antireflux surgery. Deterioration of renal function was caused within 6 months to one year. Antireflux surgery had only little influence on the improvement of renal function in this series. We emphasize the need for early detection and management of reflux to prevent progression of renal dysfunction.     

The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death

Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine / threonine kinase and participates in a signaling complex that regulates both proliferation and apoptosis to ensure the proper size and shape of the fly. Human counterparts of this complex have been found to be frequently downregulated or mutated in cancers. WARTS, a human homolog of Wts, is also known as tumor suppressor and mitotic regulator, but its molecular implications in tumorigenesis are still obscure. Here, we show that WARTS binds via its C-terminus to the PDZ domain of a proapoptotic serine protease Omi / HtrA2. Depletion of WARTS inhibited Omi / HtrA2-mediated cell death, whereas overexpression of WARTS promoted this process. Furthermore, WARTS can enhance the protease activity of Omi / HtrA2 both in vivo and in vitro. Activation of Omi / HtrA2-mediated cell death is thus a potential mechanism for the tumor suppressive activity of WARTS.