Usefulness of preoperative low dose cisplatin treatment for advanced esophageal cancer

In order to decrease the perioperative complications by preoperative cisplatin chemotherapy, the preoperative single administration of cisplatin (30 mg/m²) was performed weekly from one to six times in 36 consecutive patients with esophageal cancer classified as higher than Stage II. The survival curve of 17 patients in Stage III was significantly better (P<0.05) than that of patients who had been treated without preoperative cisplatin treatment. In 3 of the 12 patients who had locally invasive cancer, either the main tumors or the metastatic lymph nodes, which had invaded the trachea or the left main bronchus, sufficiently receded, so that a curative esophagectomy became possible; 2 of them have survived over 33 months while 1 died of pneumonia 33 months after surgery. The number of perioperative complications was minimal, and thus, we consider that the postoperative use of cisplatin and fluorouracil is indicated in patients in whom a histological response is noted in the resected specimens.This work was partially supported by Grant No. 02454315 from the Japanese Ministry of Education     

The effects of potassium concentration in reperfusion solution upon myocardial protection]

The effects of potassium in reperfusion solution (RS) and the influence of sodium on this effect were studied. Experimental time course was as followed: 20 min working perfusion, 3 min cardioplegic infusion with St. Thomas Cardioplegic Solution followed by global ischemia for 33 or 35 min at 37.5 degrees C, 15 min early Langendorff reperfusion with several different potassium concentration modified with Krebs Henseleit Bicarbonate Buffer (KHBB) containing 145 mM and 110 mM sodium and 5 min late reperfusion with KHBB, followed by 20 min working perfusion. Potassium in RS possessed bell shaped dose response nature with optimal concentration of 10 mM in the condition of 145 mM sodium but 6 m in the condition of 110 mM in terms of percent recovery of aortic flow. Although higher potassium reperfusion produced less Creatine Kinase leakage.     

Participation of rat liver cytochrome P450 2E1 in the activation of N-nitrosodimethylamine and N-nitrosodiethylamine to products genotoxic in an acetyltransferase-overexpressing Salmonella typhimurium strain (NM2009).

The possible roles of cytochrome P450 (P450) enzymes in the metabolic activation of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) by rat liver microsomes have been examined in a system containing the bacterial tester strain Salmonella typhimurium NM2009, a newly developed strain showing high O-acetyltransfer activities. The DNA-damaging activity could be determined by measuring expression of the umu gene in a plasmid containing the fused umuC-lacZ gene construct in the bacteria. The following lines of evidence support the view that both NDMA and NDEA are principally oxidized to reactive products by P450 2E1 in rat liver microsomes. First, NDMA and NDEA were activated by rat liver microsomes in a protein- and substrate-dependent manner and the former chemical was more active than the latter; both activities were induced in rats treated with P450 2E1 inducers such as ethanol, acetone and isoniazid and by starvation. Second, activation of NDMA and NDEA were both inhibited significantly by antibodies raised against rat P450 2E1 and by P450 2E1 inhibitors such as diethyldithiocarbamate and 4-methylpyrazole in rat liver microsomes. Finally, in reconstituted monooxygenase systems containing purified rat P450 enzymes, P450 2E1 gave the highest rates of the activation of both NDMA and NDEA; the addition of rabbit cytochrome b5 to the system caused about a 1.5-fold increase in both reactions. In separate experiments we also found that N-nitrosomethylacethoxymethylamine, a compound that reacts with DNA after ester cleavage, is more genotoxic in S.typhimurium NM2009 than in S.typhimurium NM2000, a strain that is defective in O-acetyltransferase activity. Part of the pathway involved in the activation of nitrosamines is suggested to be acetylation of alkyldiazohydroxides formed by P450 or acetylesterase, because the genotoxic activity of N-nitrosomethylacethoxymethylamine in S.typhimurium NM2009 could be inhibited by the O-acetyltransferase inhibitor pentachlorophenol. These results indicate that NDMA and NDEA are oxidized to gentoxoic products by rat liver microsomes and that a P450 2E1 enzyme plays a major role in the activation of these two potent carcinogens. The activation pathway of N-nitrosodialkylamines through acetylation by O-acetyltransferase has been proposed. This simple bacterial system for measuring genotoxicity should facilitate studies on the activation of N-nitroso alkylamines.     

Suppressive effect of LD78 on the proliferation of human hemopoietic progenitors.

LD78 is a cDNA newly isolated from human stimulated tonsillar lymphocytes. The expression of LD78 is related to inflammatory responses and its structure has a homology with macrophage inflammatory protein 1-alpha, which is known to have an inhibitory effect on murine CFU-S. Using a colony assay technique, we examined the effects of LD78 on human hemopoietic progenitors. The addition of doses of 100 ng/ml or more of LD78 suppressed the colony formation of KMT-2, a factor-dependent myelomonocytic cell line established from cord blood cells; this suppressive activity was neutralized by the addition of antibody against LD78. The same doses of LD78 suppressed the formation of neutrophil, macrophage, and megakaryocytic colonies which were supported by human interleukin-3 and erythropoietin; however, LD78 did not affect colony formation by either non-phagocytic mononuclear cells or sorted CD34+ cells. The conditioned medium of KMT-2 cells or peripheral blood mononuclear cells cultured with LD78 suppressed colony formation by CD34+ cells. From these findings, it is suggested that LD78 affects phagocytic cells and induces factors that are inhibitory for hemopoiesis. We consider LD78 to be a new cytokine that plays an inhibitory role in hemopoiesis.