Synthesis and pharmacological evaluation of new flosulide analogues, synthesized from natural safrole

OBJECTIVE: To study the effect of adjuvant chemotherapy after curative hepatic resection in patients with hepatocellular carcinoma. DESIGN: A randomized controlled trial. SETTING: A tertiary referral center. PATIENTS: During a 54-month period, 142 patients with hepatocellular carcinoma underwent hepatic resection at 1 institution. Sixty-six patients who survived the operation and had no demonstrable evidence of residual disease on ultrasonographic examination and hepatic angiographic testing at 1 month after surgery agreed to participate in the study. The median follow-up time was 28.3 months. INTERVENTION: Thirty patients received a combination of intravenous epirubicin hydrochloride (8 doses of 40 mg/m2 each at 6-week intervals) and transarterial chemotherapy using an emulsion of iodized oil and cisplatin (3 courses with a maximum dose of 20 mL each at 2-month intervals). Thirty-six patients had no adjuvant treatment. MAIN OUTCOME MEASURES: Recurrence rate and disease-free survival. RESULTS: A total of 138 courses of intravenous epirubicin was given to the 30 patients. Sixty-one courses of transarterial chemotherapy were given to only 29 of the 30 patients assigned to the treatment group, because the hepatic artery in 1 patient was thrombosed. Six patients (20%) had chemotherapy-related complications with no mortality. Twenty-three of 30 patients in the treatment group and 17 of 36 patients in the control group had recurrences (P=.01). Patients who received adjuvant chemotherapy had a higher incidence of extrahepatic metastases (11 patients vs 5 patients; P=.03). The respective disease-free survival rates at 1, 2, and 3 years were 50%,36%, and 18% for the treatment group and 69%, 53%, and 48% for the control group (P=.04). CONCLUSION: In a group of patients who underwent curative resection of hepatocellular carcinoma, postoperative adjuvant chemotherapy using the present regimen was associated with more frequent extrahepatic recurrences and a worse outcome.     

Use of the method of mixed substrates to study the specificity of tRNA methylases

The absence of summation of the rate of methylation of positionally analogous cytidine residues in tRNA1Val, tRNAPhe, and tRNAMet in the case of simultaneous presence of two substrates in the incubation mixture was demonstrated by the method of mixed substrates. The same result was also obtained in the methylation of A19 (counting from the 3' end of the molecule) in tRNA1Val, tRNAPhe, tRNAfMet, tRNASer, and tRNAGlu individually and in the case of their mixing in pairs. These data are evidence that positionally analogous nucleotides in different RNAs are attacked by the same enzyme. Yeast tRNASer, already possessing a methyl group at the cytidine residue studied, proved to be an effective inhibitor of methylase, forming m5C with valine and phenylalanine tRNAs. The results obtained are evidence that differences in the primary and secondary structures at the site of methylation are not the deciding factors in the interaction of tRNA with methylases.