Monitoring antioxidants by coulometry: Quantitative assessment of the strikingly high antioxidant capacity of bergamot (Citrus bergamia R.) by-products.

A recently optimized rapid, cheap, and accurate coulometric method has been exploited to determine the antioxidant capacity of bergamot (Citrus bergamia Risso) by-products, including first (FPJ) and second press juices (SPJ), in comparison to analogous products from several citrus species. Extracts from the entire edible part (i.e., juice and pulp) and de-oiled peel of bergamot were also assayed. The Coulometrically Determined Antioxidant Capacity (CDAC) data, expressed as moles of electrons per mass of sample, were evaluated with other parameters such as total phenolic compounds, ascorbic acid, total carotenoids, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical inhibition. The CDAC of bergamot FPJ (39 mmol e- kg-1) was comparable with other citrus juices (20-65 mmol e- kg-1 range), whereas the CDAC of bergamot SPJ (816 mmol e- kg-1) was strikingly higher than the counterparts from other citrus fruits. This value approached that of bergamot peel extracts (822 mmol e- kg-1). Bergamot peel and SPJ also exhibited the highest DPPH inhibition. The CDAC values were associated with the HPLC-determined content of flavonoids, namely neoeriocitrin, naringin, and neohesperidin, which were 4-10-fold more concentrated in bergamot SPJ and peel than in SPJ from other citrus species. These findings contribute to point at bergamot by-products as rich sources of antioxidant compounds on a quantitative basis, highlighting their enormous potential for pharmaceutical, nutraceutical and food applications.

Effects of intra-arterial chemotherapy with a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol on experimental liver tumor in rats.

Anticancer effects and biodistribution of a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol (LPD) were investigated as an intra-arterial chemotherapy (IAC) on Walker 256 carcinosarcoma grown in the liver of 136 Wistar rats. All rats treated with KM2210 (10 mg)-LPD survived for 90 days after administration, whereas none of the rats with LPD alone were alive for more than 19 days. Histological examination revealed that there was no viable tumor cell in the encapsulated necrotic tumor at 21 days after administration. There was no significant liver dysfunction or leukopenia due to KM2210. The biodistribution study using [14C, 3H]KM2210-LPD solution showed that KM2210 accumulated selectively in tumor and that the tumor-to-normal-liver and tumor-to-blood ratios were 10 and 1,000, respectively, at 21 days after administration. These results suggest that KM2210 has potential clinical application in the treatment of human liver cancer.

Effects of intraarterial chemotherapy using the new lipophilic anticancer agent 'KM2210' (estradiol-chlorambucil) dissolved in lipiodol on Walker 256 carcinosarcoma in Wistar rats--a preliminary report.

The effect of a new oil-soluble anticancer agent 'KM2210' (estradiol-chlorambucil) dissolved in lipiodol (LPD) was investigated as intraarterial chemotherapy, using 40 Wistar rats bearing Walker 256 carcinosarcoma in the extremities. KM2210-LPD significantly inhibited tumor growth and prolonged the survival time, as compared to LPD alone or saline alone, p less than 0.01 and p less than 0.01, respectively. Pathological study revealed that KM2210-LPD made the tumor necrotic. It was revealed that KM2210-LPD injected into the femoral artery was retained in the hind limb tumor. These findings suggest that KM2210 may possibly become a new anticancer agent with potential clinical use in LPD chemoembolization.

Premarin priming before prednimustine, high-dose folinic acid and 5-fluorouracil as salvage chemotherapy for advanced breast cancer.

Thirty patients with advanced and mainly pretreated breast cancer were treated with a combination of premarin, prednimustine, high-dose folinic acid and 5-fluorouracil. Among the 30 evaluable patients, 9 (30%) achieved an objective response (median duration: 9 months). Oral mucositis was the limiting toxicity, while myelosuppression was quite mild. In spite of considerable activity as salvage regimen, these results do not seem better than those achieved in our Institute with high-dose folinic acid and 5-fluorouracil alone.

Antitumor activity and pharmacokinetics of estra-1,3,5 (10)-triene-3,17 beta-diol, 3-benzoate, 17-((4-(4-bis(2-chloroethyl)amino)phenyl)-1-oxobutoxy) acetate) (Bestrabucil) in human tumor xenografts serially transplanted into nude mice.

Bestrabucil (KM2210), the benzoate of an estradiol-chlorambucil conjugate, was used experimental cancer chemotherapy against 13 human tumor xenografts serially transplanted into nude mice, and its pharmacokinetics was studied. The tumors were one esophageal, two gastric, six colon, one cholecystic and three breast carcinomas. Two tumor tissue fragments approximately 3 X 3 X 3 mm were inoculated into BALB/cA nude mice, which were then treated with KM2210 at doses of 100, 200 and 300 mg/kg/day orally starting 24 hr after the transplantation or when the tumor reached a weight of 100-300 mg. The concentration of KM2210 and its derivatives in the tumor xenografts, normal muscular tissue and blood were assayed by high performance liquid chromatography. Six out of 13 xenografts were found to be sensitive to KM2210. The concentrations of KM2210 and its derivatives in the tumor tissues of the sensitive xenografts were five to 10 times higher than those in blood and muscular tissue, and the antitumor activity correlated well with the area under the curve of active metabolites of KM2210 in the tumor.