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Biomedical subjects

E Frei

Publications and source records attributed to E Frei.

439 records · Page 25Linked to original sources
PubMedDate not supplied

Phase I trial of bruceantin.

Bruceantin was administered to 33 patients with advanced solid tumors or hematologic neoplasms. The schedule consisted of four weekly iv injections at one dose level followed by a 2-week "no-treatment" period; this program was repeated every 6 weeks. A total of 156 weekly injections were given over a dose range of 0.8-8.5 mg/m2. Systolic and diastolic hypotension was dose-related and dose-limiting at doses of greater than or equal to 6.0 mg/m2. Transient febrile reactions were dose-related. Gastrointestinal toxicity was commonly observed but was not dose-limiting. There was no hematologic or renal toxicity; hepatic toxicity was subclinical and reversible. Of 18 patients evaluable for antitumor response one patient with adenocarcinoma of the cervix experienced a less than 50% disease regression lasting 10 months and one patient with pleural mesothelioma experienced disease stabilization lasting 4 months. A phase II study of bruceantin is recommended at a starting dose of 5.5 mg/m2 weekly for 4 weeks as a 4-hour iv infusion repeated at 6-week intervals.

Adenocarcinoma↗
PubMedDate not supplied

Phase I trial of combination therapy with PALA and 5-FU.

PALA is an inhibitor of de novo pyrimidine biosynthesis. Studies combining PALA with 5-FU in experimental models have demonstrated synergistic antitumor activity with only additive toxicity. The phase I study of PALA in combination with 5-FU is described. Sixteen patients received a total of 29 courses of PALA given as a 24-hour infusion daily for 5 days and 5-FU given by iv bolus at the end of each 24-hour PALA infusion. Cycles were repeated at 28-day intervals. Mucositis was dose-limiting when 940 mg/m3/day of PALA was given with 345 mg/m2/day of 5-FU. Diarrhea, skin rash, and myelosuppression (in decreasing order of frequency) occurred but were not dose-limiting. Alopecia occurred in all patients. Objective responses were seen in single patients with large cell carcinoma of the lung, fibrous histiocytoma, and adenocarcinoma of the colon refractory to prior 5-FU therapy. These studies support further phase II evaluation of the PALA and 5-FU combination.

Adenocarcinoma↗
PubMedDate not supplied

Differential interactions of Pgp inhibitor thaliblastine with adriamycin, etoposide, taxol and anthrapyrazole CI941 in sensitive and multidrug-resistant human MCF-7 breast cancer cells.

The reversing effect of p-glycoprotein (Pgp) inhibitors on the multidrug resistance (MDR) phenotype is well established in a variety of MDR cell lines. The interactions of these inhibitors with individual MDR drugs in the respective parental lines, however, is less documented. This kind of information is not only essential for understanding of the outcome of clinical trials for MDR modulation in heterogeneous tumor populations but also important for evaluating of new Pgp blockers. Interaction of the Pgp inhibitor, thaliblastine (TBL), with several MDR drugs was therefore investigated in sensitive human breast cancer cell line (MCF-7) as well as adriamycin (AdR) selected MDR subline MCF/AdR. While the resistance to anthrapyrazole CI941 was completely overcome by simultaneous exposure to TBL (8 microM) in a 48 h exposure MTT assay compared with MCF-7 cells exposed to the same combination, only partial reversal was achieved in the case of AdR and etoposide (VP-16), but 240-fold hypersensitivity (or collateral sensitivity) was obtained in the MCF/AdR cells treated with taxol plus TBL, with IC50s of 0.10 +/- 0.03 microM and 24.6 +/- 5.0 microM in the resistant and sensitive cell lines, respectively. In the parental MCF-7 cells, on the other hand, no change of AdR cytotoxicity by simultaneous exposure to TBL was observed. There was an enhancement of CI941 cytotoxicity but an antagonism against taxol and VP-16 obtained upon addition of TBL to the treatment with the drugs in the MCF-7 parental cell line. Our results demonstrate that while TBL can overcome the resistance to each of the MDR drugs studied in MCF/AdR cells, albeit to a different extent varying from the partial reversal to the hypersensitivity, TBL co-exposure does not uniformly increase the cytotoxicity of these drugs in the parental MCF-7 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Chemopreventive effects of dithiocarbamates on aflatoxin B1 metabolism and formation of AFB1 adducts with glutathione.

Several agents with anticarcinogenic potential such as diethyldithiocarbamate (DDTC), lactose-DDTC, proline-dithiocarbamate (PDTC), its dimer proline-thiuramdisulfide (PTDS) and 4-carboxy-piperazine-TDS (4-pip-TDS) were investigated for their influence on the metabolism and the detoxication of aflatoxin B1 (AFB1) in vitro and in vivo. Aflatoxins are a group of mycotoxins produced by aspergillus species and are among the most important risk factors for hepatocellular carcinoma in certain areas of the world. AFB1 metabolism measured by the formation of tris-diol adducts showed that the thiuramdisulfides 4-carboxy-piperazine-TDS and PTDS were better inhibitors in vitro than the corresponding dithiocarbamates. Ex vivo studies in rats showed that dithiocarbamates (DTCs) including sugar linked lactose-DDTC decreased the formation of tris-diol adducts. Among the dithiocarbamates administered, DDTC showed a 40% inhibition whereas the other compounds showed only marginal effects. In vivo experiments on the formation of glutathione-adducts derived from AFB1-endo- and exo-epoxides showed that lactose-DDTC enhanced the formation of AFB1-GSH adducts, whereas PDTC, 4-pip-TDS, PTDS and DDTC displayed inhibitory effects. We conclude that DTCs may be promising agents in the chemoprevention of liver carcinogenesis caused by AFB1.

Aflatoxin B1↗