bay-12-9566 and Neoplasm-Metastasis

The prognosis of pancreatic cancer is poor at any stage. The complete resection of the tumour offers the only chance of cure, but 10-25 % of the patients at most present with operable disease, and median survival following surgery with curative intention is 18 months. Local recurrence is often accompanied or rapidly followed by distant metastasis. Studies of postoperative (adjuvant) treatment have yielded contradictory results. Combined radiochemotherapy resulted in improved survival in a few studies while others failed to demonstrate any survival benefit. Intraoperative radiation therapy given in addition to percutaneous irradiation may improve local tumour control at best. At present only few data support the benefit of adjuvant systemic chemotherapy alone. Unfortunately, the recently completed ESPAC-1 study was not very helpful in settling this issue due to its problematic design. Therefore, the results of ongoing studies of adjuvant chemotherapy are eagerly awaited. These studies have also included arms with gemcitabine, the current standard for palliative treatment of pancreatic cancer, and will hopefully allow firm conclusions as to the role of postoperative chemotherapy.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Intraoperative Care; Metalloendopeptidases; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organic Chemicals; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Phenylbutyrates; Postoperative Care; Prognosis; Radiotherapy Dosage; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Time Factors

To compare the selective matrix metalloproteinase inhibitor BAY 12-9566 with the nucleoside analog gemcitabine in the treatment of advanced pancreatic cancer.. Patients with advanced pancreatic adenocarcinoma who had not previously received chemotherapy were randomly assigned to receive BAY 12-9566 800 mg orally bid continuously or gemcitabine 1,000 mg/m2 administered intravenously on days 1, 8, 15, 22, 29, 36, and 43 for the first 8 weeks, and then days 1, 8, and 15 of each subsequent 28-day cycle. The primary end point was overall survival; secondary end points were progression-free survival, tumor response, quality of life, and clinical benefit. The planned sample size of the study was 350 patients. Two formal interim analyses were planned.. The study was closed to accrual after the second interim analysis on the basis of the recommendation of the National Cancer Institute of Canada Clinical Trials Group Data Safety Monitoring Committee. There were 277 patients enrolled onto the study, 138 in the BAY 12-9566 arm and 139 in the gemcitabine arm. The rates of serious toxicity were low in both arms. The median survival for the BAY 12-9566 arm and the gemcitabine arm was 3.74 months and 6.59 months, respectively (P <.001; stratified log-rank test). The median progression-free survival for the BAY 12-9566 and gemcitabine arms was 1.68 and 3.5 months, respectively (P <.001). Quality-of-life analysis also favored gemcitabine.. Gemcitabine is significantly superior to BAY 12-9566 in advanced pancreatic cancer.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Biphenyl Compounds; Deoxycytidine; Disease Progression; Female; Gemcitabine; Humans; Male; Neoplasm Metastasis; Organic Chemicals; Pancreatic Neoplasms; Phenylbutyrates; Proportional Hazards Models; Quality of Life; Statistics, Nonparametric; Survival Analysis; Treatment Outcome

Matrix metalloproteinases (MMPs) have been implicated in the invasion, metastasis, and angiogenesis associated with human cancer by mediating the degradation of extracellular matrix components. In this paper, we report data that show that BAY 12-9566, a novel inhibitor of MMPs, inhibits angiogenesis, tumor regrowth, and the growth of lung metastases. BAY 12-9566, at 15-100 microM, inhibited tubule formation by human endothelial cells in an in vitro model, but did not prevent the proliferation of endothelial and human breast cancer cells. In the MDA-MB-435 human mammary carcinoma xenograft model, in which the primary tumor is transplanted into the murine mammary fat pad, BAY 12-9566, administered daily at a dose of 100 mg/kg/day p.o. after resection of the primary tumor, inhibited local tumor regrowth by 58% without causing any toxic effect. In addition, BAY 12-9566 treatment inhibited the number and volume of lung metastases by 57 and 88%, respectively. These effects were highly correlated with the serum concentration of BAY 12-9566 at the end of treatment. The serum of the treated animals, harvested 24 h after the last treatment, and the tumor regrown at the site of tumor transplant in the treated animals, contained less protein with MMP-9 activity (as measured in a gelatin zymography assay) than the corresponding controls. However, no difference in the activity of MMP-2 was observed. Although all clinical trials in cancer involving BAY 12-9566 have been halted, this MMP inhibitor has never been used in clinical trials in breast cancer. These results suggest that the novel MMP inhibitor BAY 12-9566 maybe a useful and safe oral treatment for breast cancer, adjunctive to surgery.

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Breast Neoplasms; Cell Division; Cells, Cultured; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Organic Chemicals; Phenylbutyrates; Time Factors; Tumor Cells, Cultured; Umbilical Veins