Clin Cancer Res
-
Clinical Trial
Phase I and pharmacokinetic study of the new taxane analog BMS-184476 given weekly in patients with advanced malignancies.
The study was designed to establish the maximum administered dose and maximum tolerated dose (MTD) of BMS-184476, an analogue of paclitaxel, given weekly for 3 consecutive weeks every 28 days, later amended to a regimen of weekly administration for 2 consecutive weeks every 21 days. ⋯ The recommended dose and schedule of weekly BMS-184476 is 50 mg/m(2) on days 1 and 8 every 21 days.
-
Glioblastoma multiforme (GBM) is an aggressive cancer characterized by extensive brain invasion. Matrix metalloproteinase (MMP)-9 plays a major role in this process. GBMs can be divided into two subtypes based on distinct clinical and molecular features. Primary GBMs arise de novo and frequently overexpress the epidermal growth factor receptor (EGFR) and its ligand-independent variant, EGFR variant III (EGFRvIII); secondary GBMs progress from a lower grade glioma and commonly harbor p53 mutations. Because EGFR signaling promotes MMP-9 expression and activation in other cancer cell types, we analyzed whether MMP-9 was associated with primary GBM subtype. ⋯ These results identify a novel association between MMP-9 activation and primary GBM subtype and suggest that primary GBM patients, especially those whose tumors express EGFRvIII, may benefit from anti-MMP therapy.
-
Irofulven is a novel, small molecular weight semisynthetic compound, derived from a family of mushroom toxins known as illudins. This DNA alkylating agent has a chemical structure unlike any other chemotherapeutic agent in clinical use. The molecule is currently being studied in several Phase I, II, and III trials. ⋯ At 2 mg/kg only 3 of 15 tumors tested demonstrated objective regressions, and in 3 additional tumors volume regressions were not achieved at a higher dose level (3 mg/kg), hence were not additionally tested. After administering the maximum tolerated dose (tolerated for one or two cycles of treatment) of Irofulven, 7 mg/kg, to mice bearing sensitive and resistant human tumors plasma concentration-time profiles were determined. Tumors were highly sensitive to Irofulven, but the systemic exposure required for a significant rate of objective response in this panel of tumors is in excess of that achievable in patients at tolerable doses, using this schedule of drug administration.
-
Vascular endothelial growth factor (VEGF), which is produced by tumor cells, is a potent endothelial cell mitogen. The aim of the present study was to evaluate the response of orthotopic prostate cancer xenografts and prostate cancer bone metastasis to anti-VEGF receptor (flk-1) antibody (DC101) treatment. ⋯ This study confirms the principle of tumor growth inhibition by targeting angiogenesis within tumors and supports the use of anti-VEGF receptor agents.
-
Randomized Controlled Trial Clinical Trial
A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer.
Protein kinase C (PKC)-alpha and Raf-1 are important elements of proliferative signal transduction pathways in both normal and malignant cells. Abrogation of either Raf-1 or PKC-alpha function can both inhibit cellular proliferation and induce apoptosis in several experimental cancer models including prostate cancer cell lines. ISIS 3521 and ISIS 5132 are antisense phosphorothioate oligonucleotides that inhibit PKC-alpha and Raf-1 expression, respectively, and induce a broad spectrum of antiproliferative and antitumor effects in several human tumor cell lines. In Phase I evaluation both ISIS 3521 and ISIS 5132 could be safely administered on 21-day i.v. infusion schedules and demonstrated preliminary evidence of antitumor activity. On the basis of these findings, a randomized Phase II study of ISIS 3521 and ISIS 5132 was performed in two comparable cohorts of patients who had chemotherapy-naïve, hormone-refractory prostate cancer (HRPC). ⋯ The antisense oligonucleotides ISIS 3521 and ISIS 5132, at these doses and on this schedule, do not possess clinically significant single-agent antitumor activity in HRPC. Protracted stable disease in some patients may indicate a cytostatic effect. Additional work is required to define the optimal role of PKC-alpha or Raf-1 inhibition in the treatment of HRPC.