A Phase I and Pharmacologic Trial of Two Schedules of the Proteasome Inhibitor, PS-341 (Bortezomib, Velcade), in Patients with Advanced Cancer
Tóm tắt
Purpose: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies.
Patients and Methods: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity.
Results: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade ≥3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade ≥3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response.
Conclusion: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.
Từ khóa
Tài liệu tham khảo
Voorhees PM, Dees EC, O'Neil B, et al. The proteasome as a target for cancer therapy. Clin Cancer Res 2003;9:6316–25.
Jentsch S. Ubiquitin-dependent protein degradation: a cellular perspective. Trends Cell Biol 1992;2:98–103.
Palombella VJ, Rando OJ, Goldberg AL, et al. The ubiquitin-proteasome pathway is required for processing the NFκ-B1 precursor protein and the activation of NF-B. Cell 1994;78:773–85.
Read MA, Neish AS, Luscinskas FW, et al. The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity 1995;2:493–506.
Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999;59:2615–22.
Teicher BA, Ava G, Herbst R, et al. The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 1999;5:2638–45.
Lightcap ES, McCormack TA, Pien CS, et al. Proteasome inhibition measurements: clinical application. Clin Chem 2000;46:673–83.
Jagannath S, Barlogie B, Berenson J, et al. A phase II multicenter randomized study of the proteasome inhibitor bortezomib (VELCADE™, formerly PS-341) in multiple myeloma patients relapsed after front-line therapy. Blood 2002;100:3027a.
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348:2609–17.
Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS341 in patients with refractory hematologic malignancies. J Clin Oncol 2002;20:4420–7.
Cortes J, Thomas D, Koller C, et al. Phase I study of bortezomb in refractory or relapsed acute leukemias. Clin Cancer Res 2004;10:3371–6.
Papandreou C, Daliani D, Millikan RE, et al. Phase I study of intravenous proteasome inhibitor PS-341 in patients with advanced malignancies. J Clin Oncol 2004;22:2108–21.
Aghajanian C, Soignet S, Dizon DS, et al. A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 2002;8:2505–11.
Pagano M, Tam SW, Theodora AM, et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 1995;4:269:682–5.
Chang YC, Lee YS, Tejima T, et al. mdm2 and bax, downstream mediators of the p53 response, are degraded by the ubiquitin-proteasome pathway. Cell Growth Differ 1998;1:79–84.
Kazi A, Daniel KG, Smith DM, et al. Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. Biochem Pharmacol 2003;66:965–76.
Fan XM, Wong BC, Wang WP, et al. Inhibition of proteasome function induced apoptosis in gastric cancer. Int J Cancer 2001;93:481–8.