Chronic lymphocytic leukemia (CLL) is an incurable adult leukemia characterized by disrupted apoptosis. OSU03012 is a bioavailable third-generation celecoxib derivative devoid of cyclooxygenase-2 inhibitory activity that potently induces apoptosis in prostate cancer cell lines and is being developed as an anticancer therapy in the National Cancer Institute (NCI) Rapid Access to Intervention Development (RAID) program. We assessed the ability of OSU03012 to induce apoptosis in primary CLL cells and the mechanism by which this occurs. The LC 50 (lethal concentration 50%) of OSU03012 at 24 hours was 7.1 M, and this decreased to 5.5 M at 72 hours. Additionally, we have demonstrated that OSU03012 mediates apoptosis by activation of the intrinsic, mitochondrial pathway of apoptosis but also activates alternative cell death pathways that are caspase independent. The early activation of both caspasedependent and -independent pathways of apoptosis is novel to OSU03012 and suggests it has great potential promise for the treatment of CLL. Moreover, unlike the great majority of therapeutic agents used to treat leukemia or other forms of cancer, OSU03012 induces cell death entirely independent of bcl-2 expression. Overall, these data provide justification for further preclinical development of OSU03012 as a potential therapeutic agent for CLL. (Blood. 2005;105:2504-2509)

The 1D10 antigen is the target for Hu1D10 (apolizumab), a humanized HLA-DR ␤-chain-specific antibody that is currently in clinical trials for hematologic malignancies. We demonstrate that Hu1D10 induces caspase-independent apoptosis following secondary crosslinking in primary chronic lymphocytic leukemia ( IntroductionChronic lymphocytic leukemia (CLL) is one of the most common types of leukemia diagnosed in the Western Hemisphere, with a median survival of 18 months to 3 years in patients with advanced stage disease. [1][2][3] Therapeutic options for the initial treatment of CLL can include either alkylator therapy (chlorambucil or cyclophosphamide) or a nucleoside analog (fludarabine or cladribine), 4,5 with recent studies demonstrating the ability of fludarabine to prolong progression-free survival. [6][7][8] Attempts to improve outcome further by combining fludarabine with cyclophosphamide have shown promising results [9][10][11] and are currently being evaluated in phase 3 testing. Even this combination yields a complete response rate of less than 50% in all series reported, 9-11 emphasizing the need for pursuit of new therapies for the treatment of CLL.Immunotherapy with unconjugated monoclonal antibodies in CLL represents one new potentially exciting mode of therapy for CLL. Of the many antibodies tested in CLL, rituximab and alemtuzumab have the highest reported success rate to date. Studies with rituximab in small lymphocytic lymphoma (SLL) and CLL [12][13][14][15][16][17] initially demonstrated marginal results, although subsequent studies directed at overcoming the adverse pharmacokinetic parameters 13 have led to improved efficacy. 18,19 Rituximab has also been demonstrated to improve complete response to fludarabine-based therapy. 20 The alemtuzumab antibody has similarly demonstrated activity in patients with CLL refractory to fludarabine, [21][22][23][24][25] but use has been somewhat limited by a high frequency of serious infections. Studies by our group have demonstrated that both rituximab and alemtuzumab induce caspase-dependent apoptosis in vivo, 26,27 similar to that induced by fludarabine and other chemotherapeutic agents. Neither of these therapies produces consistent complete remissions, providing support for identifying therapeutic targets, particularly ones that induce apoptosis in a different manner.Class II major histocompatibility complex (MHC) antigens are expressed only on a subset of immune effector cells, including B cells, monocytes, and dendritic cells and represent one such potential novel target. It is notable that several groups have reported that murine antibodies targeting either the ␣ or ␤ chain of HLA-DR induce apoptosis in B-cell lymphoma cell lines, [28][29][30][31][32][33] normal B cells, and mature B-cell malignancies. Interrogation of the pathway leading to apoptosis in cell lines has demonstrated varied results, with some studies noting caspase-8 activation and others noting use of a caspaseindependent pathway. [28][29][30][31][32][33][34][35][36] These studies ex...

Summary We have quantitated the levels of mRNAs in bone marrow samples from patients with multiple myeloma of the mdrl gene (responsible for the Multidrug Resistance phenotype) and for two of the glutathione S-transferase gene. GST-2 and GST-3 (which can also inactivate a wide variety of cytotoxic drugs) and examined the relationship between the levels of expression of these genes and response to subsequent chemotherapy. From a total of 47 patients. 37 were treated with chemotherapy with 34 evaluable for response. Twenty-nine of the patients treated had not received any treatment prior to the marrow sampling while eight had previously received chemotherapy. Patients who failed to respond to initial chemotherapy had significantly higher levels of mdrl than patients who responded (P = 0.01). In the total myeloma patient data set. mRNA levels for mdrl and GST-2 were significantly correlated (Spearman rank correlation coefficient (r) = 0.54. P = 0.0004) as were expression levels of GST-2 with GST-3 (r = 0.43. P = 0.017). GST-3 and mdrl levels were more weekly associated (r = 0.16. P = 0.4). These data would suggest a significant relationship between failure of chemotherapy in multiple myeloma patients and increases in expression of the mdrl gene together with other genes whose products will generate additional mechanisms of resistance to chemotherapeutic agents.

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